Parenteral lysophosphatidylcholine preparation such as LPC-DHA and LPC-epa, and their use in therapy

Abstract

To provide means for increasing an LPC-DHA level in blood serum, and also for securing a high level in blood plasma for a long period.SOLUTION: The present invention relates to pharmaceutical formulations of phospholipids, and in particular pharmaceutical formulations which are administered intravascularly such as intravenously. In particular, the present invention provides pharmaceutical compositions for intravascular administration comprising phosphatidylcholine derived compounds carrying an omega-3 fatty acid for use in prophylaxis or therapy.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a pharmaceutical preparation of phospholipids, particularly a pharmaceutical preparation administered into blood vessels such as intravenously. In particular, the present invention provides a pharmaceutical composition for intravascular administration comprising a compound derived from phosphatidylcholine carrying omega-3 fatty acids for use in prevention or treatment.

Background Art

[0002] Docosahexaenoic acid (DHA), an essential omega-3 fatty acid, is uniquely concentrated in the brain, nerve tissue, and retina and is essential for normal neurological development and function. Deficiency of DHA is associated with several neurological disorders including Alzheimer's disease, Parkinson's disease, schizophrenia, and depression.

[0003] Unlike the liver, the brain cannot efficiently convert dietary alpha-linolenic acid (18:3, n-3) to DHA and is almost completely dependent on the uptake of pre-formed DHA from plasma. However, dietary supplementation with currently available DHA preparations such as fish oil, algal DHA, DHA-enriched egg phospholipids, and sardines enriches peripheral tissues with DHA under the same conditions in adult mammals, but brain DHA levels do not significantly increase.

[0004] One possible explanation for this is that DHA from the above dietary supplements is hydrolyzed to free DHA by pancreatic enzymes and absorbed into chylomicrons as triacylglycerol (TAG), whereas the brain uniquely takes up DHA in the form of lysophosphatidylcholine (LPC). This mechanism is further supported by the recent demonstration of a transporter (Mfsd2a) at the blood-brain barrier that specifically transports LPC-DHA but not free DHA (Nature. 2014 May 22;509(7501):503-6.). Therefore, the hypothesis has been proposed that it is necessary to increase the plasma LPC-DHA level in order to efficiently enrich brain DHA.

[0005] In order to increase the LPC-DHA levels in plasma, it has been proposed in recent years that dietary DHA provided at the sn-1 position of phosphatidylcholine (PC) or in the form of LPC in the diet can escape hydrolysis by pancreatic PLA2 and be absorbed as PC-DHA. Furthermore, a hypothesis has been put forward that PC-DHA is more likely to be taken up by the brain after being converted to LPC-DHA in plasma or liver by phospholipase, compared to TAG-DHA which requires extensive metabolic conversion in the liver to form LPC-DHA.

[0006] In a prior art search, the above hypothesis that providing DHA in the form of LPC can actually increase the amount of DHA absorbed in the form of phospholipids by up to 5-fold compared to free DHA was confirmed. It was also found that the uptake of DHA into intestinal-derived HDL increased 2-fold during the absorption of LPC-DHA compared to the absorption of free DHA.

[0007] In the above study, it was also tested whether the increased absorption of phospholipid-type DHA not only raises brain DHA levels but also improves cognition and memory in normal adult mice. After daily forced administration of the compound in corn oil solvent for 30 days, the uptake of dietary free DHA and LPC-DHA into the brain and other tissues was compared. The results showed that the DHA content in most regions of the brain more than doubled by giving LPC-DHA, but when giving free DHA, although other tissues were enriched, it did not exceed twice in the brain. Furthermore, mice treated with LPC-DHA also showed a significant enhancement of spatial learning and memory in the Morris water maze test. These studies were the first to show a targeted enrichment of brain DHA by diet that results in a functional improvement of memory in normal adult mice. The question is whether this treatment strategy may also have the potential to prevent and treat other neurological disorders associated with low brain DHA levels or that can benefit from increased brain DHA levels.

[0008] Traumatic brain injury (TBI) is a neurological disorder that is a leading cause of death and permanent physical disability in people under 45 years old who can benefit from increased brain DHA levels. This injury often occurs in military personnel and professional athletes, leading to loss of limb function, speech impairment, memory impairment, and emotional reactions. It is a multifaceted disorder associated with excitotoxicity, oxidative stress, long-term secondary pathological formation of inflammation, and persistent harmful neurological sequelae such as secondary epilepsy, chronic headache, post-traumatic stress disorder, neurocognitive deficits, as well as neurodegenerative diseases such as Alzheimer's disease or Parkinsonism. Current TBI treatments focus on intracranial pressure management, prevention and treatment of hypotension, and appropriate ventilation, but no specific medical treatments for neuroprotection and recovery are particularly provided.

[0009] Recent animal experiments have shown that functional outcomes are improved by supplementing DHA from the diet either before or after TBI (Brain Injury. ASN Neuro 7,1-15,2015). Mechanistic studies suggest that DHA affects multiple aspects of the pathological molecular signaling cascade, such as reduction of neuroinflammation and oxidative stress, supplementation of neurotrophin, and activation of cell survival pathways. An increase in plasma levels of DHA was observed on the first day but decreased 3 days after injury (J Neurosci.30,3220-3226,2010).

[0010] Considering the above, it is clear that there are many different conditions, particularly neurological conditions (especially TBI) that can benefit from increased brain DHA levels. Furthermore, the hypothesis has already been established that an increase in plasma levels of LPC-DHA is a prerequisite for efficient enrichment of brain DHA levels.

[0011] Therefore, in this technical field, there is a need for means to increase the level of LPC-DHA in serum.

[0012] LPC is only found in trace amounts in most animal tissues because it is known to promote cell membrane disruption at relatively high concentrations. To reduce the effective concentration in plasma to a safe level, LPC molecules generally bind to albumin and lipoproteins in serum.

[0013] Therefore, in order to avoid cell membrane disruption and other potential side effects, any increase in plasma LPC-DHA levels should preferably be maintained at a safe level.

[0014] Furthermore, it has already been suggested that dietary DHA provided at the sn-1 position of phosphatidylcholine (PC) or in the form of dietary LPC may be an effective way to increase serum LPC-DHA levels. However, in the case of neurological conditions such as TBI, the time from ingestion of dietary DHA to an increase in serum LPC-DHA levels may be of utmost importance.

[0015] Therefore, in the art, there is an urgent need for means to rapidly increase the level of LPC-DHA in plasma.

[0016] Another issue to consider is the need for a continuous supply of DHA to the brain. It is well known that administered drugs are usually removed from circulation by various excretion processes, and such processes for excreting LPC-DHA can of course be potential problems to be solved.

[0017] Therefore, in the art, there is a need for means to increase the level of LPC-DHA in serum and ensure high levels in plasma over the long term.

[0018] Means for solving most or all of the above problems may be preventive and / or therapeutic agents for many different conditions that can benefit from an increase in DHA levels in the brain. Examples of such conditions are neurological conditions such as depression, schizophrenia, Alzheimer's disease, Parkinson's disease, or traumatic brain injury. A non-limiting list of other conditions that can benefit from an increase in DHA levels in the brain is post-traumatic stress disorder (PTSD) and anxiety.

[0019] The above considerations focus on DHA levels in the brain. However, those skilled in the art will recognize other omega-3 fatty acids that are similarly assumed to be directly or indirectly important for normal neurological development and function of the brain. This is in the sense that they can be converted into omega-3 fatty acids that are important for normal neurological development and function. A non-limiting list of such omega-3 fatty acids that are thought to affect neurological development and function of the brain is docosapentaenoic acid (n3-DPA), stearidonic acid (SDA), and eicosapentaenoic acid (EPA). Alpha-linolenic acid (ALA) is another omega-3 fatty acid that can affect neurological development and function of the brain. Thus, the advantages of increasing LPC-DHA levels in serum are similarly relevant for LPC-DPA, LPC-SDA, LPC-EPA, and LPC-ALA, and particularly for LPC-DPA, LPC-SDA, and LPC-EPA.

