WO2022101678A2 - Lysophospholipid formulations - Google Patents

Lysophospholipid formulations Download PDF

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WO2022101678A2
WO2022101678A2 PCT/IB2021/000791 IB2021000791W WO2022101678A2 WO 2022101678 A2 WO2022101678 A2 WO 2022101678A2 IB 2021000791 W IB2021000791 W IB 2021000791W WO 2022101678 A2 WO2022101678 A2 WO 2022101678A2
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lpc
formulation
disease
dha
epa
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WO2022101678A3 (en
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Finn Myhren
Petter-Arnt HALS
Andreas Berg STORSVE
Nils Hoem
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Aker Biomarine Antarctic As
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    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
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Abstract

The present invention relates to formulations of lyso-phospholipids for use in medicine, in particular nasal formulations of lysophosphatidylcholine for treating, preventing and/or relieving one or more symptoms and/or signs of a 1) disease or condition of the eye, 2) a metabolic disorder or disease, 3) a disease or condition of the heart or circulatory system, 4) a cognitive disorder or disease, 5) a neurodegenerative disorder or disease, 6) an injury, disease or disorder of the brain, or 7) an inflammatory disease or condition.

Description

LYSOPHOSPHOLIPID FORMULATIONS FIELD OF THE INVENTION The present invention relates to formulations of lyso-phospholipids for use in medicine, and therapeutic formulations for preventing diseases and for nasal and ophthalmic use. In particular, the present invention provides nasal formulations or ophthalmic formulations for treating, preventing and/or relieving one or more symptoms and/or signs of a 1) disease or condition of the eye, 2) a metabolic disorder or disease, 3) a disease or condition of the heart or circulatory system, 4) a cognitive disorder or disease, 5) a neurodegenerative disorder or disease, 6) an injury, disease or disorder of the brain, or 7) an inflammatory disease or condition. The invention provides compositions comprising phosphatidylcholine derived compounds, i.e. lyso-phosphatidylcholines, carrying an omega-3 fatty acid for use in prophylaxis or therapy, particularly when administered systemically via ocular or nasal administration. BACKGROUND OF THE INVENTION The bloodstream contains a diversity of lipids, the majority of species belonging to the phospholipids, fatty acids, and sphingolipid classes. Many members of these classes have structural roles, such as phosphatidylcholines and signaling roles, such as sphingosine-1 - phosphate. One lipid species, lysophosphatidylcholines (LPCs), is shown to be important for transporting fatty acids to different organs trough the LPC-transporter, Mfsd2a (Nature. 2014 May 22;509(7501):503-6. doi: 10.1038/nature13241. Epub 2014 May 14). Mfsd2a is expressed at the blood-brain and blood-retinal barriers and is demonstrated to be the major pathway for brain and eye accretion of docosahexanoic acid (DHA) (Adv Exp Med Biol. 2020;1276:223-234. doi: 10.1007/978-981-15-6082-8_14). The Mfsd2a-transporter is also expressed in other organs in the body as well as at the blood-testis and blood-placenta barriers. The placenta, seminal vesicles, vas deferens, testis, lungs and liver are the subject of numbers of studies related to Mfsd2a. LPCs are structurally composed of three major lipid components: a glycerol, phosphocholine, and a fatty acid esterified to either the sn- 1 or sn-2 hydroxyls of glycerol. LPC is found only in trace amounts in most animal tissues, since greater concentrations are known to facilitate disruption of cell membranes. LPCs are naturally present at low levels in the cell membrane (≤ 3%) and in the blood plasma (8–12%). Due to is specificity towards Mfsd2a, LPC is previously proposed as a vehicle for targeted transport of fatty acids, in particular omega-3 fatty acids like EPA and DHA, and other molecules to specific organs via the transporter Mfsd2a (WO2015048554). Deficiency of omega-3 fatty acid has been linked with several neurological disorders, including Alzheimer’s, Parkinson’s, schizophrenia, and depression. In addition, DHA has been shown to be neuroprotective in models of traumatic brain injury (TBI) (Journal of Neurotrauma, 2020, 37(1), pp.66-79) and to increase the functional recovery promoted by rehabilitation after cervical spinal cord injury (J Neurotrauma. 2017 May 1;34(9):1766- 1777. doi: 10.1089/neu.2016.4556. Epub 2017 Jan 13). Animal models have shown that dietary LPC-DHA and LPC-EPA derived from krill oil can increase levels of DHA and EPA in brain regions, liver and eyes (WO2021/202680). In addition, it has been demonstrated that intravenous administration of LPC-DHA and LPC- EPA will give rapid increase of DHA and EPA in deep tissues, like for instance brain, spleen, retina, liver and reproductive organs (WO2020254675A1). Use of LPC in different therapeutic applications will require exploring a diversity of formulations, both to aid in compliance and other requirements of the subjects in need of the active components. Different formulations and modes of administration may suit different needs. As an example, treatment of severe cases of TBI in a hospital can very well be by intravenous injections or infusions, and dietary supplements can be optimal for supplementing a well-balanced diet. However, this may not be the best mode of administration for example for prophylactic treatment of professional athletes at risk of concussions or other injuries. Accordingly, it is the object of this invention to explore new formulations of LPC for a broader application. It would be highly preferable if the new formulation could provide for easy administration to the subjects, and if it could aid in compliance of any active components. SUMMARY OF THE INVENTION In some preferred embodiments, the present invention provides nasal formulations comprising a lysophosphatidylcholine (LPC) composition comprising a LPC-compound of formula 1 or formula 2, or derivates, conjugates or salts thereof, Formula 1 Formula 2
Figure imgf000005_0001
wherein R1 is an acyl or alkyl chain length of at least 14 carbons; R2 is OH or O-CO-(CH2)n-CH3; and n is 0, 1 or 2 and one or more additional components selected from the group consisting of an effective amount of a buffer component, an effective amount of a tonicity component, an effective amount of a preservative component and water. In some preferred embodiments, the LPC composition comprising one or more LPC-compounds selected from the group consisting of LPC-16:0, LPC-18:0, LPC-18: 1, LPC-18:2 n-6, LPC-18:3 n-3, LPC-18:4 n-3, LPC-20:4 n-6, LPC-22:5 n-3, LPC-22:6 n-3, LPC-20:5 n-3. In further preferred embodiments, R1 is DHA, EPA, DPA, SDA or ALA and R2 is OH. In some preferred embodiments, the formulation is characterized with the proviso that: if the LPC composition comprises i) a compound according to formula 1 and/or formula2, wherein R1 is DHA and R2 is OH; then the LPC composition further comprises at least one of the other LPC-compounds referred to in claim 2. In some preferred embodiments, the LPC-compound is selected from: a compound according to formula 1 and/or formula 2 wherein R1 is DHA; and a compound according to formula 1 and/or formula 2 wherein R1 is EPA. In some preferred embodiments, R1 is OH; and the molar ratio of lysoPC-DHA : lysoPC-EPA is in the range 1:1 to 5:1; or molar ratio of lysoPC-EPA : lysoPC-DHA is in the range 1:1 to 5:1; with the proviso that i) the number of moles of lysoPC-EPA is the number of moles 1-lysoPC-EPA + the number of moles 2-lysoPC-EPA; and ii) the number of moles of lysoPC-DHA is the number of moles 1-lysoPC-DHA + the number of moles 2- lysoPC-DHA. In some preferred embodiments, the LPC composition in the nasal formulation comprises an amount of total LPC of at least 0.01 % by weight of the nasal formulation. In some preferred embodiments, the LPC composition in the nasal formulation comprises an additional lipid different from LPC. In some preferred embodiments, the additional lipid is selected from the group consisting of triglycerides and phospholipids such as phosphatidylethanolamine and phosphatidylcholine. In some preferred embodiments, the LPC composition comprises a predominant amount of the LPC- compound compared to an amount of phosphatidylcholine. In some preferred embodiments, the LPC-compound is selected from LPC-EPA, LPC-DHA and any combination thereof. In some preferred embodiments, the nasal formulation further comprises a component selected from the group consisting of lutein, astaxanthin, zeaxanthin and any combinations thereof. In some preferred embodiments, the nasal formulation is provided as a nasal spray. In some preferred embodiments, the nasal spray formulation is provided in a nozzle spray device. In some preferred embodiments, the nasal formulation is provided as a nasal drop. In some preferred embodiments, the nasal spray formulation is provided in a nasal drop device. In some preferred embodiments, the nasal formulation is provided in an amount effective to treat, prevent and/or relief one or more symptoms and/or signs of a 1) disease or condition of the eye, 2) a metabolic disorder or disease, 3) a disease or condition of the heart or circulatory system, 4) a cognitive disorder or disease, 5) a neurodegenerative disorder or disease, 6) an injury, disease or disorder of the brain, or 7) an inflammatory disease or condition. In some preferred embodiments, the nasal formulations described above are provided for use in treating, preventing and/or relieving one or more symptoms and/or signs of a disease selected from the group consisting of a 1) disease or condition of the eye, 2) a metabolic disorder or disease, 3) a disease or condition of the heart or circulatory system, 4) a cognitive disorder or disease, 5) a neurodegenerative disorder or disease, 6) an injury, disease or disorder of the brain, or 7) an inflammatory disease or condition. In some preferred embodiments, the injury, disease, or disorder of the brain is selected from the group consisting of traumatic brain injury, concussion, chronic traumatic encephalopathy, and combinations thereof. In some preferred embodiments, the metabolic disorder or disease is selected from the group consisting of dyslipidemia, hypertriglyceridemia, hypertension, low HDL levels, high LDL levels, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, chronic kidney disease, omega-3 deficiency, phospholipid deficiency, diabetic nephropathy, non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) and diabetic autonomic neuropathy. In some preferred embodiments, the disease or condition of the heart or circulatory system is selected from the group consisting of atherosclerosis, arteriosclerosis, coronary aortic and mitral valve disorders, arrhythmia/atrial fibrillation, cardiomyopathy and heart failure, angina pectoris, acute myocardial infarction, hypertension, embolism (pulmonary and venous), endocarditis, peripheral arterial disease, Kawasaki disease, congenital heart disease, stroke, heart failure, cardiac arrhythmias, endocarditis, arterial occlusive diseases, cerebral atherosclerosis, cerebrovascular disorders, myocardial ischemia, and coagulopathies leading to thrombus formation in a vessel. In some preferred embodiments, the cognitive disorder or disease is selected from the group consisting of Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), autism/autism spectrum disorder (ASD), dyslexia, age-associated memory impairment and learning disorders, amnesia, mild cognitive impairment, and age- related cognitive decline. In some preferred embodiments, the neurodegenerative disease or condition is selected from the group consisting of pre-Alzheimer's disease, Alzheimer's disease, epilepsy, Pick's disease, Huntington's disease, Parkinson disease, Lou Gehrig's disease, pre-dementia syndrome, Lewy body dementia, dentatorubropallidoluysian atrophy, Freidreich's ataxia, multiple system atrophy, spinocerebellar ataxia, amyotrophic lateral sclerosis, familial spastic paraparesis, spinal cord injury, spinal muscular atrophy, spinal and bulbar muscular atrophy, and AIDS-related neurodegeneration. In some preferred embodiments, the inflammatory disease or condition is selected from the group consisting of organ transplant rejection, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease (CD), asthma, acute respiratory distress syndrome (ARDS), inflammatory diseases or conditions of the olfactory system, chronic obstructive pulmonary disease (COPD, gingivitis, glomerulonephritis, nephrosis, sclerodermatitis, psoriasis, eczema; chronic demyelinating diseases, and multiple sclerosis. In some preferred embodiments, the disease or condition of the eye is a dry eye caused by a factor the group consisting of inflammation of the eye, corneal nerve abnormalities and abrasions on the surface of the eye. In some preferred embodiments, the disease or condition of the eye is a neurodegenerative disease of the eye. In some preferred embodiments, the neurodegenerative disease of the eye is selected from the group consisting of age-related macular degeneration, diabetic retinopathy, non-proliferative retinopathy, proliferative retinopathy, diabetic macular edema, retinitis pigmentosa, central vein occlusion and glaucoma. In some preferred embodiments, the present invention provides ophthalmic formulations comprising a lysophosphatidylcholine (LPC) composition comprising a LPC- compound of formula 1 or formula 2, or derivates, conjugates or salts thereof, Formula 1 Formula 2
Figure imgf000008_0001
wherein R1 is an acyl or alkyl chain length of at least 14 carbons; R2 is OH or O-CO-(CH2)n-CH3; and n is 0, 1 or 2 and one or more additional components selected from the group consisting of an effective amount of a buffer component, an effective amount of a tonicity component, an effective amount of a preservative component and water. In some preferred embodiments, R1 is DHA, EPA, DPA, SDA or ALA and R2 is OH. In some preferred embodiments, the formulation are characterized with the proviso that: if the LPC composition comprises i) a compound according to formula 1 and/or formula2, wherein R1 is DHA and R2 is OH; then the LPC composition further comprises at least one of the other LPC-compounds referred to in claim 2. In some preferred embodiments, the LPC-compound is selected from: a compound according to formula 1 and/or formula 2 wherein R1 is DHA; and a compound according to formula 1 and/or formula 2 wherein R1 is EPA. In some preferred embodiments, R1 is OH; and the molar ratio of lysoPC-DHA : lysoPC-EPA is in the range 1:1 to 5:1; or molar ratio of lysoPC-EPA : lysoPC-DHA is in the range 1:1 to 5:1; with the proviso that i) the number of moles of lysoPC-EPA is the number of moles 1-lysoPC-EPA + the number of moles 2-lysoPC-EPA; and ii) the number of moles of lysoPC-DHA is the number of moles 1-lysoPC-DHA + the number of moles 2- lysoPC-DHA. In some preferred embodiments, the LPC composition in the ophthalmic formulation comprises an amount of total LPC of at least 0.01 % by weight of the ophthalmic formulation. In some preferred embodiments, the LPC composition in the ophthalmic formulation comprises an additional lipid different from LPC. In some preferred embodiments, the additional lipid is selected from the group consisting of triglycerides and phospholipids such as phosphatidylethanolamine and phosphatidylcholine. In some preferred embodiments, the LPC composition comprises a predominant amount of the LPC-compound compared to an amount of phosphatidylcholine. In some preferred embodiments, the LPC-compound is selected from LPC-EPA, LPC-DHA and any combination thereof. In some preferred embodiments, the ophthalmic formulation is provided in an amount effective to treat, prevent and/or relief one or more symptoms and/or signs of a disease or condition of the eye. In some preferred embodiments, the ophthalmic formulation further comprises a component selected from the group consisting of lutein, astaxanthin, zeaxanthin and any combinations thereof. In some preferred embodiments, the ophthalmic formulation is an eye drop formulation. In some preferred embodiments, the eye drop formulation is provided in an eye drop device. In some preferred embodiments, the ophthalmic formulations defined above are provided for use in treating, preventing and/or relieving one or more symptoms and/or signs of a disease or condition of the eye. In some preferred embodiments, the disease or condition of the eye is dry eye, such as dry eye disease selected from the group consisting of inflammation of the eye, corneal nerve abnormalities and abrasions on the surface of the eye. In some preferred embodiments, the disease or condition of the eye is a neurodegenerative disease of the eye. In some preferred embodiments, the neurodegenerative disease of the eye is selected from the group consisting of age-related macular degeneration, diabetic retinopathy, non-proliferative retinopathy, proliferative retinopathy, diabetic macular edema, retinitis pigmentosa, central vein occlusion and glaucoma. In some preferred embodiments, the present invention provides parenteral formulations comprising a lysophosphatidylcholine (LPC) composition comprising a LPC- compound of formula 1 or formula 2, or derivates, conjugates or salts thereof, Formula 1 Formula 2