[0020] Furthermore, there has been some discussion in the art as to whether the uptake of omega-3 fatty acids into the brain may be affected by the location of the omega-3 fatty acid in the LPC molecule (i.e., whether the omega-3 fatty acid is in the sn1 position (2-LPC) or the sn2 position (1-LPC) of the LPC molecule). However, those skilled in the art will recognize that there is an equilibrium between these two LPC forms, and that an equilibrium mixture of 90% 2-lysoPC and 10% 1-lysoPC is typically obtained with a half-life of about 10 minutes under physiological conditions.

Chemical formula

[0021] When it is of interest to have a ratio of 1-LPC and 2-LPC different from the normal equilibrium state under physiological conditions, or to have a composition containing only LPC-1 or LPC-2, there are developed compounds that block the translocation of acyl groups from the sn-1 position to the sn-2 position (and vice versa) of the glycerol backbone. This is achieved by reacting the OH group of the glycerol backbone with a protecting group such as O-CO-CH 3 etc. (WO2018162617, WO2008068413). SUMMARY OF THE INVENTION

[0022] The present inventors have addressed the above-mentioned need by providing a pharmaceutical composition for intravascular administration containing compounds derived from phosphatidylcholine carrying omega-3 fatty acids. The pharmaceutical composition is designed for intravascular administration such as intravenous administration, and surprisingly, it has been shown to significantly increase the uptake of omega-3 fatty acids into the brain at high speed and over a long period.

[0023] Accordingly, a first aspect of the present invention relates to a pharmaceutical composition suitable for intravascular administration such as intravenous administration, the pharmaceutical composition comprising one or more active ingredients and one or more pharmaceutically acceptable excipients, wherein the one or more active ingredients are selected from the group consisting of a compound according to any one of formulas 1 to 8, or a pharmaceutically acceptable salt thereof, and any combination thereof,

Chemical formula

[0024] In one embodiment according to the present invention, the intravascular administration is intravenous administration. The intravenous administration can be performed by injection (e.g., using a syringe at high pressure) or infusion (e.g., using only the pressure exerted by gravity). In one embodiment, the intravenous administration is performed by one or more injections, preferably less than 5 injections, more preferably less than 3 injections, and most preferably 2 or 1 injection.

[0025] A preferred embodiment according to the first aspect of the present invention relates to a pharmaceutical composition suitable for intravascular administration such as intravenous administration, and the pharmaceutical composition comprises i) LPC-EPA or a pharmaceutically acceptable salt thereof, and ii) LPC-DHA or a pharmaceutically acceptable salt thereof. Preferably, LPC-EPA and LPC-DHA constitute 10 to 99% by dry weight or weight of the pharmaceutical composition, for example, 15 to 99% by dry weight or weight of the pharmaceutical composition, 20 to 99% by dry weight or weight of the pharmaceutical composition, 25 to 99% by dry weight or weight of the pharmaceutical composition (e.g., 27% by dry weight or weight), 35 to 99% by dry weight or weight of the pharmaceutical composition, 55 to 99% by dry weight or weight of the pharmaceutical composition, 75 to 99% by dry weight or weight of the pharmaceutical composition, and most preferably 80 to 99% by dry weight or weight of the pharmaceutical composition, for example, 85 to 95% by dry weight or weight (e.g., about 89% by dry weight or weight).

[0026] In another embodiment, the intravenous administration can be performed by infusion such as long-term infusion. In a preferred embodiment, the long-term period is more than 6 hours, for example, more than 12 hours, more than 24 hours, or 48 hours or more.

[0027] In one embodiment, one or more active ingredients are compounds according to formula 1 (wherein R 2 is OH or O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2).

[0028] In another embodiment according to the present invention, one or more active ingredients are compounds of formula 2 (wherein R 2 is OH or O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2).

[0029] In another embodiment according to the present invention, one or more active ingredients are compounds of formula 3 (wherein R 1 is OH or O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2).

[0030] In yet another embodiment according to the present invention, one or more active ingredients are compounds of formula 4 (wherein R 1 is OH or O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2).

[0031] In yet another embodiment according to the present invention, one or more active ingredients are compounds of formula 5 (wherein R 2 is OH or O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2).

[0032] In yet another embodiment according to the present invention, one or more active ingredients are compounds of formula 6 (wherein R 2 is OH or O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2).

[0033] In yet another embodiment according to the present invention, one or more active ingredients are compounds of formula 7 (wherein R 1 is OH or O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2).

[0034] In yet another further embodiment according to the present invention, one or more active ingredients are compounds according to formula 8, wherein R 1 is OH or O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2).

[0035] In yet another further embodiment according to the present invention, one or more active ingredients are combinations of two or more of the above-mentioned active ingredients.

[0036] In yet another further embodiment according to the present invention, one or more active ingredients are combinations of three, four, or five or more of the above-mentioned active ingredients.

[0037] One embodiment according to the first aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention, provided that when this pharmaceutical composition contains i) a compound according to formula 1, wherein R 2 is OH) or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 3, wherein R 1 is OH) or a pharmaceutically acceptable salt thereof, this pharmaceutical composition further contains at least one of the other active ingredients mentioned in the first aspect of the present invention.

[0038] The above expression "at least one of the other active ingredients" means i) a compound according to formula 1, wherein R 2 is OH) or a pharmaceutically acceptable salt thereof, and is different from ii) a compound according to formula 3, wherein R 1 is OH) or a pharmaceutically acceptable salt thereof, and refers to at least one active ingredient different therefrom.

[0039] In yet another embodiment according to the present invention, one or more active ingredients are: i) a compound according to formula 1, or a pharmaceutically acceptable salt thereof; ii) a compound according to formula 2, or a pharmaceutically acceptable salt thereof; iii) a compound according to formula 3, or a pharmaceutically acceptable salt thereof; and iv) a compound according to formula 4, or a pharmaceutically acceptable salt thereof.

[0040] In yet another embodiment according to the present invention, one or more active ingredients are: i) a compound according to formula 5, or a pharmaceutically acceptable salt thereof; ii) a compound according to formula 6, or a pharmaceutically acceptable salt thereof; iii) a compound according to formula 7, or a pharmaceutically acceptable salt thereof; and iv) a compound according to formula 8, or a pharmaceutically acceptable salt thereof.

[0041] In yet another embodiment according to the present invention, one or more active ingredients are as follows: - a compound according to formula 1, or a pharmaceutically acceptable salt thereof, or a compound according to formula 3, or a pharmaceutically acceptable salt thereof, and, - a compound according to formula 2, or a pharmaceutically acceptable salt thereof, or a compound according to formula 4, or a pharmaceutically acceptable salt thereof.

[0042] In another embodiment according to the present invention, one or more active ingredients are: i) a compound according to formula 1, or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 3, or a pharmaceutically acceptable salt thereof.

[0043] In another embodiment according to the present invention, one or more active ingredients are: i) a compound according to formula 2, or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 4, or a pharmaceutically acceptable salt thereof.

[0044] In another embodiment according to the present invention, - R 1 and R 2 are OH, - One or more active ingredients are i) a compound according to formula 2, or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 4, or a pharmaceutically acceptable salt thereof.

[0045] In another embodiment according to the present invention, - R 1 and R 2 are O-CO-(CH 2 ) n - CH 3 wherein, - n is 0, 1 or 2, preferably 0, - One or more active ingredients are i) a compound according to formula 2, or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 4, or a pharmaceutically acceptable salt thereof.

[0046] In another embodiment according to the present invention, - R 1 and R 2 are OH, - One or more active ingredients are i) a compound according to formula 5, or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 7, or a pharmaceutically acceptable salt thereof.

[0047] In another embodiment according to the present invention, - R 1 and R 2 are O-CO-(CH 2 ) n - CH 3 wherein, - n is 0, 1 or 2, preferably 0, - One or more active ingredients are i) a compound according to formula 5, or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 7, or a pharmaceutically acceptable salt thereof.

[0048] In another embodiment according to the present invention, - R 1 and R 2 are OH, - The one or more active ingredients are i) a compound according to formula 6, or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 8, or a pharmaceutically acceptable salt thereof.