Figure imgf000010_0001
wherein R1 is an acyl or alkyl chain length of at least 14 carbons; R2 is OH or O-CO-(CH2)n-CH3; and n is 0, 1 or 2 for use in treating an injury, disease, or disorder of the brain selected from the group consisting of traumatic brain injury, concussion, chronic traumatic encephalopathy, and combinations thereof. In some preferred embodiments, the LPC composition comprising one or more LPC-compounds selected from the group consisting of LPC-16:0, LPC-18:0, LPC-18: 1, LPC-18:2 n-6, LPC-18:3 n-3, LPC-18:4 n-3, LPC-20:4 n-6, LPC-22:5 n-3, LPC-22:6 n-3, LPC-20:5 n-3. In further preferred embodiments, R1 is DHA, EPA, DPA, SDA or ALA and R2 is OH. In some preferred embodiments, the formulation are characterized with the proviso that: if the LPC composition comprises i) a compound according to formula 1 and/or formula2, wherein R1 is DHA and R2 is OH; then the LPC composition further comprises at least one of the other LPC-compounds referred to in claim 2. In some preferred embodiments, the LPC-compound is selected from: a compound according to formula 1 and/or formula 2 wherein R1 is DHA; and a compound according to formula 1 and/or formula 2 wherein R1 is EPA. In some preferred embodiments, R1 is OH; and the molar ratio of lysoPC-DHA : lysoPC-EPA is in the range 1:1 to 5:1; or molar ratio of lysoPC-EPA : lysoPC-DHA is in the range 1:1 to 5:1; with the proviso that i) the number of moles of lysoPC-EPA is the number of moles 1-lysoPC-EPA + the number of moles 2-lysoPC-EPA; and ii) the number of moles of lysoPC-DHA is the number of moles 1-lysoPC-DHA + the number of moles 2- lysoPC-DHA. In some preferred embodiments, the LPC composition in the parenteral formulation comprises an amount of total LPC of at least 1 % by weight of the nasal formulation. In some preferred embodiments, the LPC composition in the parenteral formulation comprises an additional lipid different from LPC. In some preferred embodiments, the additional lipid is selected from the group consisting of triglycerides and phospholipids such as phosphatidylethanolamine and phosphatidylcholine. In some preferred embodiments, the LPC composition comprises a predominant amount of the LPC- compound compared to an amount of phosphatidylcholine. In some preferred embodiments, the LPC-compound is selected from LPC-EPA, LPC-DHA and any combination thereof. In some preferred embodiments, the parenteral formulation is an intravascular formulation. In some preferred embodiments, the injury, disease, or disorder of the brain is traumatic brain injury. In an alternative aspect the present invention relates to a method for treating, preventing and/or relieving one or more symptoms and/or signs of a disease or condition of the eye comprising administering to a subject in need thereof an effective amount of a formulation comprising a lysophosphatidylcholine (LPC) composition comprising a LPC-compound selected from the group consisting of any one of formula 1 to 8, and any combination thereof so that the symptoms of the disease or condition are improved, controlled, reduced or alleviated Formula 3 Formula 4
Figure imgf000012_0001
Formu a 7 Formu a 8
Figure imgf000012_0002
wherein R1 is OH or O-CO-(CH2)n-CH3; R2 is OH or O-CO-(CH2)n-CH3; and n is 0, 1 or 2. In one embodiment of this alternative aspect the R1 is OH and R2 is OH. In one embodiment of this alternative aspect the, with the proviso that: if the LPC composition comprises i) a compound according to formula 1, wherein R2 is OH; and/or ii) a compound according to formula 3, wherein R1 is OH; then the LPC composition further comprises at least one of the other LPC-compounds referred to in the first aspect. In one embodiment of this alternative aspect, the one or more LPC-compound is: - a compound according to formula 1; and/or a compound according to formula 3; and - a compound according to formula 2; and/or a compound according to formula 4. In one embodiment of this alternative aspect the, - R1 and R2 are OH; and - molar ratio of lysoPC-DHA : lysoPC-EPA is in the range 1:1 to 3:1; or molar ratio of lysoPC-EPA : lysoPC-DHA is in the range 1:1 to 5:1; with the proviso that i) the number of moles of lysoPC-EPA is the number of moles 1-lysoPC-EPA + the number of moles 2-lysoPC-EPA; and ii) the number of moles of lysoPC-DHA is the number of moles 1-lysoPC-DHA + the number of moles 2-lysoPC-DHA. In one embodiment of this alternative aspect, the disease or condition is dry eye, such as dry eye disease selected from the group consisting of inflammation of the eye, corneal nerve abnormalities and abrasions on the surface of the eye. In one embodiment of this alternative aspect, the disease or condition is a neurodegenerative disease of the eye. In one embodiment of the alternative aspect, the neurodegenerative disease of the eye is selected from the group consisting of age-related macular degeneration, diabetic retinopathy, Non-Proliferative Retinopathy, Proliferative Retinopathy, Diabetic macular edema, Retinitis pigmentosa, Central vein occlusion and glaucoma. In one embodiment of the alternative aspect, the administering is by a mode selected from the group consisting of oral administration, intravenous administration, nasal administration and ophthalmic administration. In one embodiment of the alternative aspect, the mode of administration is oral administration. In one embodiment of the alternative aspect, the mode of administration is extra-oral administration. In one embodiment of the alternative aspect, the mode of administration is intravenous administration. In one embodiment of the alternative aspect, the mode of administration is nasal administration. In one embodiment of the alternative aspect, the mode of administration is ophthalmic administration. In one embodiment of the alternative aspect, the LPC composition in the formulation comprises a LPC-compound selected from the group consisting of any one of formula 1 to 8, and wherein the LPC composition comprises an amount of total LPC corresponding to from 10-100 % by weight of the LPC-composition. In one embodiment of the alternative aspect, the LPC composition further comprises a lipid different from LPC. In one embodiment of the alternative aspect, the LPC composition comprises from 5 % to 12 % by weight of DHA, wherein the DHA is a free fatty acid or ethyl ester or lipid in the LPC-composition. In one embodiment of the alternative aspect, the LPC composition comprises from 10 % to 24 % by weight of EPA, wherein the EPA is a free fatty acid or a ethyl ester or bound to any lipid in the LPC-composition. In one embodiment of the alternative aspect, the LPC composition further comprises palmitoleic acid and/or palmitic acid. In one embodiment of the alternative aspect, the LPC composition comprises from 2 % to 5 % by weight of palmitoleic acid, wherein the palmitoleic acid is bound to any lipid in the LPC-composition. In one embodiment of the alternative aspect, the LPC composition comprises from 10 % to 15 % by weight of palmitic acid, wherein the palmitic acid is bound to any lipid in the LPC-composition. In one embodiment of the alternative aspect, the lipid different from LPC is selected from the group consisting of triglycerides, ethyl esters, free fatty acids and phospholipids such as phosphatidyletanolamin and phosphatidylcholine. In one embodiment of the alternative aspect, the LPC composition comprises an amount of total phospholipids corresponding to at least 35 % by weight of the LPC-composition. In one embodiment of the alternative aspect, the LPC composition comprises an amount of total LPC corresponding to at least 23 % by weight of the LPC-composition. In one embodiment of the alternative aspect, the LPC composition comprises an amount of total LPC corresponding to at least 60 % by weight of the LPC-composition. In one embodiment of the alternative aspect, the LPC composition comprises an amount of total LPC corresponding to at least 90 % by weight of the LPC-composition. In one embodiment of the alternative aspect, the LPC composition comprises an amount of total LPC corresponding to from 90-98 % by weight of the LPC-composition. In one embodiment of the alternative aspect, the LPC composition comprises an amount of total LPC corresponding to at least 95 % by weight of the LPC-composition. In one embodiment of the alternative aspect, the formulation comprises from 1 % to 35 % by weight of the LPC-composition. In one embodiment of the alternative aspect, the formulation comprises from 25 % by weight of the LPC-composition. In one embodiment of the alternative aspect, the LPC composition comprises a predominant amount of the LPC-compound compared to an amount of phosphatidylcholine. In one embodiment of the alternative aspect, the LPC-compound is selected from LPC- EPA, LPC-DHA and any combination thereof. In one embodiment of the alternative aspect, the LPC composition comprises a predominant amount of the LPC-compound compared to an amount of phosphatidylcholine. In one embodiment of the alternative aspect, the formulation further comprises a component selected from the group consisting of lutein, astaxanthin, zeaxanthin and any combinations thereof. In one embodiment of the alternative aspect, the formulation further comprises one or more of a component selected from the group consisting of an effective amount of a buffer component, an effective amount of a tonicity component, an effective amount of a preservative component and water. In one embodiment of the alternative aspect, the subject is a mammalian subject. In one embodiment of the alternative aspect, the subject is a human subject. In a second alternative aspect the present invention relates to an ophthalmic formulation or a nasal formulation comprising a lysophosphatidylcholine (LPC) composition comprising a LPC-compound selected from the group consisting of any one of formula 3 to 10, and any combination thereof Formula 3 Formula 4
Figure imgf000016_0001
Formula 7 Formula 8
Figure imgf000016_0002
wherein R1 is OH or O-CO-(CH2)n-CH3; R2 is OH or O-CO-(CH2)n-CH3; and n is 0, 1 or 2 and one or more additional components selected from the group consisting of an effective amount of a buffer component, an effective amount of a tonicity component, an effective amount of a preservative component and water. In one embodiment of the second alternative aspect, R1 is OH and R2 is OH. In one embodiment of the second alternative aspect, with the proviso that: if the LPC composition comprises i) a compound according to formula 3, wherein R2 is OH; and/or ii) a compound according to formula 5, wherein R1 is OH; then the LPC composition further comprises at least one of the other LPC-compounds referred to in the second alternative aspect. In one embodiment of the second alternative aspect, the compound is: - a compound according to formula 3; and/or a compound according to formula 5; and - a compound according to formula 4; and/or a compound according to formula 6. In one embodiment of the second alternative aspect, - R1 and R2 are OH; and - molar ratio of lysoPC-DHA : lysoPC-EPA is in the range 1:1 to 3:1; or molar ratio of lysoPC-EPA : lysoPC-DHA is in the range 1:1 to 5:1; with the proviso that i) the number of moles of lysoPC-EPA is the number of moles 1-lysoPC-EPA + the number of moles 2-lysoPC-EPA; and ii) the number of moles of lysoPC-DHA is the number of moles 1-lysoPC-DHA + the number of moles 2-lysoPC-DHA. In one embodiment of the second aspect, the formulation is provided in an amount effective to treat, prevent and/or relief one or more symptoms and/or signs of a disease or condition of the eye. In one embodiment of the second alternative aspect, the ophthalmic formulation or the nasal formulation comprises from 1 % to 35 % by weight of the LPC-composition. In one embodiment of the second alternative aspect, the ophthalmic formulation or the nasal formulation comprises from 25 % by weight of the LPC-composition. In one embodiment of the second alternative aspect, the LPC composition comprises an amount of total LPC corresponding to from 10 % to 100 % by weight of the LPC- compound. In one embodiment of the second alternative aspect, the LPC composition comprises an amount of total LPC corresponding to at least 70 % by weight of the LPC-composition. In one embodiment of the second alternative aspect, the LPC composition comprises an amount of total LPC corresponding to at least 90 % by weight of the LPC-composition. In one embodiment of the second alternative aspect, the LPC composition comprises an amount of total LPC corresponding to from 90-98 % by weight of the LPC-composition. In one embodiment of the second alternative aspect, the LPC composition comprises an amount of total LPC corresponding to at least 95 % by weight of the LPC-composition. In one embodiment of the second alternative aspect, the LPC composition comprises a lipid different from LPC. In one embodiment of the second alternative aspect, the LPC composition comprises from 5 % to 12 % by weight of DHA, wherein the DHA is bound to any lipid in the LPC- composition. In one embodiment of the second alternative aspect, the LPC composition comprises from 10 % to 24 % by weight of EPA, wherein the EPA is bound to any lipid in the LPC- composition. In one embodiment of the second alternative aspect, the LPC composition further comprises palmitoleic acid and / or palmitic acid. In one embodiment of the second alternative aspect, the LPC composition comprises from 2 % to 5 % by weight of palmitoleic acid, wherein the palmitoleic acid is bound to any lipid in the LPC-composition. In one embodiment of the alternative aspect, the LPC composition comprises from 10 % to 15 % by weight of palmitic acid, wherein the palmitic acid is bound to any lipid in the LPC-composition. In one embodiment of the second alternative aspect, the lipid different from LPC is selected from the group consisting of triglycerides, ethyl esters, free fatty acids and phospholipids such as phosphatidyletanolamin and phosphatidylcholin. In one embodiment of the second alternative aspect, the LPC composition comprises a predominant amount of the LPC-compound compared to an amount of phosphatidylcholine. In one embodiment of the second alternative aspect, the LPC-compound is selected from LPC-EPA, LPC-DHA and any combination thereof. In one embodiment of the second alternative aspect, the formulation further comprises a component selected from the group consisting of lutein, astaxanthin, zeaxanthin and any combinations thereof. In one embodiment of the second alternative aspect, ophthalmic formulation is for use in treating, preventing and/or relieving one or more symptoms and/or signs of a disease or condition of the eye. In one embodiment of the second alternative aspect, the disease or condition of the eye is dry eye, such as dry eye disease selected from the group consisting of inflammation of the eye, corneal nerve abnormalities and abrasions on the surface of the eye. In one embodiment of the second alternative aspect, the disease or condition of the eye is a neurodegenerative disease of the eye. In one embodiment of the second alternative aspect, the neurodegenerative disease of the eye is selected from the group consisting of age-related macular degeneration, diabetic retinopathy, Non-Proliferative Retinopathy, Proliferative Retinopathy, Diabetic macular edema, Retinitis pigmentosa, Central vein occlusion and glaucoma. In one embodiment of the second alternative aspect, the formulation is an eye drop formulation. In one embodiment of the second alternative aspect, the eye drop formulation is provided in an eye drop device. BRIEF DESCRIPTION OF THE FIGURES Figure 1: Area under time concentration curve of ocular tissue after oral and i.v. administration. Figure 2: Area under time concentration curve of ocular tissue (whole eye) after oral and i.v. administration of LPC-EPA and LPC-DHA for the first 24 hours. Figure 3: Area under time concentration curve of ocular tissue (whole eye) after oral and i.v. administration of LPC-EPA and LPC-DHA for the first 72 hours. Figure 4A-D: Modified Neurological Severity Scores of mice that had CCI or sham craniotomy and were subsequently treated with DHA or LPC-DHA. A) mNSS scores for all treatment groups. Y-axis: mNSS score. X-axis: Days post injury. The capital letters in brackets for each group were used for identification by the blinded experimenter.