[0049] In another embodiment according to the present invention, -R 1 and R 2 is O-CO-(CH 2 ) n -CH 3 and -n is 0, 1 or 2, preferably 0, - The one or more active ingredients are i) a compound according to formula 6, or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 8, or a pharmaceutically acceptable salt thereof.

[0050] In yet another embodiment according to the present invention, the one or more pharmaceutically acceptable excipients are selected from the group consisting of vegetable oils, triolein, soybean oil, safflower oil, sesame oil, castor oil, coconut oil, triglycerides, tributyrin, tricaprylin, tricaprin, vitamin E, antioxidants, α-tocopherol, ascorbic acid, deferoxamine mesylate, thioglycolic acid, emulsifiers, lecithin, polysorbate 80, methylcellulose, gelatin, serum albumin, sorbitan laurate, sorbitan oleate, sorbitan trioleate, polyethylene glycol (PEG), PEG400, polyethylene glycol-modified phosphatidylethanolamine (PEG-PE), poloxamer, glycerin, sorbitol, xylitol, pH adjusters; sodium hydroxide, antibacterial agents EDTA, sodium benzoate, benzyl alcohol, and proteins such as albumin.

[0051] In a preferred embodiment, the one or more pharmaceutically acceptable excipients include: i) one or more components suitable for dissolving one or more active ingredients, and ii) one or more components having emulsifying properties. Further, it is also preferred that the one or more pharmaceutically acceptable excipients include one or more antioxidants such as α-tocopherol, ascorbic acid, deferoxamine mesylate, thioglycolic acid, etc. Further, it is also preferred that the one or more pharmaceutically acceptable excipients include components for adjusting the tonicity to a physiological state such as glycerin, sorbitol, xylitol, etc. Further, it is also preferred that the one or more pharmaceutically acceptable excipients include a pH adjuster such as sodium hydroxide. Further, it is also preferred that the one or more pharmaceutically acceptable excipients include one or more antibacterial agents such as EDTA, sodium benzoate, benzyl alcohol, etc.

[0052] In a preferred embodiment, the one or more pharmaceutically acceptable excipients are phospholipid-stabilized oils such as phospholipid-stabilized soybean oil, particularly the Intralipid emulsion mentioned in Example 1.

[0053] Commercially available products for providing an injectable pharmaceutical composition containing lipids are known to those skilled in the art and include products such as Miglyol 810, 812, Neobee M5, Captex 300, MONTANE™ 20 PPI, MONTANE™ 80 PPI, Pluronic F68, pre-formed emulsions (Lipofundin or Intralipid (Intralipid was used in Example 2)) and others.

[0054] In yet another further embodiment according to the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, particularly a lipid carrier such as liposomes (including mixtures thereof).

[0055] In one embodiment according to the present invention, the composition has a pH in the range of 5.5 to 8.5, for example, a pH in the range of 6 to 8, more preferably a pH in the range of 6.5 to 8, and most preferably, the composition has a pH similar to that which is normal and common in the human body, such as a pH in the range of 7.3 to 7.5.

[0056] In one embodiment according to the present invention, R 1 is OH. In another embodiment according to the present invention, R 2 is OH. In yet another embodiment according to the present invention, R 1 and R 2 are both OH.

[0057] In another embodiment according to the present invention, R 1 is OH, and / or R 2 is OH. Preferably, both R 1 and R 2 are OH.

[0058] In another embodiment according to the present invention, R 1 is O-CO-CH 3 and / or R 2 is O-CO-CH 3 Preferably, both R 1 and R 2 are O-CO-CH 3

[0059] In another embodiment according to the present invention, R 1 is O-CO-(CH 2 ) n -CH 3 and / or R 2 is O-CO-(CH 2 ) n -CH 3 Preferably, both R 1 and R 2 are O-CO-(CH 2 ) n -CH 3 n is 0, 1 or 2, more preferably, n is 0 or 1, and most preferably, n is 0.

[0060] In yet another embodiment according to the first aspect of the present invention, n is 0 or 1, and most preferably, n is 0.

[0061] In another embodiment according to the present invention, one or more active ingredients constitute 0.1 to 100 dry weight % or weight % of the pharmaceutical composition, for example, 0.5 to 100 dry weight % or weight % of the pharmaceutical composition, or 1 to 100 dry weight % or weight % of the pharmaceutical composition.

[0062] In another embodiment according to the present invention, one or more active ingredients constitute 0.1 to 80 dry weight % or weight % of the pharmaceutical composition, for example, 0.5 to 60 dry weight % or weight % of the pharmaceutical composition, or 1 to 40 dry weight % or weight % of the pharmaceutical composition.

[0063] In another embodiment according to the present invention, one or more active ingredients constitute 0.1 to 20 dry weight % or weight % of the pharmaceutical composition, for example, 0.5 to 10 dry weight % or weight % of the pharmaceutical composition, or 1 to 5 dry weight % or weight % of the pharmaceutical composition.

[0064] In another embodiment according to the present invention, one or more active ingredients constitute 0.1 to 5 dry weight % or weight % of the pharmaceutical composition, for example, 0.5 to 5 dry weight % or weight % of the pharmaceutical composition, or 1 to 3 dry weight % or weight % of the pharmaceutical composition.

[0065] In another embodiment according to the present invention, one or more active ingredients constitute 0.1 to 3 dry weight % or weight % of the pharmaceutical composition, for example, 0.5 to 3 dry weight % or weight % of the pharmaceutical composition, or 1 to 2 dry weight % or weight % of the pharmaceutical composition.

[0066] In another embodiment according to the present invention, one or more active ingredients constitute 0.1 to 2 dry weight % or weight % of the pharmaceutical composition, for example, 0.1 to 1 dry weight % or weight % of the pharmaceutical composition, or 0.1 to 0.8 dry weight % or weight % of the pharmaceutical composition.

[0067] In a preferred embodiment according to the present invention, one or more active ingredients constitute 10 to 99 dry weight % or weight % of the pharmaceutical composition, for example, 15 to 99 dry weight % or weight % of the pharmaceutical composition, 20 to 99 dry weight % or weight % of the pharmaceutical composition, 25 to 99 dry weight % or weight % (e.g., 27 dry weight % or weight %) of the pharmaceutical composition, 35 to 99 dry weight % or weight % of the pharmaceutical composition, 55 to 99 dry weight % or weight % of the pharmaceutical composition, 75 to 99 dry weight % or weight % of the pharmaceutical composition, most preferably 80 to 99% dry weight % or weight % of the pharmaceutical composition, for example, 85 to 95 dry weight % or weight % (e.g., about 89 dry weight % or weight %).

[0068] In yet another further embodiment according to the present invention, the molar ratio of lysophosphatidylcholine-DHA:lysophosphatidylcholine-EPA is in the range of 1:1 to 10:1, for example, in the range of 1:1 to 7:1, or in the range of 1:1 to 5:1, or in the range of 1:1 to 3:1, or the molar ratio of lysophosphatidylcholine-EPA:lysophosphatidylcholine-DHA is in the range of 1:1 to 10:1, for example, in the range of 1:1 to 7:1, or in the range of 1:1 to 5:1, or in the range of 1:1 to 3:1 (provided that i) the number of moles of lysophosphatidylcholine-EPA is the number of moles of 1-lysophosphatidylcholine-EPA + the number of moles of 2-lysophosphatidylcholine-EPA, and ii) the number of moles of lysophosphatidylcholine-DHA is the number of moles of 1-lysophosphatidylcholine-DHA + the number of moles of 2-lysophosphatidylcholine-DHA).

[0069] In yet another further embodiment according to the present invention, -R 1 and R 2 is OH, -Lysophosphatidylcholine (LPC)-DHA: The molar ratio of LPC-EPA to LPC-DHA is within the range of 1:1 to 10:1, for example within the range of 1:1 to 7:1, or within the range of 1:1 to 5:1, or within the range of 1:1 to 3:1, or the molar ratio of LPC-EPA to LPC-DHA is within the range of 1:1 to 10:1, for example, within the range of 1:1 to 7:1, or within the range of 1:1 to 5:1, or within the range of 1:1 to 3:1 (provided that i) the number of moles of LPC-EPA is the number of moles of 1-LPC-EPA + the number of moles of 2-LPC-EPA, and ii) the number of moles of LPC-DHA is the number of moles of 1-LPC-DHA + the number of moles of 2-LPC-DHA).