Figure imgf000019_0001
Figure imgf000020_0001
B) mNSS scores for animals treated with 1.136 mg/kg, 0.284 mg/kg or 4.544 mg/kg LPC- DHA. Y-axis: mNSS score. X-axis: Days post injury. A 2-way ANOVA was conducted and there was an overall statistically significant difference in mNSS scores based on treatment effect (F (2.61,13.04) = 61.41, p<0.0001), days post-injury effect (F(2.67,13,33) = 18.43, p<0.0001) and the combined effect of treatment group and days post-surgery (F (3.485,17.43) = 4.34, p<0.05). At days 1,2,3, 7 and 10 there was a statistically significant difference in mNSS scores when comparing the naive group to all the individual groups, with the exception of the sham vehicles group at day 7 (Dunnett’s multiple comparison analysis).
Figure imgf000020_0002
P values of <0.05 and <0.01, <0.0002 and <0.0001 are denoted respectively by *,**,*** and ****. Data shown as mean ± SEM with n = 6 for all individual groups. C) mNSS scores for animals treated with 0.164 mg/kg DHA. Y-axis: mNSS score. X-axis: Days post injury. A 2-way ANOVA was conducted and there was an overall statistically significant difference in mNSS scores based on treatment effect (F (2.56,12.78) = 37.27, p<0.0001), days post-injury effect (F(1.90, 9.51) = 24.60, p<0.0001) and the combined effect of treatment group and days post-surgery (F (3.28,16.40) = 4.50, p<0.05). At days 1,2,3,7, 10 and 14 there was a statistically significant difference in mNSS scores when comparing the naïve group (n=6) to the 0.164 mg/kg DHA, CCI vehicles and sham vehicles, with the exception of the sham vehicles group at day 7, sham vehicles group at day 14 and the CCI vehicles group at day 14 (Dunnett’s multiple comparison analysis).
Figure imgf000020_0003
Figure imgf000021_0001
P values of <0.05 and <0.01, <0.0002 and <0.0001 are denoted respectively by *,**,*** and ****. Data shown as mean ± SEM with n = 6 for all individual groups. D) mNSS scores for animals treated with 4.544 mg/kg LPC-DHA. Y-axis: mNSS score. X- axis: Days post injury. ANOVA was conducted and there was an overall statistically significant different in mNSS scores based on treatment effect (F (2.37,11,87) = 70.62, p<0.0001), days post-injury effect (F(2.07,10.36) = 20.09, p<0.001) and the combined effect of treatment group and days post-surgery (F (3.08,15.40) = 5.735, p<0.01). At days 1,2,3, 7 and 10 there was a statistically significant difference in mNSS scores when comparing the naive group to all the individual groups with the exception of the sham vehicles group at day 7 (Dunnett’s multiple comparison analysis).
Figure imgf000021_0002
P values of <0.05 and <0.01, <0.0002 and <0.0001 are denoted respectively by *,**,*** and ****. Data shown as mean ± SEM with n = 6 for all individual groups. Figure 5:  Modified Neurological Severity Scores of mice that had CCI or craniotomy and were subsequently treated with various concentrations of DHA and EPA esterified to LPC. Y-axis: mNSS score. X-axis: Days post injury. A 2-way ANOVA was conducted and there was an overall statistically significant difference in mNSS scores based on treatment effect (F (4, 25) = 13.19, p<0.0001) and days post-injury effect (F(2.160, 53.99) = 93.68, p<0.0001); however, the combined effect of treatment group and days post-injury was not statistically different (p=0.641). At days 1 to 14 all treatment groups showed a statistically significant difference in mNSS scores as compared to the sham vehicles group with the exception of the group that received 4.544 mg/kg LPC-DHA at days 10 and 14 (Dunnett's multiple comparison analysis).
Figure imgf000021_0003
Figure imgf000022_0001
P values of <0.05 and <0.01, and <0.0002 are denoted respectively by *,** and ***. Data shown as mean ±SEM with n=6 per group. Figure 6: Modified Neurological Severity Scores in mice that had CCI or craniotomy and were subsequently treated with 4.544 mg/kg LPC-DHA or vehicle. Data sets are combined results from study 1 and study 2. Y-axis: mNSS score. X-axis: Days post injury. A 2-way ANOVA was conducted and there was an overall statistically significant difference in mNSS scores based on treatment effect (F (1.921, 126) = 13.19, p<0.0001) and days post-injury effect (F(5,66) = 41.33, p<0.0001); the combined effects of treatment group and days post-injury were not statistically different (p=0.437). At days 1 to 14 the combined CCI vehicles group (n=12) showed statistically significant improved mNSS scored as compared to the combined sham vehicles group (n=12) (Dunnett’s multiple comparison analysis).
Figure imgf000022_0002
P values of <0.05 and <0.01 are denoted respectively by * and **. Data shown as mean ±SEM with n = 12 per group. Figure 7: Distribution of radioactivity in the olfactory system at 0.5 and 8 hours following a single intranasal dose administration of [14C]LPC-DHA to male Sprague Dawley rats at a target dose of 613 μL/subject. Definitions Throughout the present disclosure relevant terms are to be understood consistently with their typical meanings established in the relevant art, i.e. the art of pharmaceutical chemistry, medicine, biology, biochemistry and physiology. However, further clarifications and descriptions are provided for certain terms as set forth below. Formula 1 Formula 2
Figure imgf000023_0001
The term “LPC-compound” and “LPC-conjugate” are used herein and refers to a compound or conjugate according to formula 1 and 2, wherein R1 is an acyl or alkyl chain length of at least 14 carbons and R2 is OH or O-CO-(CH2)n-CH3; and n is 0, 1 or 2. The term “conjugate” as used herein refers to a compound having a molecule or moiety attached to it. For example, a compound or moiety may be attached to a LPC-compound to form a LPC-conjugate molecule that interacts with the Mfsd2a protein. As such, “LPC compound” or “LPC conjugate” refers to any molecule that allows transport via the Mfsd2a protein. Formula 3 Formula 4
Figure imgf000023_0002
Formula 5 Formula 6
Figure imgf000023_0003
Formula 7 Formula 8
Figure imgf000024_0002
Formula 9 Formula 10
Figure imgf000024_0001
The terms “2-lysoPC-DHA” and “2-LPC-DHA” are used interchangeably herein and refer to a compound according to formula 3, wherein R2 is OH. The terms “2-lysoPC-EPA” and “2-LPC-EPA” are used interchangeably herein and refer to a compound according to formula 4, wherein R2 is OH. The terms “2-lysoPC-DPA” and “2-LPC-DPA” are used interchangeably herein and refer to a compound according to formula 7, wherein R2 is OH. The terms “2-lysoPC-SDA” and “2-LPC-SDA” are used interchangeably herein and refer to a compound according to formula 8, wherein R2 is OH. The terms “1-lysoPC-DHA” and “1-LPC-DHA” are used interchangeably herein and refer to a compound according to formula 5, wherein R1 is OH. The terms “1-lysoPC-EPA” and “1-LPC-EPA” are used interchangeably herein and refer to a compound according to formula 6, wherein R1 is OH. The terms “1-lysoPC-DPA” and “1-LPC-DPA” are used interchangeably herein and refer to a compound according to formula 9, wherein R1 is OH. The terms “1-lysoPC-SDA” and “1-LPC-SDA” are used interchangeably herein and refer to a compound according to formula 10, wherein R1 is OH. The terms “lysoPC-DHA” and “LPC-DHA” and “LPC-22:6 n-3” are used interchangeably herein and includes both 1-lysoPC-DHA and 2-lysoPC-DHA. The terms “lysoPC-EPA” and “LPC-EPA” and “LPC-20:5 n-3” are used interchangeably herein and includes both 1-lysoPC-EPA and 2-lysoPC-EPA. The terms “lysoPC-DPA” and “LPC-DPA” and “LPC-22:5 n-3” are used interchangeably herein and includes both 1-lysoPC-DPA and 2-lysoPC-DPA. The terms “lysoPC-SDA” and “LPC-SDA” and “LPC-18:4 n-3” are used interchangeably herein and includes both 1-lysoPC-SDA and 2-lysoPC-SDA. The term “EPA” refers to eicosapentaenoic acid, 20:5 n-3. The term “DHA” refers to docosahexaenoic acid, 22:6 n-3. The term “DPA” refers to n3-docosapentaenoic acid, 22:5 n-3. The term “n3” specifying that the compound is an omega-3 fatty acid. The term “SDA” refers to stearidonic acid, 18:4 n-3. EPA, DHA, DPA, SDA, as used herein in connection with the compositions of the invention, refers to the fatty acid chain that can be bound to a lipid backbone, such as to phospholipids, lysophospholipids, triacylglycerides, diacylglyceride, monoacylglyceride or any other lipid backbound, or it can exist in the compositions as a free fatty acid or ethyl ester. The term “total LPC” is used herein to describe the total content of lysophosphatidylcholin in a composition. The term “total phospholipids” is used herein to describe the total content of phospholipids, including lyso-phospholipids, in a composition. The term “intravenous administration” as used herein refers to a mode of administration where a liquid substance is delivered directly into a vein. The intravenous route of administration can be used for injections (with a syringe at higher pressures) or infusions (typically using only the pressure supplied by gravity). The term “pharmaceutically acceptable excipients” refer to substances different from the components of the LPC-compositions referred to in the claims and which are commonly used with oily pharmaceuticals. Such excipients include, but are not limited to triolein, soybean oil, safflower oil, sesame oil, castor oil, coconut oil, triglycerides, tributyrin, tricaproin, tricaprylin, vitamin E, antioxidants, α-tocopherol, ascorbic acid, deferoxamine mesylate, thioglycolic acid, emulsifiers, lecithin, polysorbate 80, methylcellulose, gelatin, serum albumin, sorbitan lauraute, sorbitan oleate, sorbitan trioleate, polyethylene glycol (PEG), PEG 400, polyethylene glycol-modified phosphatidylethanolamine (PEG-PE), poloxamers, glycerin, sorbitol, Xylitol, pH adjustment agents; sodium hydroxide, antimicrobial agents EDTA, sodium benzoate, benzyl alcohol and proteins such as albumin. The pharmaceutically acceptable excipients must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. Used herein, the term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of pharmaceutical salts properties, Selection, and Use; 2002. The term “prophylaxis” means measures taken to prevent, rather than treat, diseases or conditions. The term "therapeutically effective amount" is an art-recognized term. In certain embodiments, the term refers to an amount of the composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to the medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate, reduce or alleviate medical symptoms for a period of time. The effective amount may vary depending on such factors as the disease or condition being treated, the particular composition being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation. The term "treating" is art -recognized and includes preventing a disease, disorder or condition from occurring in a subject which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating dry eye disease selected from inflammation of the eye, corneal nerve abnormalities and abrasions on the surface of the eye or neurodegenerative disease of the eye selected from age-related macular degeneration, diabetic retinopathy, Non-Proliferative Retinopathy, Proliferative Retinopathy, Diabetic macular edema, Retinitis pigmentosa, Central vein occlusion and glaucoma and other related diseases or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. The term “ophthalmic formulation” is an art-recognized term. An ophthalmic formulation is sterile and may be a liquid, semi-solid or solid preparation that contain one or more active ingredient(s) such as a pharmaceutical. The formulation is intended for application to the eye such as to the conjunctiva, the conjunctival sac or the eyelids. An ophthalmic formulation may be in form of an emulsion, a solution, a suspension or an ointment. A form of ophthalmic formulation as described herein is for ocular administration: a solution that enables the active ingredient to be administered directly onto the surface of the eye. The term “nasal spray” or “nasal formulation” are art-recognized terms. A nasal spray is used to deliver medications locally in the nasal cavities or systemically. Nasal sprays are seen as a more efficient way of transporting drugs with potential use in crossing the blood– brain barrier or the blood-retina barrier. The term “ocular administration” is used herein to describe administration of an active ingredient to the eyes. The term “nasal administration” is an art-recognized term. Nasal administration is a route of administration in which drugs are insufflated through the nose, i.e through the nasal delivery route. It can be a form of either topical administration or systemic administration, as the drugs thus locally delivered can go on to have either purely local or systemic effects. The nasal delivery route is preferred for systemic therapy because it provides an agreeable alternative to injection, in particular when the drug needs to avoid oral first pass effects, such as degradation via the gastrointestinal tract. Substances can be assimilated extremely quickly and directly through the nose. The term “extra-oral administration” is used herein to define a route of administration different from the oral route where a substance is taken through the mouth. Extra-oral administration can be rectal administration, sublingual administration, parental administration, ocular administration or nasal administration (non-exhaustive list). As used herein, “traumatic brain injury” or “TBI” refers to acquired brain injury or a head injury when a trauma causes damage to the brain. The damage can be focal, i.e. confined to one area of the brain, or diffuse, involving more than one area of the brain. As used herein, “closed head injury” refers to a brain injury when the head suddenly and violently hits an object, but the object does not break through the skull. DETAILED DESCRIPTION OF THE INVENTION Unless specifically defined herein, all technical and scientific terms used have the same meaning as commonly understood by a skilled artisan in the fields of medicine, pharmacology, pharmaceutical chemistry, biology, biochemistry and physiology. All methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, with suitable methods and materials being described herein. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will prevail. Where a numerical limit or range is stated herein, the endpoints are included. Also, all values and sub ranges within a numerical limit or range are specifically included as if explicitly written out. As previously discussed, there are a number of medical conditions, including dry eye disease (DED) (Deinema et al., American Academy of Ophthalmology 2016, ISSN 0161- 6420) and neurological conditions (such as for example TBI), PTSD and anxiety, that are either associated with low omega-3 levels or which would benefit from increased levels of long-chain omega-3 levels. DHA, EPA, DPA and SDA are omega-3 fatty acids of particular interest in this respect. DHA has been shown to be neuroprotective in models of traumatic brain injury (TBI) and to increase the functional recovery promoted by rehabilitation after cervical spinal cord injury (J Neurotrauma. 