[0070] In yet another further embodiment according to the present invention, the molar ratio of 2-LPC-EPA / DHA to 1-LPC-EPA / DHA is within the range of 1:8 to 18:1, for example within the range of 1:8 to 15:1, or within the range of 1:8 to 10:1 (provided that i) the number of moles of 2-LPC-EPA / DHA is the number of moles of 2-LPC-EPA + the number of moles of 2-LPC-DHA, and ii) the number of moles of 1-LPC-EPA / DHA is the number of moles of 1-LPC-EPA + the number of moles of 1-LPC-DHA).

[0071] In yet another further embodiment according to the present invention, -R 1 and R 2 is OH, -The molar ratio of 2-LPC-EPA / DHA to 1-LPC-EPA / DHA is within the range of 1:8 to 18:1, for example within the range of 1:8 to 15:1, or within the range of 1:8 to 10:1 (provided that i) the number of moles of 2-LPC-EPA / DHA is the number of moles of 2-LPC-EPA + the number of moles of 2-LPC-DHA, and ii) the number of moles of 1-LPC-EPA / DHA is the number of moles of 1-LPC-EPA + the number of moles of 1-LPC-DHA).

[0072] In one embodiment according to the present invention, the pharmaceutical composition comprises a compound of general formula 9 that is less than 10% by dry weight or % by weight of the pharmaceutical composition, for example, less than 5% by dry weight or % by weight of the pharmaceutical composition, less than 1% by dry weight or % by weight of the pharmaceutical composition, less than 0.5% by dry weight or % by weight of the pharmaceutical composition, less than 0.1% by dry weight or % by weight of the pharmaceutical composition, less than 0.01% by dry weight or % by weight of the pharmaceutical composition, or less than 0.001% by dry weight or % by weight of the pharmaceutical composition, wherein R 1 is OH and R 3 is O-CO-(CH 2 ) 12 ).

[0073] In one embodiment according to the present invention, the pharmaceutical composition comprises a compound of general formula 9 that is less than 10% by dry weight or % by weight of the pharmaceutical composition, for example, less than 5% by dry weight or % by weight of the pharmaceutical composition, less than 1% by dry weight or % by weight of the pharmaceutical composition, less than 0.5% by dry weight or % by weight of the pharmaceutical composition, less than 0.1% by dry weight or % by weight of the pharmaceutical composition, less than 0.01% by dry weight or % by weight of the pharmaceutical composition, or less than 0.001% by dry weight or % by weight of the pharmaceutical composition, wherein R 1 is OH and R 3 is O-CO-(CH 2 ) 14 ).

[0074] In one embodiment according to the present invention, the pharmaceutical composition comprises a compound of general formula 9 that is less than 10% by dry weight or % by weight of the pharmaceutical composition, for example, less than 5% by dry weight or % by weight of the pharmaceutical composition, less than 1% by dry weight or % by weight of the pharmaceutical composition, less than 0.5% by dry weight or % by weight of the pharmaceutical composition, less than 0.1% by dry weight or % by weight of the pharmaceutical composition, less than 0.01% by dry weight or % by weight of the pharmaceutical composition, or less than 0.001% by dry weight or % by weight of the pharmaceutical composition, wherein R 1 is OH and R 3 is O-CO-(CH 2 ) 16 ).

[0075] In one embodiment according to the present invention, the pharmaceutical composition comprises a compound of general formula 10 in an amount of 10% or less by dry weight or weight of the pharmaceutical composition, for example, 5% or less by dry weight or weight of the pharmaceutical composition, 1% or less by dry weight or weight of the pharmaceutical composition, 0.5% or less by dry weight or weight of the pharmaceutical composition, 0.1% or less by dry weight or weight of the pharmaceutical composition, 0.01% or less by dry weight or weight of the pharmaceutical composition, or 0.001% or less by dry weight or weight of the pharmaceutical composition (wherein R 2 is OH and R 4 is O-CO-(CH 2 ) 12 ).

[0076] In one embodiment according to the present invention, the pharmaceutical composition comprises a compound of general formula 10 in an amount of 10% or less by dry weight or weight of the pharmaceutical composition, for example, 5% or less by dry weight or weight of the pharmaceutical composition, 1% or less by dry weight or weight of the pharmaceutical composition, 0.5% or less by dry weight or weight of the pharmaceutical composition, 0.1% or less by dry weight or weight of the pharmaceutical composition, 0.01% or less by dry weight or weight of the pharmaceutical composition, or 0.001% or less by dry weight or weight of the pharmaceutical composition (wherein R 2 is OH and R 4 is O-CO-(CH 2 ) 14 ).

[0077] In one embodiment according to the present invention, the pharmaceutical composition comprises a compound of general formula 10 in an amount of 10% or less by dry weight or weight of the pharmaceutical composition, for example, 5% or less by dry weight or weight of the pharmaceutical composition, 1% or less by dry weight or weight of the pharmaceutical composition, 0.5% or less by dry weight or weight of the pharmaceutical composition, 0.1% or less by dry weight or weight of the pharmaceutical composition, 0.01% or less by dry weight or weight of the pharmaceutical composition, or 0.001% or less by dry weight or weight of the pharmaceutical composition (wherein R 2 is OH and R 4 is O-CO-(CH 2 ) 16 ). [Chemical formula]

[0078] In one embodiment according to the present invention, the content of LPC molecules in which the O-CO-(CH 2 ) 12 -CH 3 moiety is bonded to the glycerol backbone of the LPC molecule is less than 10% of the LPC molecules in the pharmaceutical composition on a molar basis, for example, less than 5% of the LPC molecules, less than 1% of the LPC molecules, less than 0.5% of the LPC molecules, less than 0.1% of the LPC molecules, or less than 0.01% of the LPC molecules.

[0079] In one embodiment according to the present invention, the content of LPC molecules in which the O-CO-(CH 2 ) 14 -CH 3 moiety is bonded to the glycerol backbone of the LPC molecule is less than 10% of the LPC molecules in the pharmaceutical composition on a molar basis, for example, less than 5% of the LPC molecules, less than 1% of the LPC molecules, less than 0.5% of the LPC molecules, less than 0.1% of the LPC molecules, or less than 0.01% of the LPC molecules.

[0080] In one embodiment according to the present invention, the content of LPC molecules in which the O-CO-(CH 2 ) 16 -CH 3 moiety is bonded to the glycerol backbone of the LPC molecule is less than 10% of the LPC molecules in the pharmaceutical composition on a molar basis, for example, less than 5% of the LPC molecules, less than 1% of the LPC molecules, less than 0.5% of the LPC molecules, less than 0.1% of the LPC molecules, or less than 0.01% of the LPC molecules.

[0081] In one embodiment according to the present invention, the pharmaceutical composition further comprises phosphatidylcholine (PC). In one embodiment according to the present invention, at least one of the fatty acid acyl moieties of the PC molecule is an omega-3 fatty acid acyl, preferably both of the fatty acid acyl moieties are omega-3 fatty acid acyls. The omega-3 fatty acid acyl is preferably selected from the group consisting of DHA, EPA, DPA, and SDA.

[0082] In one embodiment, phosphatidylcholine (PC) constitutes 1 to 95 dry weight % or weight % of the pharmaceutical composition, for example, 5 to 80 dry weight % or weight % of the pharmaceutical composition, or 10 to 80 dry weight % or weight % of the pharmaceutical composition. In another embodiment, phosphatidylcholine (PC) constitutes 10 to 70 dry weight % or weight % of the pharmaceutical composition, for example, 10 to 50 dry weight % or weight % of the pharmaceutical composition, or 5 to 50 dry weight % or weight % of the pharmaceutical composition.

[0083] The PC molecule has a choline head group attached to one end of the glycerol backbone, and the other two positions of the glycerol backbone are occupied by fatty acid acyl moieties. Thus, there are two fatty acid acyl moieties per one PC molecule, that is, 2 moles of fatty acid acyl per 1 mole of PC.

[0084] A composition containing 100 molecules of PC, - eight of the above PC molecules have two O-CO-(CH 2 ) 12 -CH 3 moieties attached to the glycerol backbone, - four of the above PC molecules have one O-CO-(CH 2 ) 12 -CH 3 moiety attached to the glycerol backbone, - eighty-eight of the above PC molecules have no O-CO-(CH 2 ) 12 -CH 3 moiety attached to the glycerol backbone, the composition has a total of 200 fatty acid acyl groups, 20 of which are O-CO-(CH 2 ) 12 -CH 3 moieties. In such a composition, 10% on a molar basis of the fatty acid acyl moieties attached to the glycerol backbone of PC are O-CO-(CH 2 ) 12 -CH 3 moieties.

[0085] When the pharmaceutical composition of the present invention contains PC, less than 10% on a molar basis of the fatty acyl moiety bonded to the glycerol backbone of PC, for example, less than 5%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% is O-CO-(CH 2 ) 12 -CH 3 moiety is preferred.

[0086] When the pharmaceutical composition of the present invention contains PC, less than 10% on a molar basis of the fatty acyl moiety bonded to the glycerol backbone of PC, for example, less than 5%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% is O-CO-(CH 2 ) 14 -CH 3 moiety is preferred.

[0087] When the pharmaceutical composition of the present invention contains PC, less than 10% on a molar basis of the fatty acyl moiety bonded to the glycerol backbone of PC, for example, less than 5%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% is O-CO-(CH 2 ) 16 -CH 3 moiety is preferred.

[0088] In one embodiment according to the present invention, the pharmaceutical composition contains PC. In a preferred embodiment, less than 10% on a molar basis of the fatty acyl moiety bonded to the glycerol backbone of PC, for example, less than 5%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% is O-CO-(CH 2 ) 12 -CH 3 moiety.

[0089] In one embodiment according to the present invention, the pharmaceutical composition contains PC. In a preferred embodiment, less than 10% on a molar basis of the fatty acyl moiety bonded to the glycerol backbone of PC, for example, less than 5%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% is O-CO-(CH 2 ) 14 -CH 3 moiety.

[0090] In one embodiment according to the present invention, the pharmaceutical composition comprises PC. In a preferred embodiment, less than 10% on a molar basis of the fatty acyl moieties attached to the glycerol backbone of PC, such as less than 5%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% is the O-CO-(CH 2 ) 16 -CH 3 moiety.

[0091] In one embodiment according to the present invention, the pharmaceutical composition does not contain any significant amount of free omega-3 fatty acids (e.g., does not contain any free omega-3 fatty acids at all).

[0092] In another embodiment according to the present invention, the pharmaceutical composition contains less than 10% on the weight or dry weight of the pharmaceutical composition, such as less than 5%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, or less than 0.001% of free omega-3 fatty acids.

[0093] In another embodiment according to the present invention, the pharmaceutical composition does not contain any significant amount of free fatty acids (e.g., does not contain any free fatty acids at all).

[0094] In another embodiment according to the present invention, the pharmaceutical composition contains less than 10% on the weight or dry weight of the pharmaceutical composition, such as less than 5%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, or less than 0.001% of free fatty acids.

[0095] In another embodiment according to the present invention, the pharmaceutical composition does not contain any significant amount of free myristic acid (e.g., does not contain any free myristic acid at all).

[0096] In another embodiment according to the present invention, the pharmaceutical composition contains less than 10% on the weight or dry weight of the pharmaceutical composition, such as less than 5%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, or less than 0.001% of free myristic acid.

[0097] In another embodiment according to the present invention, the pharmaceutical composition does not contain any significant amount of free palmitic acid (e.g., contains no free palmitic acid at all).

[0098] In another embodiment according to the present invention, the pharmaceutical composition contains less than 10%, e.g., less than 5%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, or less than 0.001% of free palmitic acid, by weight or dry weight of the pharmaceutical composition.

[0099] In some embodiments, the pharmaceutical composition according to the present invention is provided for use in increasing the amount of EPA, DHA, DPA, and / or SDA in a target tissue or organ, such as the brain, by intravascular administration, such as intravenous administration.

[0100] A second aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use as a medicament, wherein the pharmaceutical composition is administered by intravascular administration, such as intravenous administration.

[0101] A third aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in prevention and / or treatment, wherein the pharmaceutical composition is administered by intravascular administration, such as intravenous administration.

[0102] A fourth aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in the prevention and / or treatment of a condition that may benefit from an increase in brain EPA levels, wherein the pharmaceutical composition is administered by intravascular administration, such as intravenous administration.

[0103] A fifth aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in the prevention and / or treatment of a condition that may benefit from an increase in brain DHA levels, wherein the pharmaceutical composition is administered by intravascular administration, such as intravenous administration.

[0104] In one embodiment according to the fifth aspect of the present invention, the condition that may benefit from an increase in brain DHA levels is a neurological condition.

[0105] In another embodiment according to the fifth aspect of the present invention, the neurological condition is depression, schizophrenia, Alzheimer's disease, Parkinson's disease, or traumatic brain injury.

[0106] In a preferred embodiment according to the fifth aspect of the present invention, the condition that can benefit from an increase in brain DHA levels is traumatic brain injury.

[0107] In a preferred embodiment according to the fifth aspect of the present invention, the condition that can benefit from an increase in brain DHA levels is traumatic brain injury, and the pharmaceutical composition is administered in combination with i) a progestogen or its prodrug, and / or ii) an estrogen or its prodrug.

[0108] In a preferred embodiment according to the fifth aspect of the present invention, the condition that can benefit from an increase in brain DHA levels is traumatic brain injury, and the traumatic brain injury is derived from a closed head injury.

[0109] In one embodiment according to the fifth aspect of the present invention, the condition that can benefit from an increase in brain DHA levels is post-traumatic stress disorder (PTSD) or anxiety.

[0110] The sixth aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in the prevention and / or treatment of a condition that can benefit from an increase in brain DPA levels, and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0111] The seventh aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in the prevention and / or treatment of a condition that can benefit from an increase in brain SDA levels, and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0112] It should be understood that since at least a part of EPA in the brain can be converted to DHA, for example, a condition that can benefit from an increase in brain DHA levels can be treated by increasing brain EPA levels.

[0113] The eighth aspect of the present invention is a pharmaceutical composition according to the first aspect of the present invention for use in prophylaxis and / or treatment (wherein R 1 and R 2 are OH), and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0114] The ninth aspect of the present invention is a pharmaceutical composition according to the first aspect of the present invention for use in prophylaxis and / or treatment of a condition that can benefit from an increase in brain DHA level (wherein R 1 and R 2 are OH), and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0115] In one embodiment according to the ninth aspect of the present invention, the condition that can benefit from an increase in brain DHA level is a neurological condition, and the neurological condition is preferably traumatic brain injury.

[0116] In one embodiment according to the ninth aspect of the present invention, the condition that can benefit from an increase in brain DHA level is post-traumatic stress disorder (PTSD) or anxiety.

[0117] In one embodiment according to any one of Aspects 2 to 9, the pharmaceutical composition is administered to a subject at risk of traumatic brain injury. To reduce the risk of the pathological effects of traumatic brain injury, it is preferably administered in a prophylactically effective amount for a sufficient period before engaging in activities associated with the risk of traumatic brain injury. Traumatic head injury can be derived from a closed head injury.