2017 May 1;34(9):1766- 1777. doi: 10.1089/neu.2016.4556. Epub 2017 Jan 13). It is further known that post TBI- recoveries are divided in three phases, 1) acute, 2) sub-acute and 3) chronic. It is hypothesized that the mechanisms and potential treatments effects may be different in the different phases. Thus, there is a need for means to increase the levels of omega-3 fatty acids in the brain and/or the retina, and in particular to increase the levels of DHA, EPA, DPA and/or SDA in the brain or retina. Unlike other tissues, the uptake of omega-3 does not occur through the lipoprotein receptors in the retina or in the brain. Previous studies in animal models have reported that DHA in the form of LPC passes through the blood retinal and blood-brain barriers via Mfsd2a, the sodium-dependent lysophosphatidylcholine (LPC) symporter that transports LPCs containing DHA and other long-chain fatty acids. The discovery of Mfsd2a and LPC-mediated transport of fatty acids with a minimum acyl chain length of 14 carbons was a major scientific breakthrough with widespread implications and exciting potential clinical application areas. By searching for gene expression in humans in the Expression Atlas database, the inventors have mapped the expression levels of Mfsd2a in human tissues and organs. The result show that the expression level of Mfsd2a in humans is highest in seminal vesicle, placenta, testis, vas deferens, lung, liver, brain, spinal cord, midbrain, hindbrain, cerebral cortex, diencephalon, cerebellum and zone of skin. With this in mind, the inventors propose that LPC mediated transport of fatty acids to these organs can be utilized in prevention or treatment of different diseases, particularly diseases that are influenced by an increased level of fatty acids. Accordingly, the invention provides formulations as described for use in treating, preventing and/or relieving one or more symptoms and/or signs of a disease selected from the group consisting of a 1) disease or condition of the eye, 2) a metabolic disorder or disease, 3) a disease or condition of the heart or circulatory system, 4) a cognitive disorder or disease, 5) a neurodegenerative disorder or disease, 6) an injury, disease or disorder of the brain, or 7) an inflammatory disease or condition. In different embodiments the invention provides formulations as described for use in treating, preventing and/or relieving one or more symptoms and/or signs of a disease in a organ or tissue selected from the group consisting of seminal vesicle, placenta, testis, vas deferens, lung, liver, brain, spinal cord, midbrain, hindbrain, cerebral cortex, diencephalon, cerebellum, eye or zone of skin. Eye photoreceptor membrane discs in outer rod segments are highly enriched in the visual pigment rhodopsin and the omega3 fatty acid docosahexaenoic acid (DHA). The eye acquires DHA from blood, and it has been demonstrated LPC transport via Mfsd2a as an important pathway for DHA uptake in eye and for development of photoreceptor membrane discs. Further it has been demonstrated that Mfsd2a is highly expressed in retinal pigment epithelium in embryonic eye, before the development of photoreceptors, and is the primary site of Mfsd2a expression in the eye. Even though dietary supplements containing omega-3 EFA in general seems to both influence the prevalence of ocular diseases and have a potential in the treatment of such diseases, it seems like the uptake and effects is influenced by in which form the omega-3’s are delivered. This has also recently been demonstrated for retinal uptake by Sugasini et al (Nutrients. 2020 Oct 12;12(10):3114. Doi: 10.3390/nu12103114.). In this article it is described that both the EPA and DHA content of the retina is more enriched from lipase-treated krill oil than with EPA and DHA from ordinary krill oil and fish oil . Thus, it is the object of this application to provide compositions that will increase the uptake of EPA and DHA in the ocular tissue and retina, as well as optimizing the omega-6/omega-3 ratio in ocular tissue. Without being bound by theory, it is believed that increased uptake of Omega-3 essential fatty acids will alter the inflammatory status of the eye through modulating cytokine production, thus aid in treatment and prevention of inflammation. As most eicosanoids derived from the omega-6 fatty acid pathway are proinflammatory, omega-3 EFAs bias prostaglandin metabolism toward the production of anti-inflammatory eicosanoids, which limit and resolve inflammation. Local administration, and in particular ophthalmic or nasal administration, of omega-3 fatty acids may provide an increased level of omega-3 fatty acids in the eye, olfactory system and plasma at a fast rate. Furthermore, this can also be an effective way of by- passing negative effects of the enzymes of the digestive system experienced by the oral route. A length of 14 carbon atoms or more have been indicted in the prior art to be essential for transport across the blood brain barrier (BBB) or the blood retinal barrier (BRB) by the Mfsd2a transporter. DHA, EPA, SDA and DPA are considered to be of high importance with respect to positive health effects in humans, and all of these have more than 14 carbon atoms. Thus, based on the information we have at date, each and all of these fatty acids should be transported efficiently across the blood retinal barrier when bound to LPC. In previous experiments it has been found that a single shot intravenously of LPC-EPA and LPC-DHA will result in rapid uptake of DHA and EPA in different organs, including the brain, liver and intestinal mucosa (WO2020254675). It is demonstrated that iv administration will provide a rapid systemic uptake, and bioavailability of LPC-DHA and LPC-EPA are demonstrated in organs that are thought to be well transfused and that also carries the transporter Mfsd2a. Three different studies are presented, demonstrating effects of LPC as a transporter of fatty acids through different modes of administration. In Example 2, uptake in ocular tissue and eyes is compared after oral and intravenous administration. LPC-DHA and LPC-EPA were selected as model molecules in the present study, but all data provided herein regarding uptake into the eye are also believed to indicate expected uptake profiles of the other two omega-3 fatty acids rereferred to above, i.e. SDA and DPA. LPC-DHA and LPC-EPA were to be administered by both oral and intravenous administration in this study. For the intravenous administration, it was decided to mix the LPC-DHA and LPC-EPA with one or more pharmaceutically acceptable excipients. Intralipid (IV) provided by Sigma Aldrich is compatible with oily substances and was therefore selected as the one or more pharmaceutically acceptable excipients. Reference is made to example 1 for further details to the pharmaceutical composition that was used in this study. 32 male Sprague Dawley rats received either an oral administration or a single intravenous administration of either LPC-DHA or LPC-EPA. The intravenous dose was administered directly into a tail vein as a slow bolus over 30 seconds. A single rat was euthanized by overdose of carbon dioxide gas at each of the following times: 0.5, 3, 8, 24, 72, 96, 168 and 336 hours post-dose. Each carcass was snap frozen in a hexane / solid carbon dioxide mixture immediately after collection and were then stored at approximately -20°C, pending further analysis. The frozen carcasses were subjected to quantitative ocular autoradiography, as detailed in example 2, to study the uptake of DHA and EPA into the ocular tissues at 0.5, 3, 8, 24, 72, 96, 168 and 336 hours post-dose. The final results of LPC-DHA are presented in example 2, table 1a and 1b. The final results of LPC-EPA are presented in example 2, table 2a and 2b. The data are also illustrated in figures 1-3. When administered intravascularly to avoid first exposure to the gut, DHA and surprisingly also EPA in its LPC form (as measured by their respective 14C radiolabelled carboxylic acid residues) exhibit very rapid and persistent uptake and massive accumulation into ocular tissue. For LPC-EPA given as a short intra vascular (i.v.) bolus the area under the concentration time curve (AUC) for the first 24 hours was demonstrated to be more than 5 times higher than the equivalent measure for the oral dose LPC. For LPC-DHA given as a short intra vascular (i.v.) bolus the area under the concentration time curve (AUC) for the first 24 hours was demonstrated to be more than 40 times higher than the equivalent measure for the oral dose LPC-DHA. This demonstrate that an administration route that can avoid first exposure to the gut results in a very rapid and persistent uptake of LPC-EPA and LPC-DHA into ocular tissue. Based on these results, the inventors have formulated an LPC-composition that are suitable for extra-oral administration, such as an ophthalmic or nasal formulation. Example 5 demonstrate uptake in blood, plasma and the olfactory system after intranasal administration. In this study, 5 male Sprague Dawley rats received a single intranasal administration of LPC-DHA. Dose utensils for intranasal administration consisted of a positive displacement pipette with disposable tips. Serial samples of whole blood were collected via a tail vein from each animal at 0.2, 0.5, 0.75, 1, and 2 hours post-dose. As shown in table 6 and 7 a significant amount of radioactivity appeared in the systemic circulation (whole plod and plasma) already during the first 20 minutes after administration and continued to increase until the last measurement. This demonstrate that nasal administration is an alternative route for systemic uptake of LPC. Figure 7 shows distribution of radioactivity in the olfactory system at 0.5 and 8 hours following a single intranasal dose administration of [14C]LPC-DHA to male Sprague Dawley rats at a target dose of 613 μL/subject. As is clearly visualized in the photos, radioactivity was detected in the whole olfactory system of the animals after 8 hours. The observed uptake of LPC-DHA in the olfactory system of the animals clearly points to the nasal LPC-formulation as an effective way to facilitate transport of fatty acids or other active ingredients (for example as part of an LPC-conjugate) to the olfactory system such as the olfactory nerves and bulb. The result demonstrate that nasal LPC-formulations have a great potential in treatment of diseases or conditions in an olfactory system, such as inflammatory diseases or for example loss of smell due to virus infections (ARDS or other covid-19 related diseases). Example 6 demonstrate acute neuroprotective effect of LPC-DHA in a model for TBI using intravenous administration. As such it is proof of concept of LPC as a transporter of an active ingredients. A controlled cortical impact (CCI) model was used based on previously described methods (Journal of Neurotrauma, 1998, 15(8), pp.599-614) and as used in previous work with DHA (Journal of Neurotrauma, 2020, 37(1), pp.66-79). Mice (n=6 per group for all groups) received a single intravenous injection of either LPC-DHA, LPC-DHA/EPA, or DHA free fatty acid or corresponding vehicle, at 30 min post-surgery, in a volume of 100 μl, over 30 s. The reference active dose of DHA was 500nmol/kg, and all dose equivalence calculations for LPC forms were based on this dose. The data obtained in this first pilot study on the efficacy of various forms of LPC as a carrier into the CNS for DHA and EPA clearly indicate that: a) LPC-DHA injected intravenously at 30 min after injury, induces a marked improvement in neurological outcome; the active dose identified induces an improvement comparable to that reported previously with DHA (free fatty acid). This was the case in both experiments: the first experiment which explored the dose-response for LPC-DHA, and the second in which LPC-DHA was used as an active comparator for LPC-DHA/EPA. Therefore, this clearly indicates the potential of LPC-DHA as a neuroprotectant via the parenteral route in TBI. The cumulated LPC-DHA data from the two different experiments carried out in this pilot study are shown in Table 8 and illustrated in Figure 6. Figure 6 shows that the neurological score of animals receiving LPC-DHA was not statistically significant from the score of sham animals – therefore the impact of the injury was markedly reduced by treatment with LPC-DHA. b) in contrast with LPC-DHA, the administration of LPC-DHA/EPA did not lead to any indication of efficacy in this model of brain injury, over the dose range tested. This indicates that for this model it is essential that DHA reaches a higher level than possible with the dose range tested, and that the LPC-EPA component does not enhance the effect of LPC-DHA; it may have at best a neutral effect. Without being bound by theory, this may not be so surprising. It is previously hypothesized that effects of LPC-EPA may be connected to its ability to influence the DHA-level as intracranial EPA is known to elongate to DHA. However, in this study the CCI-model is utilized to test the immediate effects of LPC-DHA as an acute neuroprotectant, accordingly EPA may not have time to be effective. In a first aspect, the present invention provides nasal formulations comprising a lysophosphatidylcholine (LPC) composition comprising a LPC-compound of formula 1 or formula 2, or derivates, conjugates or salts thereof, Formula 1 Formula 2
Figure imgf000034_0001
wherein R1 is an acyl or alkyl chain length of at least 14 carbons; R2 is OH or O-CO-(CH2)n-CH3; and n is 0, 1 or 2 and one or more additional components selected from the group consisting of an effective amount of a buffer component, an effective amount of a tonicity component, an effective amount of a preservative component and water. In different embodiments, R2 is OH or a protecting group. One example of a protective group being O-CO-(CH2)n-CH3, wherein n is 0, 1 or 2. The protecting group is preferably a group which do not interfere with binding to the Mfsd2a transporter and at the same time it blocks migration of the omega-3 (i.e. DHA, EPA, SDA and DPA) acyl group. If the omega-3 fatty acid moiety (e.g. DHA moiety, EPA moiety, SDA moiety and DPA moiety) is positioned on the sn-1 position of the glycerol backbone, the protecting group will typically block migration of the omega-3 fatty acid moiety from the sn-1 position to the sn-2 position. If the omega-3 fatty acid moiety (e.g. DHA moiety) is positioned on the sn-2 position of the glycerol backbone, the protecting group will typically block migration of the omega-3 fatty acid moiety from the sn-2 position to the sn-1 position. In some embodiments, the present disclosure provides nasal formulations for delivery of LPC-compounds or LPC-conjugates via the Mfsd2a protein. In a second aspect the present invention relates to an ophthalmic formulation or a nasal formulation comprising a lysophosphatidylcholine (LPC) composition as disclosed herein. Formula 3 and 5 refers to a compound with an attached DHA moiety. Formula 4 and 6 refers to a compound with an attached EPA moiety. Formula 7 and 9 refers to a compound with an attached n-3 DPA moiety. Formula 8 and 10 refers to a compound with an attached SDA moiety. In practice, the DHA, EPA, DPA and SDA moieties may in principle be replaced by any omega-3 fatty acid as long as the omega-3 fatty acid has 14 or more C- atoms. However, DHA, EPA, DPA and SDA are believed to be of most relevance with respect to human eye health and human brain health. An alternative aspect according to the present invention relates to the first aspect of the present invention, wherein the DHA, EPA, DPA and SDA moieties are replaced by any omega-3 moiety; at least i) any omega-3 moiety which has 14 or more C-atoms in its chain or ii) any omega-3 moiety which has a length corresponding to a chain length of 14 or more C-atoms. An alternative aspect according to the present invention relates to the first aspect of the present invention, wherein the DHA, EPA, DPA and SDA moieties are replaced by DHA, EPA, DPA, ALA and SDA moieties. Throughout this application the term LPC-compound and the term “active component”/”active ingredient” all refers to compounds of formula 1 to 10. The one or more active components referred to in the first aspect of the present invention, wherein R1 is OH and R2 is OH are all LPC molecules having either a DHA, an EPA, a DPA or a SDA molecule attached to the triacylglycerol moiety of LPC. Technical effect has been demonstrated for LPC-DHA and LPC-EPA. Based on the data presented in WO2018162617 and WO2008068413 it is also believed that similar effects would be obtained for the one or more active components referred to in the first aspect of the present invention where R1 is O-CO-(CH2)n-CH3 and R2 is O-CO-(CH2)n-CH3; and n is 0, 1 or 2, and in particular n=0. Even though the results presented herein are impressive for extra-orally administration of a formulation comprising an LPC-composition, the effect may be even further improved e.g. by including a pharmaceutically acceptable carrier. Liposomes may e.g. be suitable carriers for the oily constituents of the present invention by providing a hydrophobic interior for the oily substance and a hydrophilic exterior facing the hydrophilic environment. Further, it is also known that LPC is typically associated to proteins, such as albumin, in the blood to reduce the effective concentration of LPC. Thus, in one embodiment according to the present invention, the pharmaceutical composition also comprises a protein, such as albumin, which is suitable to reduce the effective concentration of the one or more active components when administered extra- orally. The formulation comprising the LPC composition of the present invention may or may not comprise one or more solvents, such as ethanol and/or water. If the composition comprises one or more solvents, the amount of the one or more active components in the composition may be referred to as % by dry-weight of the composition. However, if the composition does not comprise one or more solvents, the amount of the one or more active components in the composition may be referred to as % by weight of the composition. In one embodiment according to the present invention, the formulation comprising the LPC composition may comprise a combination of two or more of the one or more active components. One of the active components may have a DHA moiety attached to the glycerol backbone and another active component may have an EPA moiety attached to the glycerol backbone. Thus, in one embodiment according to the present invention, the formulation comprising the LPC composition comprises a combination of two or more of the one or more active components. One of the active components having a DHA moiety attached to the glycerol backbone and the other active component having an EPA moiety attached to the glycerol backbone. In a preferred embodiment, there is a specific molar ratio of the active components having a DHA moiety attached to the glycerol backbone and the active components having an EPA moiety attached to the glycerol backbone. The molar ratio of the active components having a DHA moiety attached to the glycerol backbone : the active components having a EPA moiety attached to the glycerol backbone preferably being in the range 1:1 to 10:1, such as in the range 1:1 to 7:1, or in the range 1:1 to 5:1, or in the range 1:1 to 3:1. In another embodiment according to the present invention, the molar ratio of the active components having a EPA moiety attached to the glycerol backbone : the active components having a DHA moiety attached to the glycerol backbone preferably being in the range 1:1 to 10:1, such as in the range 1:1 to 7:1, or in the range 1:1 to 5:1, or in the range 1:1 to 3:1. Reference is made to the following example illustrating how the molar ratio is to be calculated. If a composition comprises 10 mol LPC-DHA and 2 mol LPC-EPA, then the molar ratio of the active components having a DHA moiety attached to the glycerol backbone and the active components having a EPA moiety attached to the glycerol backbone is 10:2, i.e. 5:1. If not specified otherwise, the number of moles of LPC-EPA is the number of moles 1-LPC-EPA + the number of moles 2-LPC-EPA and the number of moles of LPC-DHA is the number of moles 1-LPC-DHA + the number of moles 2-LPC- DHA. It has previously been discussed that the position of the omega-3 fatty acid moiety on the glycerol backbone may affect the uptake of that fatty acid. Thus, in one embodiment according to the present invention, the listed omega-3 fatty acid moieties are bond to sn1 position of the glycerol backbone. In another embodiment according to the present invention, the listed omega-3 fatty acid moieties are bond to sn2 position of the glycerol backbone. In an alternative embodiment according to the present invention, there is a specific molar ratio of the active components having an omega-3 fatty acid moiety bound to sn1 position of the glycerol backbone and the active components having an omega-3 fatty acid moiety bound to sn1 position of the glycerol backbone. The molar ratio of the active components having an omega-3 fatty acid moiety bound to sn2 position of the glycerol backbone : the active components having an omega-3 fatty acid moiety bound to sn1 position of the glycerol backbone preferably being in the range 1:8 to 18:1, such as in the range 1:8 to 15:1 or in the range 1:8 to 10:1. Reference is made to the following example illustrating how the molar ratio is to be calculated. If a composition comprises 5 mol 2-LPC-DHA, 5 mol 2-LPC-EPA and 2 mol 1- LPC-DHA, then the molar ratio of the active components having an omega-3 fatty acid moiety bound to sn1 position of the glycerol backbone : the active components having an omega-3 fatty acid moiety bound to sn2 position of the glycerol backbone is 10:2, i.e. 5:1. A third aspect the present invention relates to a formulation comprising a LPC composition according to the second aspect of the present invention for use in prophylaxis and/or therapy, wherein the formulation is to be administered systemically by an extra-oral administration route, such as by rectal administration, sublingual administration, any form of parental administration, ocular administration or nasal administration. The three primary methods of delivery of ocular medications to the eye are topical, local ocular (ie, subconjunctival, intravitreal, retrobulbar, intracameral), and systemic. The most appropriate method of administration depends on the area of the eye to be medicated. The conjunctiva, cornea, anterior chamber, and iris usually respond well to topical therapy. The eyelids can be treated with topical therapy but more frequently require systemic therapy. The posterior segment may also require systemic therapy, because most topical medications do not penetrate to the posterior segment. Retrobulbar and orbital tissues are typically treated systemically. A fourth aspect the present invention relates to a formulation comprising a LPC composition according to the second and the third aspect of the present invention for use in prophylaxis and/or therapy, wherein the formulation is administered local ocular or ophthalmic administration. In some embodiments according to any of the above aspects the present invention relates to a formulation comprising a LPC composition for use in prophylaxis and/or therapy of a condition which would benefit from increased levels of retinal DHA and/or EPA levels. As described in Example 6 below, the ability of purified LPC composition to dissolve in purified water was surprising and makes an excellent starting point for further formulations for ophthalmic or nasal use. In contrast, concentrated krill oil phospholipid (PL) compositions needed a mix of PEG400 and ethanol to solubilize and modify viscosity (WO 2016097854). Nasal sprays are typically used to deliver medications locally in the nasal cavities or systemically. In some situations, the nasal delivery route is preferred for systemic therapy because it provides an agreeable alternative to injection when first exposure to the gut is to be avoided. Many pharmaceutical drugs exist as nasal sprays for systemic administration, examples being sedative-analgesics, treatments for migraine, osteoporosis and nausea. Hormone replacement therapy, such as used for treatment of Alzheimer's disease and Parkinson's disease are also administrated systemically through the nasal route. Substances can be assimilated extremely quickly and directly through the nose. Nasal sprays are also seen as a more efficient way of transporting active ingredients and drugs with potential use in crossing the blood–brain barrier. Accordingly, nasal sprays are of particular interest for administrating the LPC-composition as described herein, as the Mfsd2a-reseptor for uptake of DHA and EPA across the blood-brain barrier and blood-retina barrier are well documented. In addition, as it is now surprisingly demonstrated that the LPC compositions described herein are soluble in water making them eligible for formulations as nasal sprays. Thus, in a fifth aspect the present invention relates to a formulation comprising a LPC composition comprising LPC-compounds according to Formel 1-10 for use in prophylaxis and/or therapy, wherein the formulation is administered by nasal administration. Furthermore, in a sixth aspect the present invention relates to an ophthalmic formulation comprising a LPC composition according to the second aspect of the present invention suitable for administration to the eye; and one or more additional components selected from the group consisting of an effective amount of a buffer component, an effective amount of a tonicity component, an effective amount of a preservative component and water. The ophthalmic formulation is for use in prophylaxis and/or therapy, wherein composition is by administration to the eye. The formulation is administrated in an effective amount to treat, prevent and/or relief one or more symptoms and/or signs of a disease or condition of the eye. An ophthalmic formulation according to the invention is sterile and may be a liquid, semi- solid or solid preparation that contain one or more active ingredient(s) such as a pharmaceutical. The formulation may in certain aspects be in form of an eye drop formulation. The eye drop formulation according to the invention may be provided in a device comprising a single dose or multiple doses. The formulation is intended for application to the eye such as to the conjunctiva, the conjunctival sac or the eyelids. The ophthalmic formulation may be in form of an emulsion, a solution, a suspension or an ointment. A form of ophthalmic formulation as described herein is for ocular administration: a solution that enables the active ingredient to be administered directly onto the surface of the eye. The LPC composition The LPC compositions are analyzed according to the methods as described in WO 2019/123015. In some preferred embodiments, according to any of the above aspects the lysophosphatidylcholine (LPC) composition comprising a LPC-compound of formula 1 or formula 2, or derivates, conjugates or salts thereof, Formula 1 Formula 2
Figure imgf000039_0001
wherein R1 is an acyl or alkyl chain length of at least 14 carbons; R2 is OH or O-CO-(CH2)n-CH3; and n is 0, 1 or 2 In some preferred embodiments, the LPC composition comprising one or more LPC- compounds selected from the group consisting of LPC-16:0, LPC-18:0, LPC-18: 1, LPC- 18:2 n-6, LPC-18:3 n-3, LPC-18:4 n-3, LPC-20:4 n-6, LPC-22:5 n-3, LPC-22:6 n-3, LPC- 20:5 n-3. In further preferred embodiments, R1 is DHA, EPA, DPA, SDA or ALA and R2 is OH. The LPC-compounds or LPC-conjugates may be synthetically made or be derived from natural sources. In some other embodiments according to any of the above aspects the LPC composition comprises at least one of the LPC-compound is selected from the group consisting of any one of formula 3 to 10, and any combination thereof Formula 3 Formula 4
Figure imgf000040_0001
Formula 5 Formula 6
Figure imgf000040_0002
Formula 7 Formula 8
Figure imgf000041_0001
Formula 9 Formula 10
Figure imgf000041_0002
In some embodiments, the LPC composition further comprises a lipid different from LPC, selected from the group consisting of triglycerides, ethyl esters, free fatty acids and phospholipids such as phosphatidyletanolamin and phosphatidylcholine. In some embodiments, the LPC composition comprises an amount of total LPC corresponding to from 10-100 % by weight of the LPC-composition, such as from 10 % to 100 % by weight, preferably 15 % to 100 % by weight, more preferably 20 % to 100 % by weight, further preferably 30 % to 100 % by weight, most preferably 50 % to 100 % by weight of the LPC composition. In some embodiments, the LPC composition comprises a fatty acid profile wherein the amount of DHA corresponds to from 5 % to 12 % by weight of the composition, wherein the DHA is as free fatty acid or as ethyl ester or bound to any lipid in the LPC- composition. In one embodiment, the LPC composition comprises a fatty acid profile wherein the amount of EPA corresponds to from 10 % to 24 % by weight of the composition, wherein the EPA is as free fatty acid or as ethyl ester or bound to any lipid in the LPC-composition. In one embodiment, the LPC composition further comprises palmitoleic acid and/or palmitic acid. In one embodiment, the LPC composition comprises a fatty acid profile wherein the amount of palmitoleic acid corresponds to from 2 % to 5 % by weight of the composition, wherein the palmitoleic acid is as free fatty acid or as ethyl ester or bound to any lipid in the LPC-composition. In one embodiment, the LPC composition comprises a fatty acid profile wherein the amount of from 10 % to 15 % by weight of the composition, wherein the palmitic acid is as free fatty acids or as ethyl esters or bound to any lipid in the LPC-composition. In one embodiment, the LPC composition comprises an amount of total phospholipids corresponding to at least 35 % by weight of the LPC-composition. In further embodiments, the LPC composition comprises a predominant amount or a major portion of at least one LPC-compound according to the invention compared to an amount of phosphatidylcholine. In one embodiment, the LPC composition comprises an amount of total LPC corresponding to at least 23, 24, 25, 26, 27 or 28 % by weight of the LPC-composition. In one embodiment, the LPC composition comprises an amount of total LPC corresponding to at least 60 % by weight of the LPC-composition. In one embodiment of the first aspect, the LPC composition comprises an amount of total LPC corresponding to at least 90 % by weight of the LPC-composition. In one embodiment of the first aspect, the LPC composition comprises an amount of total LPC corresponding to from 90 % to 98 % by weight of the LPC-composition. In one embodiment of the first aspect, the LPC composition comprises an amount of total LPC corresponding to about 95 % by weight of the LPC-composition. For instance, in one embodiment the LPC composition comprises from 60 % to 100 % by weight of total LPC, such as about 60% to 95% by weight of total LPC. In some embodiments of the invention the LPC-compound means any krill-derived processed phospholipid product containing a predominant amount of LPC compared to PC manufactured by Aker Biomarine. In a further embodiment of any of the above aspect the LPC-compound is selected from LPC-EPA, LPC-DHA and any combination thereof. The formulations In some preferred embodiments, according to any of the above aspects the invention provides new formulation of LPC-compositions, wherein the formulation is selected form the group consisting of 1) a nasal formulation, 2) an intravascular formulation or 3) an ophthalmic formulation. The formulation as described is demonstrated to generate systemic uptake of an LPC- compound or an LPC-conjugate, as defined herein. In general, the nasal or ophthalmic formulation may comprise an amount of the active ingredient which may vary from 0.01% - 15% by weight of the total weight of the nasal or ophthalmic formulation any specific value within said range. According to some embodiments, the amount of LPC ranges from 0.01% - 15% by weight, such as from about 0.1% to about 5% w/v, or any specific value within said range. In different embodiments, the amount of LPC compound ranges from about 0.5% to about 3% w/v, or any specific value within said range. More info re nasal formulation according to different aspects In still a further embodiment of any of the above aspects, the formulations as disclosed herein can combine one or more known anti-inflammatory compounds with compounds of the present invention. The combination of which is administered in a therapeutically effective amount to treat or prevent the effects of inflammation of the eye. Known anti- inflammatory compounds are preferably selected from lutein, astaxanthin, zeaxanthin and any combinations thereof. The LPC composition comprises naturally an amount of astaxanthin. In one embodiment, the formulation according to any of the above aspects comprises and effective amount of lutein and or zeaxanthin. Lutein and zeaxanthin are anti-oxidant pigments found in the macula of the eye (in the retina) and are believed to protect the macula from damage. On average, people don't consume enough lutein and zeaxanthin and/or have low levels of lutein in their blood or low macular pigment density. For them people with low levels of lutein in their blood or low macular pigment density, using a lutein supplement may slow the progression of age-related macular degeneration, as well as reduce the risk of needing cataract surgery. It may also improve some aspects of brain function. Accordingly, lutein and/or zeaxanthin are suggested as a further active ingredient in the formulations as described herein. Lutein and zeaxanthin can be in either their free or ester form. Further, lutein and zeaxanthin can derive from natural sources or from synthetic sources. In still a further embodiment of any of the above aspects the formulation may comprise palmitic acid and/or palmitoleic acid. Palmitic acid and/or palmitoleic acid has previously been shown to increase the stability and effectiveness of eye drop formulations. In particular, the stability and effectiveness of an ophthalmic formulation (Nakumara et al., Restoration of Tear Secretion in a Murine Dry Eye Model by Oral Administration of Palmitoleic Acid, Nutrients., 2017, vol.9, no.4, page 1-11). In a further embodiment of any of the above aspects the LPC composition comprises palmitic acid in an amount corresponding to from 10% to 15 % by weight of the composition. In another embodiment of any of the above aspects the LPC composition comprises palmitoleic acid in an amount corresponding to from 1 % to 5 % by weight of the composition. In one embodiment according to any of the above aspects the subject is a mammalian subject such as a human subject. Having generally described this invention, a further understanding can be obtained by reference to certain specific examples, which are provided herein for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Examples Example 1: Preparation of oral and intravenous formulations Materials