[0118] The tenth aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in treating, preventing, or improving cognitive and / or cognitive diseases, disorders, or dysfunctions (memory, concentration, learning (deficits)), or for treating or preventing neurodegenerative disorders, and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0119] In some embodiments, the cognitive disorder, impairment, or dysfunction is selected from attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), autism / autism spectrum disorder (ASD) (dyslexia, age-related memory impairment and learning disorder, amnesia, mild cognitive impairment, cognitive impairment without dementia, pre-symptomatic Alzheimer's disease, Alzheimer's disease, epilepsy, Pick's disease, Huntington's disease, Parkinson's disease, Lewy body dementia, frontotemporal dementia, corticobasal degeneration, Friedreich's ataxia, multiple system atrophy, spinocerebellar ataxia type 1, 2, 3, 6, 7, amyotrophic lateral sclerosis, familial spastic paraplegia, spinal muscular atrophy, bulbar spinal muscular atrophy, age-related cognitive decline, cognitive decline, moderate mental dysfunction, mental dysfunction as a result of aging, conditions affecting the intensity of brain waves and / or glucose utilization in the brain, stress, anxiety, concentration and attention dysfunction, mood deterioration, general cognitive and mental well-being disorders, neurodevelopmental disorders, neurodegenerative disorders, hormonal disorders, neurological disorders, or any combination thereof. In certain embodiments, the cognitive impairment is a memory impairment.

[0120] The eleventh aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in the treatment or prevention of cardiovascular disorders or metabolic syndrome, the pharmaceutical composition being administered by intravascular administration such as intravenous administration.

[0121] In some embodiments, the cardiovascular disorder is selected from atherosclerosis, arteriosclerosis, coronary heart disease (CHD or CAD), acute coronary syndrome (or ACS), valvular heart disease, aortic and mitral valve disorders, arrhythmia / atrial fibrillation, cardiomyopathy and heart failure, angina, acute myocardial infarction (or AMI), hypertension, orthostatic hypotension, shock, embolism (pulmonary and venous), endocarditis, diseases of the arteries, aorta and its branches, peripheral vascular disorders (peripheral arterial disease or PAD), Kawasaki disease, congenital heart disease (cardiovascular disorder) and stroke (cerebrovascular disease), dyslipidemia, hypertriglyceridemia, hypertension, heart failure, cardiac arrhythmia, low HDL level, high LDL level, stable angina, coronary heart disease, acute myocardial infarction, secondary prevention of myocardial infarction, cardiomyopathy, endocarditis, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypercholesterolemia, stroke, hyperlipidemia, hyperlipoproteinemia, chronic kidney disease, intermittent claudication, hyperphosphatemia, omega-3 deficiency, phospholipid deficiency, atherosclerotic carotid artery disease, peripheral arterial disease, diabetic nephropathy, hypercholesterolemia in HIV infection, acute coronary syndrome (ACS), non-alcoholic fatty liver disease / non-alcoholic steatohepatitis (NAFLD / NASH), arterial occlusive disease, cerebral atherosclerosis, arteriosclerosis, cerebrovascular disorder, myocardial ischemia, coagulation disorders leading to intravascular thrombosis, and diabetic autonomic neuropathy.

[0122] The twelfth aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in inhibiting, preventing, or treating inflammation or an inflammatory disease, the pharmaceutical composition being administered by intravascular administration such as intravenous administration.

[0123] In some embodiments, the inflammation or inflammatory disease is organ transplant rejection; reperfusion injury resulting from organ transplantation including, but not limited to, transplantation of the following organs: heart, lung, liver, and kidney (see Grupp et al., J. Mol. Cell. Cardiol. 31:297-303 (1999)); chronic inflammatory joint diseases including arthritis, rheumatoid arthritis, osteoarthritis, and bone diseases associated with increased bone resorption; inflammatory bowel diseases (IBD) such as ileitis, ulcerative colitis (UC), Barrett's syndrome, and Crohn's disease (CD); inflammatory lung diseases such as asthma, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD); inflammatory eye diseases including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmia, and endophthalmitis; chronic inflammatory gum diseases including gingivitis and periodontitis; inflammatory kidney diseases including uremic complications, glomerulonephritis, and nephrosis; inflammatory skin diseases including sclerodermatitis, psoriasis, and eczema; chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, epilepsy, amyotrophic lateral sclerosis, and viral or autoimmune encephalitis, inflammatory diseases of the central nervous system including preeclampsia; chronic liver failure, trauma to the brain and spinal cord, and cancer. The inflammatory disease can also be a systemic inflammation of the body exemplified by, for example, gram-positive or gram-negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to inflammatory cytokines, e.g., shock associated with inflammatory cytokines. Such shock can be induced, for example, by chemotherapeutic agents administered as cancer therapeutics. Other disorders include depression, obesity, allergic diseases, acute cardiovascular events, muscle wasting diseases, and cancer cachexia. Also, inflammation resulting from surgery and trauma can be treated with the lipid compositions.

[0124] The thirteenth aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in the treatment of diseases or conditions related to red blood cells and cell membranes, in particular diseases or conditions related to abnormalities of red blood cells in the cell membrane, and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0125] In some embodiments, the condition or disease is sickle cell disease, sickle cell anemia, or sickle cell trait. In some embodiments, the condition or disease is (alpha, beta, or delta) thalassemia, abnormal hemoglobinopathy (hemoglobin E, hemoglobin S, or hemoglobin C) combined thalassemia, splenomegaly, or membrane abnormalities such as acanthocytes or spurred / spiked cells, target red blood cells (target cells), echinocytes (crenated cells), elliptocytes and ovalocytes, spherocytes, stomatocytes (mouth cells), and degmacytes ("bite cells").

[0126] In one embodiment according to any one of Aspects 2 to 13, the pharmaceutical composition is administered to a subject less than 10 years old, for example, less than 1 year old, less than 1 month old, or a neonate.

[0127] In one embodiment according to any one of Aspects 2 to 13, the pharmaceutical composition is administered to a subject over 60 years old, for example, over 70 years old, over 80 years old, or an elderly subject.

[0128] In one embodiment according to any one of Aspects 2 to 13, the pharmaceutical composition is administered to a subject who is about 10 to 20 years old, about 20 to 50 years old, about 50 to 100 years old, about 60 to 100 years old, or about 70 to 100 years old.

[0129] In one embodiment according to any one of Aspects 2 to 13, the pharmaceutical composition is administered to a subject who is female.

[0130] In one embodiment according to any one of Aspects 2 to 13, the pharmaceutical composition is administered to a subject who is male.

[0131] In one embodiment according to the present invention, traumatic brain injury does not include brain injury induced by ischemia / reperfusion.

[0132] In some embodiments, a closed head injury is a concussion or a contusion. Subjects at risk of such injury can include, among others, subjects participating in a sports event involving the occurrence of a concussion. Exemplary subjects in this category can include, among others, football players, boxers, and hockey players.

[0133] A fourteenth aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in the prevention and / or treatment of a condition that can benefit from an increase in the level of EPA in the intestine, such as the intestinal mucosa, and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0134] In one embodiment, a condition that can benefit from an increase in the level of EPA in the intestine, such as the intestinal mucosa, is selected from the group consisting of inflammatory bowel diseases (IBD) such as ileitis, ulcerative colitis (UC), Barrett's syndrome, and Crohn's disease (CD).

[0135] A fifteenth aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in the prevention and / or treatment of a condition that can benefit from an increase in the level of DHA in the intestine, such as the intestinal mucosa, and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0136] In one embodiment, a condition that can benefit from an increase in the level of DHA in the intestine, such as the intestinal mucosa, is selected from the group consisting of inflammatory bowel diseases (IBD) such as ileitis, ulcerative colitis (UC), Barrett's syndrome, and Crohn's disease (CD).

[0137] A sixteenth aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in the prevention and / or treatment of a condition that can benefit from an increase in the level of EPA in the eye, such as the retina of the eye, and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0138] In one embodiment, the conditions that can benefit from an increase in the EPA level in the eye, such as the retina, are: i) degenerative diseases of the retina, such as macular degeneration, particularly age-related macular degeneration (ARMD) and retinitis pigmentosa; ii) proliferative retinopathy in diabetic patients, vascular diseases of the retina in diabetic patients, such as clinically significant macular edema in diabetic retinopathy patients; iii) cataracts, such as age-related cataracts in all patients, diabetic patients, and ARMD patients, and are selected from the group consisting of cataracts.

[0139] The seventeenth aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in the prevention and / or treatment of conditions that can benefit from an increase in the DHA level in the eye, such as the retina, and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0140] In one embodiment, the conditions that can benefit from an increase in the DHA level in the eye, such as the retina, are: i) degenerative diseases of the retina, such as macular degeneration, particularly age-related macular degeneration (ARMD) and retinitis pigmentosa; ii) proliferative retinopathy in diabetic patients, vascular diseases of the retina in diabetic patients, such as clinically significant macular edema in diabetic retinopathy patients; iii) cataracts, such as age-related cataracts in all patients, diabetic patients, and ARMD patients, and are selected from the group consisting of cataracts.

[0141] The second alternative aspect of the present invention relates to a pharmaceutical composition suitable for oral administration, the pharmaceutical composition comprising one or more active ingredients, the one or more active ingredients being selected from the group consisting of a compound according to any one of formulas 1 to 8, or a pharmaceutically acceptable salt thereof, and any combination thereof,

Chemical formula

[0142] A preferred embodiment according to a second alternative aspect of the present invention relates to a pharmaceutical composition suitable for oral administration, the pharmaceutical composition comprising i) LPC-EPA or a pharmaceutically acceptable salt thereof, and ii) LPC-DHA or a pharmaceutically acceptable salt thereof. Preferably, LPC-EPA and LPC-DHA constitute 10-99% dry weight or weight of the pharmaceutical composition, for example, 15-99% dry weight or weight of the pharmaceutical composition, 20-99% dry weight or weight of the pharmaceutical composition, 25-99% dry weight or weight of the pharmaceutical composition (e.g., 27% dry weight or weight), 35-99% dry weight or weight of the pharmaceutical composition, 55-99% dry weight or weight of the pharmaceutical composition, 75-99% dry weight or weight of the pharmaceutical composition, most preferably 80-99% dry weight or weight of the pharmaceutical composition, for example, 85-95% dry weight or weight (e.g., about 89% dry weight or weight).

[0143] In one embodiment according to a second alternative aspect of the present invention, one or more active ingredients are compounds of formula 1 (wherein R 2 is OH or O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2).

[0144] In another embodiment according to a second alternative aspect of the present invention, one or more active ingredients are compounds of formula 2 (wherein R 2 is OH or O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2).

[0145] In another embodiment according to a second alternative aspect of the present invention, one or more active ingredients are compounds of formula 3 (wherein R 1 is OH or O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2).

[0146] In yet another embodiment according to the second alternative aspect of the present invention, one or more active ingredients are compounds according to formula 4, wherein R 1 is OH or O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2).

[0147] In yet another embodiment according to the second alternative aspect of the present invention, one or more active ingredients are compounds according to formula 5, wherein R 2 is OH or O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2).

[0148] In yet another embodiment according to the second alternative aspect of the present invention, one or more active ingredients are compounds according to formula 6, wherein R 2 is OH or O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2).

[0149] In yet another embodiment according to the second alternative aspect of the present invention, one or more active ingredients are compounds according to formula 7, wherein R 1 is OH or O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2).

[0150] In yet another embodiment according to the second alternative aspect of the present invention, one or more active ingredients are compounds according to formula 8, wherein R 1 is OH or O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2).

[0151] In yet another embodiment according to the second alternative aspect of the present invention, one or more active ingredients are combinations of two or more of the above-mentioned active ingredients.

[0152] In yet another embodiment according to the second alternative aspect of the present invention, one or more active ingredients are combinations of three, four, or five or more of the above-mentioned active ingredients.

[0153] One embodiment according to the second alternative aspect of the present invention relates to a pharmaceutical composition according to the second alternative aspect of the present invention (provided that when this pharmaceutical composition contains i) a compound according to formula 1 (wherein R 2 is OH) or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 3 (wherein R 1 is OH) or a pharmaceutically acceptable salt thereof, this pharmaceutical composition further contains at least one of the other active ingredients mentioned in the second alternative aspect of the present invention).

[0154] The expression "at least one of the other active ingredients" above refers to at least one active ingredient that is different from i) the compound according to formula 1 (wherein R 2 is OH) or a pharmaceutically acceptable salt thereof and different from ii) the compound according to formula 3 (wherein R 1 is OH) or a pharmaceutically acceptable salt thereof.

[0155] In yet another embodiment according to the second alternative aspect, one or more active ingredients are i) a compound according to formula 1, or a pharmaceutically acceptable salt thereof, ii) a compound according to formula 2, or a pharmaceutically acceptable salt thereof, iii) a compound according to formula 3, or a pharmaceutically acceptable salt thereof, and iv) a compound according to formula 4, or a pharmaceutically acceptable salt thereof.

[0156] In yet another embodiment according to the second alternative aspect, the one or more active ingredients are: i) a compound according to formula 5, or a pharmaceutically acceptable salt thereof; ii) a compound according to formula 6, or a pharmaceutically acceptable salt thereof; iii) a compound according to formula 7, or a pharmaceutically acceptable salt thereof; and iv) a compound according to formula 8, or a pharmaceutically acceptable salt thereof.

[0157] In yet another embodiment according to the second alternative aspect, the one or more active ingredients are as follows: - a compound according to formula 1, or a pharmaceutically acceptable salt thereof, or a compound according to formula 3, or a pharmaceutically acceptable salt thereof, and - a compound according to formula 2, or a pharmaceutically acceptable salt thereof, or a compound according to formula 4, or a pharmaceutically acceptable salt thereof.

[0158] In another embodiment according to the second alternative aspect, the one or more active ingredients are: i) a compound according to formula 1, or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 3, or a pharmaceutically acceptable salt thereof.

[0159] In another embodiment according to the second alternative aspect, the one or more active ingredients are: i) a compound according to formula 2, or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 4, or a pharmaceutically acceptable salt thereof.

[0160] In another embodiment according to the second alternative aspect, - R 1 and R 2 are OH, - the one or more active ingredients are: i) a compound according to formula 2, or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 4, or a pharmaceutically acceptable salt thereof.

[0161] In another embodiment according to the second alternative aspect, - R 1 and R 2 are O-CO-(CH 2 ) n - CH 3and -n is 0, 1 or 2, preferably 0, -One or more active ingredients are i) a compound according to formula 2, or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 4, or a pharmaceutically acceptable salt thereof.

[0162] In another embodiment according to the second alternative embodiment, -R 1 and R 2 are OH, -One or more active ingredients are i) a compound according to formula 5, or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 7, or a pharmaceutically acceptable salt thereof.

[0163] In another embodiment according to the second alternative embodiment, -R 1 and R 2 are O-CO-(CH 2 ) n -CH 3 and -n is 0, 1 or 2, preferably 0, -One or more active ingredients are i) a compound according to formula 5, or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 7, or a pharmaceutically acceptable salt thereof.

[0164] In another embodiment according to the second alternative embodiment, -R 1 and R 2 are OH, -One or more active ingredients are i) a compound according to formula 6, or a pharmaceutically acceptable salt thereof, and / or ii) a compound according to formula 8, or a pharmaceutically acceptable salt thereof.

[0165] In 2 another embodiment according to the alternative embodiment of, -R 1 and R 2 are O-CO-(CH 2 ) n -CH 3 and -n is 0, 1 or 2, preferably 0, -One or more active ingredients are i) a compound of formula 6, or a pharmaceutically acceptable salt thereof, and / or ii) a compound of formula 8, or a pharmaceutically acceptable salt thereof.

[0166] In one embodiment according to the second alternative aspect of the present invention, R 1 is OH. In another embodiment according to the second alternative aspect of the present invention, R 2 is OH. In yet another embodiment according to the second alternative aspect of the present invention, R 1 and R 2 are both OH.

[0167] In another embodiment according to the second alternative aspect of the present invention, R 1 is OH, and / or R 2 is OH. Preferably, R 1 and R 2 are both OH.

[0168] In another embodiment according to the second alternative aspect of the present invention, R 1 is O-CO-CH 3 , and / or R 2 is O-CO-CH 3 . Preferably, R 1 and R 2 are both O-CO-CH 3 .

[0169] In another embodiment according to the second alternative aspect of the present invention, R 1 is O-CO-(CH 2 ) n -CH 3 , and / or R 2 is O-CO-(CH 2 ) n -CH 3 . Preferably, R 1 and R 2 are both O-CO-(CH 2 ) n -CH 3It is so. n is 0, 1 or 2, more preferably, n is 0 or 1, and most preferably, n is 0.