Figure imgf000044_0001
Figure imgf000044_0002
Figure imgf000045_0001
Figure imgf000045_0002
[14C]-LPC-DHA formulation, herein referred to as formulation A The formulation that was later administered intravenously was prepared according to the following target specifications:
Figure imgf000046_0001
The [14C]-LPC-DHA was mixed with the intralipid formulation to yield a dose formulation containing phospholipids at a final concentration of 190 mg/kg and the [14C]-LPC-DHA at a concentration of about 1.5 mg/kg (155 µCi/kg) as follows: 0.394 mL of ethanolic [14C]-LPC-DHA (2361 µCi/mL) was dispensed into a 20 mL glass vial and reduced to a final volume of approximately 0.30 mL under a flow of nitrogen at ambient temperature. 5.70 mL of 20% intralipid was added to the concentrated ethanolic [14C]-LPC-DHA solution and gently vortex mixed to ensure homogeneity. [14C]-LPC-EPA formulation, herein referred to as formulation B The formulation that was later administered intravenously was prepared according to the following target specifications:
Figure imgf000046_0002
Figure imgf000047_0001
The [14C]-LPC-EPA was mixed with the intralipid formulation to yield a dose formulation containing phospholipids at a final concentration of 190 mg/kg and the [14C]-LPC-EPA at a concentration of about 1.5 mg/kg (155 µCi/kg) as follows: 0.394 mL of ethanolic [14C]-LPC-EPA (2361 µCi/mL) was dispensed into a 20 mL glass vial and reduced to a final volume of approximately 0.30 mL under a flow of nitrogen at ambient temperature. 5.70 mL of 20% intralipid was added to the concentrated ethanolic [14C]-LPC-EPA solution and gently vortex mixed to ensure homogeneity. Oral dose formulations of [14C]-LPC-EPA and [14C]-LPC-DHA Oral dose formulations of [14C]-LPC-EPA and [14C]-LPC-DHA were prepared by spiking ethanolic solutions of each radiolabeled compound into a modified krill oil LPC- formulations at a concentration ratio of 10 : 90 v/v radiolabeled ethanol : modified krill oil. Each formulation that was later administered orally was prepared according to the following target specifications:
Figure imgf000047_0002
Figure imgf000048_0001
The [14C]-LPC-EPA was mixed with the phospholipid formulation to yield a dose formulation containing phospholipids at a final concentration of 855 mg/mL and the [14C]- LPC-EPA at a final concentration of ca. 1.5 mg/kg (155 μCi/kg) as follows: The final overall concentrations of ethanol in the formulation were approximately 10%. 0.328 mL of ethanolic [14C]-LPC-EPA (2361 μCi/mL) was dispensed into a 20 mL glass vial. 0.172 mL of ethanol was added (to make up to 10% in volume). 4.5 mL of the modified krill oil LPC- formulation (at a temperature of 37°C) was added to the concentrated ethanolic [14C]-LPC-EPA solution and mixed by vortex mixer and vigorous pipetting to ensure homogeneity. The [14C]-LPC-DHA formulation was spiked into the phospholipid formulation, as described for [14C]-LPC-EPA above. Example 2: Uptake of LPC in ocular tissue – Oral and intravenous administration 32 male Sprague Dawley rats, in the weight range of 213 - 289 g and approximately 7 -8 weeks old at the time of dose administration were housed in polypropylene cages and remained therein except for a short period during dosing. The room in which the animals were located was thermostatically monitored and data recorded continually (generally the temperature range was 21 ±2°C; humidity range 55 ±10%) and exposed to 12 hours fluorescent lighting and 12 hours dark per day. Animals were equilibrated under standard animal house conditions for a minimum of 3 days prior to use. The health status of the animals was monitored throughout this period and the suitability of each animal for experimental use was confirmed before use. A pellet diet (RM1 (E) SQC, Special Diets Services, Witham, Essex, UK) and water (from the domestic water supply) was available ad libitum throughout the holding, acclimatization and post-dose periods. 16 rats received a single intravenous administration of either formulation A or formulation B (eight per formulation) according to the dosage specification specified in example 1. Each rat was weighed prior to dose administration and the individual doses administered were calculated based on the bodyweight and the specified dose volume. The 16 rats selected for oral administration were fasted overnight, and the dose was administered 1 hour after reintroduction of diet. Dose utensils for oral administration consisted of a syringe and gavage tube. During dose administration, the gavage was fed down the oesophagus to enable the formulation to be dispensed directly into the stomach. Dose utensils for intravenous administration consisted of a hypodermic syringe and needle. The dose was administered directly into a tail vein as a slow bolus over 30 seconds. After administration of the formulations to the male rats, a single rat was euthanized by overdose of carbon dioxide gas at each of the following times: 0.5, 3, 8, 24, 72, 96, 168 and 336 hours post-dose. Each carcass was snap frozen in a hexane / solid carbon dioxide mixture immediately after collection and were then stored at approximately -20°C, pending analysis by QWBA (Quantitative whole body autoradiography). The frozen carcasses were subjected to QWBA using procedures based on the work of Ullberg (Acta. Radiol. Suppl 118, 2231, 1954). Sections were presented at up to five different levels of the rat body to include between 30 and 40 tissues (subject to presence of sufficient radioactivity) of which the uptake in brain, blood, kidney and spleen are disclosed herein. The freeze-dried whole-body autoradiography sections were exposed to phosphor-storage imaging plates and incubated at ambient temperature in the dark for a minimum of five days. A series of calibrated auto radiographic [14C] microscales containing known amounts of radioactivity (nCi/g, produced by Perkin Elmer) were exposed alongside the animal sections on each plate. Distribution of radioactivity was determined in ocular samples and microscales and quantified using a Fuji FLA-5100 fluorescent image analysing system and associated Tina (version 2.09) and SeeScan (version 2.0) software. A representative background radioactivity measurement was taken for each exposure plate used. The limit of accurate quantification was considered to be the lowest [14C] microscale visible. A standard curve was produced from the microscales using Seescan and from which tissue concentrations of radioactivity were determined (nCi/g). For calculation of the weight equivalent/g data, the nCi/g data was divided by the relevant specific activity (nCi/μg). Table 1a shows total amounts of radioactivity in ocular tissue following a single intravenous administration averaging 1.5510 mg/kg [14C]-LPC-DHA to male albino rats. Table 1b presents the same data as in 1a but in molar concentrations and standardized to a dose of 2.80 micro mol/kg (1.5949 mg/kg) Table 2a shows the total amounts of radioactivity in ocular following a single intravenous administration averaging 1.4968 mg/kg [14C]-LPC-EPA to male albino rats. Table 2b presents the same data as in 2a but in molar concentrations and standardized to a dose of 2.80 micro mol/kg (1.5218 mg/kg) Table 3a shows total amounts of radioactivity in ocular following a single oral dose averaging 1.6914 mg/kg [14C]-LPC-DHA to male albino rats. Table 3b presents the same data as in 3a but in molar concentrations and standardized to a dose of 2.80 micro mol/kg (1.5949 mg/kg) Table 4a shows total amounts of radioactivity in ocular following a single oral dose averaging 1.6759 mg/kg [14C]-LPC-EPA to male albino rats. Table 4b presents the same data as in 4a but in molar concentrations and standardized to a dose of 2.80 micro mol/kg (1.5218 mg/kg) The results are also presented in figure 1-3.
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
When administered extra-orally to avoid first exposure and degradation in the mouth and gut, DHA and surprisingly also EPA in its LPC form (as measured by their respective 14C radiolabelled carboxylic acid residues) exhibit very rapid and persistent uptake and massive accumulation into ocular tissue as illustrated in tables 1 to 4 and figures 8 to 10. For LPC-EPA given as a short intra vascular (i.v.) bolus the area under the concentration time curve (AUC) for the first 24 hours was demonstrated to be more than 5 times larger than the equivalent measure for the oral dose LPC (Figure 9) For LPC-DHA given as a short intra vascular (i.v.) bolus the area under the concentration time curve (AUC) for the first 24 hours was demonstrated to be more than 40 times higher than the equivalent measure for the oral dose LPC-DHA (Figure 9). Example 3: Preparation of formulations for intravenous and nasal administration The aim of this example was to prepare formulations of 1) LPC-EPA and LPC-DHA mixed in a ratio of 2:1 and 2) LPC-DHA at a concentration of 3 and 15 mg/mL. The stability of the formulations was evaluated over the course of five days in terms of pH, osmolality, droplet size, concentration, and chemical degradation (HPLC-CAD). Based on the results, formulations were produced and characterized before they were shipped to the UK for intravenous administration and for nasal administration in mice. Materials
Figure imgf000055_0001
Methods 1. Osmolality Osmometer: i Osmometer basic, Typ M 10/25uL, Löser The osmometer was calibrated using purified water and osmolality standards: 300 mOsm/kg H2O, Reagecon 900 mOsm/kg H2O, Reagecon 2. DLS measurements DLS was measured on a Malvern Zetasizer (Nanosizer ZS) in disposable 70 μL cuvettes (Brand). The measurements were carried out at 25 °C. The diameter of the micelles was derived from the size distribution by intensity. All measurements were done in technical triplicates. 3. HPLC-CAD Column: Phenomenex kinetex 5 μm, C18, 100 Å, 100 x 4.6 mm A solvent: Milli Q H2O + 0.1 % formic acid B solvent: MeOH + 0.1 % formic acid Flow 0.4 ml/min Column temp: 40° Autosampler temp 10° Injection volume 5 μL (sample diluted 6-fold to a concentration of 2.5 mg/mL prior to injection) Run time 35 minutes Gradient conditions:
Figure imgf000056_0001
CAD settings: Power function: 1.0 Data collection rate: 2 Evaporator temp. High (50 ºC) Calibration curve Samples of either the two standards of LPC-EPA and LPC-DHA or LPC-DHA alone (all from Synthetica, see Table 5) were prepared in methanol and run separately by HPLC- CAD in a dilution series from 1-3 mg/mL in technical triplicates. 4. Sample preparation 1) LPC-EPA and LPC-DHA were weighed off in a ratio of 2:1 and dissolved to 3 mg/mL (total LPC concentration: 2 mg LPC-EPA and 1 mg LPC-DHA per mL) in PBS buffer. Three unique samples were prepared (n = 3) of the mixture. The samples were left on an IntelliMixer (In Vitro, program: 6420RPM) for 30 min. The three solutions were filtered through sterile cellulose acetate filters (Q-Max, 0.22 um, Ø25, Frisenette). Three unique vials of the formulation were analyzed on the day of preparation and after five days. A formulation of ~25 mL was prepared in a similar way and shipped to the UK following the stability study. 2) LPC-DHA was weighed off and dissolved to 15 mg/mL in PBS buffer. Three unique samples were prepared (n = 3). The samples were left on an IntelliMixer (In Vitro, program: 6420RPM) for 30 min. The three solutions were filtered through cellulose acetate filters (Q-Max, 0.22 um, Ø25, Frisenette).The three unique vials of the formulation were analyzed on the day of preparation (t0) and after five days incubation at 5 °C (t5). For HPLC-CAD analyses the samples were diluted 6-fold to a concentration of 2.5 mg/mL prior to injection. The formulation was clear with a yellow color and became slightly yellow after the 6-fold dilution. Results and discussions 1) The formulation of a mixture of LPC-EPA and LPC-DHA was prepared in a ratio of 2:1 to resemble the EPA:DHA composition in krill oil. The formulation was subjected to static incubation at 5 °C for five days. HPLC-CAD was used to analyze the chemical degradation. Little changes were seen in the areas of the 1-LPC and 2-LPC peaks of LPC- EPA and LPC-DHA. When integrated as the sum of the two peaks and quantified using a calibration curve, a ~8 % decrease in the concentrations were observed for both compounds. When the two isomer peaks were split and analyzed separately for each of the two LPC compounds, no significant differences were found in the area of the 1-LPC relative to the 2-LPC peak between t0 and t5. Analysis of the pH, osmolality, and droplet size at t0 and at t5 showed no significant changes over the course of the five-day stability study. 2) The formulation of LPC-DHA at a concentration of 15 mg/ml was prepared in PBS. The formulation was subjected to static incubation at 5 °C for five days. HPLC-CAD was used to analyze the chemical degradation. Little changes were seen in the areas of the 1-LPC and 2-LPC peaks of LPC-DHA. Taking the standard deviation due to noise in the CAD signal and potential dilution factors during sample preparation into consideration there was no apparent or significant degradation taking place over the course of 5 days at 5 °C. Analysis of the pH showed a slight decrease from pH 7.1 to pH 6.9 between t0 and t5. The osmolality was stable at 284 ± 2 mOsm/kg and the droplet size showed a small decrease from 9.2 ± 0.5 to 8.5 ± 0.2 nm over the five-day stability study. In conclusion, it is possible to make LPC-DHA and/or LPC-EPA formulations at concentration of 3 mg/ml and 15 mg/ml that is stable over the course of the five-day stability study. Example 4: Nasal formulations A formulation of non-radiolabeled LPC-DHA was prepared as described in Example 3. The formulation used (Batch: BF-281021) had a pH of 7.0, osmolality of 287 mOsm/kg and a droplet size of 8.8 ± 0.3 nm in diameter with a PdI of 0.12 ± 0.03. The concentration was calculated using a freshly prepared calibration curve to 17.1 ± 1.3 mg/mL. The formulation was further labeled with [14C]-LPC-DHA as specified.
Figure imgf000058_0001
[14C]-LPC-DHA formulation for nasal administration, herein referred to as formulation C The radiolabeled formulation was prepared according to the following target specifications:
Figure imgf000059_0001
The [14C]-LPC-DHA was mixed with the unlabeled formulation to yield a dose formulation containing LPC-DHA at a final concentration of ca. 32 mg/mL (ca.1.78 mCi/mL) in physiological buffered saline with approximately 10% ethanol. A dose of 10 μL was administered to each nostril of the animal targeting a dose level of approximately 613 μg/animal, 35.6 μCi/animal based on a theoretical achieved specific activity of 3 mCi/g. The dose level is considered to be in the linear dose response range and also pharmacologically relevant. Example 5: LPC Blood uptake kinetics – Single Intranasal administration The objective of this study was to derive the concentrations and pharmacokinetic parameters of total radioactivity in plasma following a single intranasal administration of [14C]-LPC-DHA to male Sprague Dawley (non-pigmented) rats. 5 male Sprague Dawley rats, in the weight range of 296 - 314g and approximately 7-8 weeks old at the time of dose administration were housed in polypropylene cages and remained therein except for a short period during dosing. The room in which the animals were located was thermostatically monitored and data recorded continually (generally the temperature range was 21 ±2°C; humidity range 55 ±10%) and exposed to 12 hours fluorescent lighting and 12 hours dark per day. Animals were equilibrated under standard animal house conditions for a minimum of 3 days prior to use. The health status of the animals was monitored throughout this period and the suitability of each animal for experimental use was confirmed before use. A pellet diet (RM1 (E) SQC, Special Diets Services, Witham, Essex, UK) and water (from the domestic water supply) was available ad libitum throughout the holding, acclimatization, and post-dose periods. The 5 male Sprague Dawley rats each received a single intranasal administration of formulation C according to the dosage specification in Ex 4. Each rat was weighed prior to dose administration and the individual doses administered were calculated based on the bodyweight and the specified dose volume. Dose utensils for intranasal administration consisted of a positive displacement pipette with disposable tips. Serial samples of whole blood, each approximately 0.14 mL, were collected via a tail vein from each animal at: 0.2, 0.5, 0.75, 1, and 2 h post-dose. At the end of the experiment the animals were killed by cervical dislocation. As soon as practicable after collection of blood samples, triplicate aliquots of whole blood (10 μL) were dispensed onto Drug Metabolism Pharmacokinetic (DMPK) dried blood spot cards, stored desiccated at ambient temperature prior to radioactivity analysis, via sample oxidation), followed by direct Quantitative Radioactivity analysis (QRA). The concentration of radioactivity was also measured in plasma at the same timepoints. As shown in table 6 and table 7, a significant amount of radioactivity appeared in the systemic circulation already during the first 20 minutes after administration and continued to increase until the last measurement at 2 hours post dose. Figure 7 shows distribution of radioactivity in the olfactory system at 0.5 and 8 hours following a single intranasal dose administration of [14C]LPC-DHA to male Sprague Dawley rats at a target dose of 613 μL/subject. As is clearly visualized in the photos, radioactivity was detected in the whole olfactory system of the animals after 8 hours. Table 6: Concentrations of radioactivity in dried blood spots (expressed as ng equivalents/g) following a single intranasal dose administration of [14C]-LPC- DHA to male Sprague Dawley rats at a target dose of 613 μL/subject. Footnotes to table: ND None detected, NC Not calculable
Figure imgf000061_0001
Table 7: Concentrations of radioactivity in plasma (expressed as ng equivalents/g) following a single intranasal dose administration of [14C]-LPC-DHA to male Sprague Dawley rats at a target dose of 613 μL/subject.
Figure imgf000061_0002
Footnotes to table: ND None detected, NC Not calculable Conclusion: The concentration of radioactivity in blood and plasma already during the first 20 minutes as obtained in this first pilot study of LPC formulated for nasal administration clearly demonstrate that LPC as a carrier of DHA is absorbed via nasal mucosa directly into the bloodstream. As such, the nasal LPC formulation is demonstrated to have bypassed the liver and the first-pass metabolism. The obtained bioavailability of the nasal formulation of LPC-DHA is compatible with that of the injected formulation. It was interestingly also observed that the whole olfactory system of the animals had a high concentration of radioactivity that was visible after 8 hours, demonstrating that LPC formulated for nasal administration is a great way to achieve increased uptake of fatty acids in the olfactory system. Example 6: Neuroprotective effects of LPC-DHA in Traumatic Brain Injury (TBI) The aim of this study was to investigate the therapeutic potential of LPC-DHA and LPC- EPA for TBI in the acute phase. Animals 10–14-week-old male CD1 mice purchased from Charles River Laboratories (UK) were used for the experiments. All animal procedures were approved by the Animal Welfare and Ethical Review Body, at Queen Mary University of London and the UK Home Office, in accordance with the EU Directive 2010/63/EU. Prior to the experiments, animals were kept in-house on a 12-hour light-dark cycle. The animals were acclimatized for a minimum of one week in-house, after delivery from the breeder and prior to experimentation. Injury and treatment A controlled cortical impact (CCI) model was used, based on a previously described method (Journal of Neurotrauma, 1998, 15(8), pp.599-614) and as used in previous work with DHA (Journal of Neurotrauma, 2020, 37(1), pp.66-79). Animals were anaesthetized with a mixture of 0.5 mg/kg medetomidine and 50 mg/kg ketamine administered via an intraperitoneal injection, in a volume of 0.1 ml/10 g. Pre-surgical analgesia in the form of buprenorphine was also administered subcutaneously at a concentration of 0.1 mg/kg. The animals were then transferred to a stereotaxic frame and an incision to expose the skull was carried out. The craniotomy center mark was located at -2.0 mm from bregma and 2.5 mm lateral to the midline, with a 3.5 mm diameter skull region drilled to expose the brain. The skull flap was kept in sterile saline and replaced post contusion. The impact was conducted using a PCI3000 Precision Cortical Impactor™ (Hatteras Instruments, Inc.), with a 3 mm impactor. The injury was conducted at a speed of 3 m/sec and depth of 2.2 mm. Animals in the sham group had only the craniotomy, without the impact step. The reversal agent atipamezole was diluted (0.04 ml in 1 ml water) and administered at 0.05 ml/10 g body weight subcutaneously. Post-surgical palliative care was given to the animals in the form of body temperature control in a 37 ºC incubator until anesthesia had worn off, analgesic (buprenorphine) injected twice a day for 3 days, and warm saline provided for fluid support. Mice (n=6 per group for all groups) received a single intravenous injection of either LPC- DHA, LPC-DHA/EPA, or DHA free fatty acid or corresponding vehicle, at 30 min post- surgery, in a volume of 100 μl, over 30 s. Free fatty acid, DHA, 500 nmol/kg (i.e. 0.164 mg/kg), was used as an active reference dose, as determined in previous study in mice (Journal of Neurotrauma, 2020, 37(1), pp.66-79). All dose equivalence calculations for LPC forms were based on this dose. DHA stock solutions of 3.15 µg in 10 µl ethanol were diluted to the desired concentration in 0.9% saline for injection. LPC forms, e.g. LPC- DHA 3 mg/ml stock solutions in phosphate-buffered saline (PBS), were also diluted to the desired concentration with PBS. All doses are expressed in mg/kg. The vehicle groups were divided into equal numbers of animals receiving saline containing ethanol or PBS (e.g. with n=3 receiving 0.9% saline with ethanol and n=3 receiving PBS, out of a group of 6 animals per group). DHA, LPC-DHA and LPC-DHA/EPA were provided by AKER Biomarine. LPC-DHA and LPC-EPA/DHA-formulations were prepared as described in Example 3. Both was characterized on the day of preparation by pH, osmolality, DLS, and HPLC- CAD. The formulation of LPC-DHA had a pH of 7.20 and an osmolality of 286.0 mOsm/kg. The droplet size was 9.7 ± 0.3 for the LPC-DHA formulation used in the experiment described below. The concentration of LPC-DHA were 3 mg/mL. The formulation of LPC-EPA/DHA had a pH of 7.20 and an osmolality of 283.0 ± 0.6 mOsm/kg. The droplet size was 11.5 ± 0.6 nm in diameter and the formulation had a concentration of 1.94 ± 0.06 mg/mL LPC-EPA and 0.98 ± 0.02 mg/mL LPC-DHA as quantified by HPLC-CAD. The modified Neurological Severity Score (mNSS) assessment was carried out as previously (Journal of Neurotrauma, 2020, 37(1), pp.66-79), and was used in order to assess the impact of injury on the animals’ motor ability, alertness, balance and coordination. The behavioral test was conducted at days 1, 2, 3,7,10 and 14 post surgery. The experimenter was blinded to the identity of the groups. The data were checked for normality and compared with ANOVA followed by post-hoc pairwise comparisons carried out using Dunnett’s test. The experiments were carried out in two blocks. i) In the first experiment, the aim was to test increasing doses of LPC-DHA, in parallel with DHA free fatty acid, in order to compare the efficacy of the two forms and obtain a first indication of an active dose of LPC-DHA. ii) In the second experiment we compared LPC-DHA at the active dose identified previously, with LPC-DHA/EPA, in order to identify whether the use of the latter form would confer an advantage in efficacy. Results of the first experiment As illustrated in the Figure 1A, which is showing all the experimental data (without statistical analysis, for clarity), the induction of a CCI injury
Figure imgf000064_0003
led to a worse neurological outcome than that seen in sham-operated animals
Figure imgf000064_0004
or naive animals
Figure imgf000064_0005
However, it was noticed that in contrast with previously published results in adult mice in this model, the sham-operated animals recovered with some difficulty after surgery and had overall a much slower recovery than expected. –it was also noted that the body weight increase which had occurred in all animals during acclimatization in the animal unit, was much faster than usual; animals became fatter quite rapidly, and their response to anesthesia was much more erratic. The administration of DHA (free fatty acid form) at a dose shown previously to be active, failed to induce a significant improvement in neurological outcome over 14 days. The administration of LPC- DHA at increasing doses indicated an effect at the highest dose tested. For clarity, the data obtained with all doses LPC-DHA, free DHA, and the highest dose of LPC-DHA is shown separately in Figure 1B, 1C and 1D, which also indicate the statistical significance. Therefore, this first set of experiments - although the animals in general responded with a worse neurological outcome especially for the sham operation, and the reference group which received free fatty acid DHA did not improve significantly - clearly indicated that LPC-DHA can lead to an improvement in neurological outcome. Results of the second experiment As illustrated in figure 2, which shows all experimental data from the various groups, the CCI
Figure imgf000064_0001
led to a clear impairment in neurological outcome compared with the outcome seen in animals receiving sham surgery
Figure imgf000064_0002
The outcome seen after the injection of LPC-DHA (active dose identified previously) as compared with various doses of LPC- DHA/EPA, was quite different. LPC-DHA, at the dose identified previously, showed clear efficacy, with a reduced neurological impairment of the animals, compared with the CCI- vehicle group. In contrast, none of the LPC-DHA/EPA doses tested induced any improvement in outcome. Conclusion The data obtained in this first pilot study on the efficacy of various forms of LPC as a carrier into the CNS for DHA and EPA clearly indicate that: a) LPC-DHA injected intravenously at 30 min after injury, induces a marked improvement in neurological outcome; the active dose identified induces an improvement comparable to that reported previously (Journal of Neurotrauma, 202037(1), pp.66-79) with DHA (free fatty acid) at 500 nmol/kg, i.e. an improvement of around 2-3 mNSS units. This was the case in both experiments: the first experiment which explored the dose-response for LPC- DHA, and the second in which LPC-DHA was used as an active comparator for LPC- DHA/EPA. Therefore, this clearly indicates the potential of LPC-DHA as a neuroprotectant via the parenteral route in TBI. The cumulated LPC-DHA data from the two different experiments carried out in this pilot study are shown in Table 8 and illustrated in Figure 6. Figure 6 shows that the neurological score of animals receiving LPC-DHA was not statistically significant from the score of sham animals – therefore the impact of the injury was markedly reduced by treatment. b) in contrast with LPC-DHA, the administration of LPC-DHA/EPA did not lead to any indication of efficacy in this model of brain injury, over the dose range tested. This indicates that for this model it is essential that DHA reaches a higher level than possible with the dose range tested, and that the LPC-EPA component does not enhance the effect of LPC-DHA; it may have at best a neutral effect. Without being bound by theory, this may not be so surprising. It is previously hypothesized that effects of LPC-EPA may be connected to its ability to influence the DHA-level as intracranial EPA is known to elongate to DHA. However, in this study the CCI-model is utilized to test the immediate effects of LPC-DHA as an acute neuroprotectant, accordingly EPA may not have time to be effective. Table 8: The cumulated LPC-DHA data from the two different experiments
Figure imgf000066_0001
Other general comments This pilot study was carried out in two experimental blocks (first- and second experiment respectively), with animals being provided by the same breeder, Charles River UK. The first batch of animals used in the first experiment had a more rapid body weight increase than expected and it was noticeable that the animals were more affected by even the sham surgery procedure. The second batch of animals that were used in the second experiment had the usual body weight increase over time; the differential in outcome between sham animals and CCI animals was as expected in the second study. The unusual slow recovery and also faster body weight increase seen in the first group of animals was traced down to the use of a new diet in the animal unit, which was calorically richer than the rodent diet used previously. The higher body fat percentage made the response to anesthetic more erratic and difficult to control, and the recovery after surgery slower. Despite these differences, the effect of LPC-DHA held true in both experiments. This strongly supports the efficacy of this form of DHA. Another comment concerns the unexpected absence of effect in the group injected with DHA (free fatty acid), which was used for reference of an active dose in the first experiment. DHA free fatty acids are known to be unstable and the recommended storage by Sigma is at -20°C. We hypothesize that perhaps a lack of transport/storage of DHA at low temperature prior to use may have significantly compromised the stability of the fatty acid and that this is the cause of the unexpected apparent loss of efficacy of free fatty acid DHA. Example 7: Formulation of LPC-composition comprising LPC-EPA and LPC-DHA LPC from krill oil (natural source) was chromatographically purified on Silica gel as described in WO 2019123015 A1. 25 g of the purified LPC (purity corresponding to approximately 95% LPC w/w) was mixed with 75g purified water. The mixture was heated to not more than 37C and was gently shaken and blended using a vortex mixer for 5 to 10 minutes. The mixture was filtered through a 1µm filter to give a visually clear solution. The mixture was analyzed by HPLC-MS to verify the content and the integrity of the LPC. The mixture can be stored refrigerated (5ºC) for several weeks without any visual precipitation. The formulation is brought to room temperature before use in biological studies. Conclusion: The ability of the purified LPC composition to dissolve in purified water was surprising and makes for an excellent starting point for further formulations for ophthalmic or nasal use. In contrast, concentrated krill oil phospholipid (PL) compositions needed a mix of PEG400 and ethanol to solubilize and modify viscosity (WO 2016097854).

Claims

CLAIMS 1. A nasal formulation comprising a lysophosphatidylcholine (LPC) composition comprising a LPC-compound of formula 1 or formula 2, or derivates, conjugates or salts thereof, Formula 1 Formula 2
Figure imgf000068_0001
wherein R1 is an acyl or alkyl chain length of at least 14 carbons; R2 is OH or O-CO-(CH2)n-CH3; and n is 0, 1 or 2 and one or more additional components selected from the group consisting of an effective amount of a buffer component, an effective amount of a tonicity component, an effective amount of a preservative component and water.
2. The nasal formulation of claim 1, wherein R1 is DHA, EPA, DPA, SDA or ALA and R2 is OH.
3. The nasal formulation of claim 2, with the proviso that: if the LPC composition comprises i) a compound according to formula 1 and/or formula2, wherein R1 is DHA and R2 is OH; then the LPC composition further comprises at least one of the other LPC- compounds referred to in claim 2.
4. The nasal formulation of claim 3, wherein the compound is: - a compound according to formula 1 and/or formula 2 wherein R1 is DHA; and - a compound according to formula 1 and/or formula 2 wherein R1 is EPA.
5. The nasal formulation of claim 4, wherein - R1 is OH; and - molar ratio of lysoPC-DHA : lysoPC-EPA is in the range 1:1 to 5:1; or molar ratio of lysoPC-EPA : lysoPC-DHA is in the range 1:1 to 5:1; with the proviso that i) the number of moles of lysoPC-EPA is the number of moles 1-lysoPC-EPA + the number of moles 2-lysoPC-EPA; and ii) the number of moles of lysoPC-DHA is the number of moles 1-lysoPC-DHA + the number of moles 2-lysoPC-DHA.
6. The nasal formulation of any one of claims 1 to 5, wherein the LPC composition comprises an amount of total LPC of at least 0.01 % by weight of the nasal formulation.
7. The nasal formulation of any one of claims 1 to 6, wherein the LPC composition comprises an additional lipid different from LPC.
8. The nasal formulation of claim 7, wherein the additional lipid is selected from the group consisting of triglycerides and phospholipids such as phosphatidylethanolamine and phosphatidylcholine.
9. The nasal formulation of claim 8, wherein the LPC composition comprises a predominant amount of the LPC-compound compared to an amount of phosphatidylcholine.
10. The nasal formulation of claim 9, wherein the LPC-compound is selected from LPC-EPA, LPC-DHA and any combination thereof.
11. The nasal formulation of any one of claims 1 to 10, wherein the formulation further comprises a component selected from the group consisting of lutein, astaxanthin, zeaxanthin and any combinations thereof.
12. The nasal formulation of any one of claims 1 to 11, wherein the formulation is provided as a nasal spray.
13. The nasal formulation of claim 12, wherein the nasal spray formulation is provided in a nozzle spray device.
14. The nasal formulation of any one of claims 1 to 11, wherein the formulation is provided as a nasal drop.
15. The nasal formulation of claim 12, wherein the nasal spray formulation is provided in a nasal drop device.
16. The nasal formulation of any one of claims 1 to 15, wherein the formulation is provided in an amount effective to treat, prevent and/or relief one or more symptoms and/or signs of a 1) disease or condition of the eye, 2) a metabolic disorder or disease, 3) a disease or condition of the heart or circulatory system, 4) a cognitive disorder or disease, 5) a neurodegenerative disorder or disease, 6) an injury, disease or disorder of the brain, or 7) an inflammatory disease or condition.
17. The nasal formulation of any one of claims 1 to 16 for use in in treating, preventing and/or relieving one or more symptoms and/or signs of a disease selected from the group consisting of a 1) disease or condition of the eye, 2) a metabolic disorder or disease, 3) a disease or condition of the heart or circulatory system, 4) a cognitive disorder or disease, 5) a neurodegenerative disorder or disease, 6) an injury, disease or disorder of the brain, or 7) an inflammatory disease or condition.
18. The nasal formulation of claim 17, wherein the injury, disease, or disorder of the brain is selected from the group consisting of traumatic brain injury, concussion, chronic traumatic encephalopathy, and combinations thereof.
19. The nasal formulation of claim 17, wherein the metabolic disorder or disease is selected from the group consisting of dyslipidemia, hypertriglyceridemia, hypertension, low HDL levels, high LDL levels, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, chronic kidney disease, omega-3 deficiency, phospholipid deficiency, diabetic nephropathy, non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) and diabetic autonomic neuropathy.
20. The nasal formulation of claim 17, wherein the disease or condition of the heart or circulatory system is selected from the group consisting of atherosclerosis, arteriosclerosis, coronary heart disease, carotid artery disease, acute coronary syndrome, valvular heart disease, aortic and mitral valve disorders, arrhythmia/atrial fibrillation, cardiomyopathy and heart failure, angina pectoris, acute myocardial infarction, hypertension, embolism (pulmonary and venous), endocarditis, peripheral arterial disease, Kawasaki disease, congenital heart disease, stroke, heart failure, cardiac arrhythmias, endocarditis, arterial occlusive diseases, cerebral atherosclerosis, cerebrovascular disorders, myocardial ischemia, and coagulopathies leading to thrombus formation in a vessel.
21. The nasal formulation of claim 17, wherein the cognitive disorder or disease is selected from the group consisting of Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), autism/autism spectrum disorder (ASD), dyslexia, age- associated memory impairment and learning disorders, amnesia, mild cognitive impairment, and age-related cognitive decline.
22. The nasal formulation of claim 17, wherein the neurodegenerative disease or condition is selected from the group consisting of pre-Alzheimer's disease, Alzheimer's disease, epilepsy, Pick's disease, Huntington's disease, Parkinson disease, Lou Gehrig's disease, pre-dementia syndrome, Lewy body dementia, dentatorubropallidoluysian atrophy, Freidreich's ataxia, multiple system atrophy, spinocerebellar ataxia, amyotrophic lateral sclerosis, familial spastic paraparesis, spinal muscular atrophy, spinal and bulbar muscular atrophy, and AIDS-related neurodegeneration.
23. The nasal formulation of claim 17, wherein the inflammatory disease or condition is selected from the group consisting of organ transplant rejection, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease (CD), asthma, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD, gingivitis, glomerulonephritis, nephrosis, sclerodermatitis, psoriasis, eczema; chronic demyelinating diseases, and multiple sclerosis.
24. The nasal formulation of claim 17, wherein the disease or condition of the eye is a dry eye caused by a factor the group consisting of inflammation of the eye, corneal nerve abnormalities and abrasions on the surface of the eye.
25. The nasal formulation of claim 17, wherein the disease or condition of the eye is a neurodegenerative disease of the eye.
26. The nasal formulation for use of claim 25, wherein the neurodegenerative disease of the eye is selected from the group consisting of age-related macular degeneration, diabetic retinopathy, non-proliferative retinopathy, proliferative retinopathy, diabetic macular edema, retinitis pigmentosa, central vein occlusion and glaucoma.
27. An ophthalmic formulation comprising a lysophosphatidylcholine (LPC) composition comprising a LPC-compound of formula 1 or formula 2, or derivates, conjugates or salts thereof, Formula 1 Formula 2
Figure imgf000072_0001
wherein R1 is an acyl or alkyl chain length of at least 14 carbons; R2 is OH or O-CO-(CH2)n-CH3; and n is 0, 1 or 2 and one or more additional components selected from the group consisting of an effective amount of a buffer component, an effective amount of a tonicity component, an effective amount of a preservative component and water.
28. The ophthalmic formulation of claim 27, wherein R1 is DHA, EPA, DPA, SDA or ALA and R2 is OH.
29. The ophthalmic formulation of claim 28, with the proviso that: if the LPC composition comprises i) a compound according to formula 1 and/or formula2, wherein R1 is DHA and R2 is OH; then the LPC composition further comprises at least one of the other LPC-compounds referred to in claim 2.
30. The ophthalmic formulation of claim 29, wherein the compound is: - a compound according to formula 1 and/or formula 2 wherein R1 is DHA; and - a compound according to formula 1 and/or formula 2 wherein R1 is EPA.
31. The ophthalmic formulation of claim 30, wherein - R1 is OH; and - molar ratio of lysoPC-DHA : lysoPC-EPA is in the range 1:1 to 5:1; or molar ratio of lysoPC-EPA : lysoPC-DHA is in the range 1:1 to 5:1; with the proviso that i) the number of moles of lysoPC-EPA is the number of moles 1-lysoPC-EPA + the number of moles 2-lysoPC-EPA; and ii) the number of moles of lysoPC-DHA is the number of moles 1-lysoPC-DHA + the number of moles 2-lysoPC-DHA.
32. The ophthalmic formulation of any one of claims 27 to 31, wherein the LPC composition comprises an amount of total LPC of at least 1 % by weight of the nasal formulation.
33. The ophthalmic formulation of any one of claims 27 to 32, wherein the formulation is provided in an amount effective to treat, prevent and/or relief one or more symptoms and/or signs of a disease or condition of the eye.
34. The ophthalmic formulation of any one of claims 27 to 33, wherein the LPC composition comprises an additional lipid different from LPC and/or a free fatty acid.
35. The ophthalmic formulation of claim 34 wherein the additional lipid is selected from the group consisting of triglycerides and phospholipids such as phosphatidylethanolamine and phosphatidylcholine.
36. The ophthalmic formulation of claim 35, wherein the LPC composition comprises a predominant amount of the LPC-compound compared to an amount of phosphatidylcholine.
37. The ophthalmic formulation of claim 36, wherein the LPC-compound is selected from LPC-EPA, LPC-DHA and any combination thereof.
38. The ophthalmic formulation of any one of claims 27 to 37, wherein the formulation further comprises a component selected from the group consisting of lutein, astaxanthin, zeaxanthin and any combinations thereof.
39. The ophthalmic formulation of any one of claims 27 to 38, wherein the formulation is an eye drop formulation.
40. The ophthalmic formulation of claim 39, wherein the eye drop formulation is provided in an eye drop device.
41. The ophthalmic formulation of any one of claims 27 to 40 for use in treating, preventing and/or relieving one or more symptoms and/or signs of a disease or condition of the eye.
42. The ophthalmic formulation for use of claim 41, wherein the disease or condition of the eye is dry eye, such as dry eye disease selected from the group consisting of inflammation of the eye, corneal nerve abnormalities and abrasions on the surface of the eye.
43. The ophthalmic formulation for use of claim 41, wherein the disease or condition of the eye is a neurodegenerative disease of the eye.
44. The ophthalmic formulation for use of claim 43, wherein the neurodegenerative disease of the eye is selected from the group consisting of age-related macular degeneration, diabetic retinopathy, non-proliferative retinopathy, proliferative retinopathy, diabetic macular edema, retinitis pigmentosa, central vein occlusion and glaucoma.
45. A parenteral formulation comprising a lysophosphatidylcholine (LPC) composition comprising a LPC-compound of formula 1 or formula 2, or derivates, conjugates or salts thereof, Formula 1 Formula 2
Figure imgf000075_0001
wherein R1 is an acyl or alkyl chain length of at least 14 carbons; R2 is OH or O-CO-(CH2)n-CH3; and n is 0, 1 or 2 for use in treating an injury, disease, or disorder of the brain selected from the group consisting of traumatic brain injury, concussion, chronic traumatic encephalopathy, and combinations thereof.
46. The parenteral formulation of claim 45, wherein R1 is DHA, EPA, DPA, SDA or ALA and R2 is OH.
47. The parenteral formulation of claim 46, with the proviso that: if the LPC composition comprises i) a compound according to formula 1 and/or formula2, wherein R1 is DHA and R2 is OH; then the LPC composition further comprises at least one of the other LPC-compounds referred to in claim 2.
48. The parenteral formulation of claim 47, wherein the compound is: - a compound according to formula 1 and/or formula 2 wherein R1 is DHA; and - a compound according to formula 1 and/or formula 2 wherein R1 is EPA.
49. The parenteral formulation of claim 48, wherein - R1 is OH; and - molar ratio of lysoPC-DHA : lysoPC-EPA is in the range 1:1 to 5:1; or molar ratio of lysoPC-EPA : lysoPC-DHA is in the range 1:1 to 5:1; with the proviso that i) the number of moles of lysoPC-EPA is the number of moles 1-lysoPC-EPA + the number of moles 2-lysoPC-EPA; and ii) the number of moles of lysoPC-DHA is the number of moles 1-lysoPC-DHA + the number of moles 2-lysoPC-DHA.
50. The parenteral formulation of any one of claims 45 to 49, wherein the LPC composition comprises an amount of total LPC of at least 1 % by weight of the nasal formulation.
51. The parenteral formulation for use of any one of claims 45 to 50, wherein the LPC composition comprises an additional lipid different from LPC and/or a free fatty acid.
52. The parenteral formulation for use of claim 51, wherein the additional lipid is selected from the group consisting of triglycerides and phospholipids such as phosphatidylethanolamine and phosphatidylcholine.
53. The parenteral formulation for use of claim 52, wherein the LPC composition comprises a predominant amount of the LPC-compound compared to an amount of phosphatidylcholine.
54. The parenteral formulation for use of claim 53, wherein the LPC-compound is selected from LPC-EPA, LPC-DHA and any combination thereof.
55. The parenteral formulation for use of any one of claims 45 to 54, wherein the parenteral formulation is an intravascular formulation.
56. The parenteral formulation for use of any one of claims 45 to 55, wherein the injury, disease, or disorder of the brain is traumatic brain injury.
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