[0170] In yet another embodiment according to the second alternative aspect of the present invention, n is 0 or 1, and most preferably, n is 0.

[0171] In another embodiment according to the second alternative aspect of the present invention, one or more active ingredients constitute 0.1 to 100 dry weight % or weight % of the pharmaceutical composition, for example, 0.5 to 100 dry weight % or weight % of the pharmaceutical composition, or 1 to 100 dry weight % or weight % of the pharmaceutical composition.

[0172] In another embodiment according to the second alternative aspect of the present invention, one or more active ingredients constitute 0.1 to 80 dry weight % or weight % of the pharmaceutical composition, for example, 0.5 to 60 dry weight % or weight % of the pharmaceutical composition, or 1 to 40 dry weight % or weight % of the pharmaceutical composition.

[0173] In another embodiment according to the second alternative aspect of the present invention, one or more active ingredients constitute 0.1 to 20 dry weight % or weight % of the pharmaceutical composition, for example, 0.5 to 10 dry weight % or weight % of the pharmaceutical composition, or 1 to 5 dry weight % or weight % of the pharmaceutical composition.

[0174] In another embodiment according to the second alternative aspect of the present invention, one or more active ingredients constitute 0.1 to 5 dry weight % or weight % of the pharmaceutical composition, for example, 0.5 to 5 dry weight % or weight % of the pharmaceutical composition, or 1 to 3 dry weight % or weight % of the pharmaceutical composition.

[0175] In another embodiment according to the second alternative aspect of the present invention, one or more active ingredients constitute 0.1 to 3 dry weight % or weight % of the pharmaceutical composition, for example, 0.5 to 3 dry weight % or weight % of the pharmaceutical composition, or 1 to 2 dry weight % or weight % of the pharmaceutical composition.

[0176] In another embodiment according to the second alternative aspect of the present invention, one or more active ingredients constitute 0.1 to 2 dry weight % or weight % of the pharmaceutical composition, for example, 0.1 to 1 dry weight % or weight % of the pharmaceutical composition, or 0.1 to 0.8 dry weight % or weight % of the pharmaceutical composition.

[0177] In a preferred embodiment according to the second alternative aspect of the present invention, one or more active ingredients constitute 10 to 99 dry weight % or weight % of the pharmaceutical composition, for example, 15 to 99 dry weight % or weight % of the pharmaceutical composition, 20 to 99 dry weight % or weight % of the pharmaceutical composition, 25 to 99 dry weight % or weight % (e.g., 27 dry weight % or weight %) of the pharmaceutical composition, 35 to 99 dry weight % or weight % of the pharmaceutical composition, 55 to 99 dry weight % or weight % of the pharmaceutical composition, 75 to 99 dry weight % or weight % of the pharmaceutical composition, most preferably 80 to 99% dry weight % or weight % of the pharmaceutical composition, for example, 85 to 95 dry weight % or weight % (e.g., about 89 dry weight % or weight %).

[0178] In yet another embodiment according to the second alternative aspect of the present invention, the molar ratio of lysoPC-DHA:lysoPC-EPA is within the range of 1:1 to 10:1, for example, within the range of 1:1 to 7:1, or within the range of 1:1 to 5:1, or within the range of 1:1 to 3:1, or the molar ratio of lysoPC-EPA:lysoPC-DHA is within the range of 1:1 to 10:1, for example, within the range of 1:1 to 7:1, or within the range of 1:1 to 5:1, or within the range of 1:1 to 3:1 (provided that i) the number of moles of lysoPC-EPA is the number of moles of 1-lysoPC-EPA + the number of moles of 2-lysoPC-EPA, and ii) the number of moles of lysoPC-DHA is the number of moles of 1-lysoPC-DHA + the number of moles of 2-lysoPC-DHA).

[0179] In yet another embodiment according to the second alternative aspect of the present invention, -R 1 and R 2 is OH, -LysoPC-DHA: The molar ratio of lysoPC-DHA to lysoPC-EPA is within the range of 1:1 to 10:1, for example within the range of 1:1 to 7:1, or within the range of 1:1 to 5:1, or within the range of 1:1 to 3:1, or the molar ratio of lysoPC-EPA to lysoPC-DHA is within the range of 1:1 to 10:1, for example, within the range of 1:1 to 7:1, or within the range of 1:1 to 5:1, or within the range of 1:1 to 3:1 (provided that i) the number of moles of lysoPC-EPA is the number of moles of 1-lysoPC-EPA + the number of moles of 2-lysoPC-EPA, and ii) the number of moles of lysoPC-DHA is the number of moles of 1-lysoPC-DHA + the number of moles of 2-lysoPC-DHA).

[0180] In yet another embodiment according to the second alternative aspect of the present invention, the molar ratio of 2-lysoPC-EPA / DHA to 1-lysoPC-EPA / DHA is within the range of 1:8 to 18:1, for example within the range of 1:8 to 15:1, or within the range of 1:8 to 10:1 (provided that i) the number of moles of 2-lysoPC-EPA / DHA is the number of moles of 2-lysoPC-EPA + the number of moles of 2-lysoPC-DHA, and ii) the number of moles of 1-lysoPC-EPA / DHA is the number of moles of 1-lysoPC-EPA + the number of moles of 1-lysoPC-DHA).

[0181] In yet another embodiment according to the second alternative aspect of the present invention, -R 1 and R 2 is OH, -The molar ratio of 2-lysoPC-EPA / DHA to 1-lysoPC-EPA / DHA is within the range of 1:8 to 18:1, for example within the range of 1:8 to 15:1, or within the range of 1:8 to 10:1 (provided that i) the number of moles of 2-lysoPC-EPA / DHA is the number of moles of 2-lysoPC-EPA + the number of moles of 2-lysoPC-DHA, and ii) the number of moles of 1-lysoPC-EPA / DHA is the number of moles of 1-lysoPC-EPA + the number of moles of 1-lysoPC-DHA).

[0182] In one embodiment according to the second alternative aspect of the present invention, the pharmaceutical composition is less than 10% dry weight or weight% of the pharmaceutical composition, for example, less than 5% dry weight or weight% of the pharmaceutical composition, less than 1% dry weight or weight% of the pharmaceutical composition, less than 0.5% dry weight or weight% of the pharmaceutical composition, less than 0.1% dry weight or weight% of the pharmaceutical composition, less than 0.01% dry weight or weight% of the pharmaceutical composition, or less than 0.001% dry weight or weight% of the pharmaceutical composition of a compound of general formula 9 (wherein R 1 is OH and R 3 is O-CO-(CH 2 ) 12 ).

[0183] In one embodiment according to the second alternative aspect of the present invention, the pharmaceutical composition is less than 10% dry weight or weight% of the pharmaceutical composition, for example, less than 5% dry weight or weight% of the pharmaceutical composition, less than 1% dry weight or weight% of the pharmaceutical composition, less than 0.5% dry weight or weight% of the pharmaceutical composition, less than 0.1% dry weight or weight% of the pharmaceutical composition, less than 0.01% dry weight or weight% of the pharmaceutical composition, or less than 0.001% dry weight or weight% of the pharmaceutical composition of a compound of general formula 9 (wherein R 1 is OH and R 3 is O-CO-(CH 2 ) 14 ).

[0184] In one embodiment according to the second alternative aspect of the present invention, the pharmaceutical composition is less than 10% dry weight or weight% of the pharmaceutical composition, for example, less than 5% dry weight or weight% of the pharmaceutical composition, less than 1% dry weight or weight% of the pharmaceutical composition, less than 0.5% dry weight or weight% of the pharmaceutical composition, less than 0.1% dry weight or weight% of the pharmaceutical composition, less than 0.01% dry weight or weight% of the pharmaceutical composition, or less than 0.001% dry weight or weight% of the pharmaceutical composition of a compound of general formula 9 (wherein R 1 is OH and R 3 is O-CO-(CH 2 ) 16 ).

[0185] In one embodiment according to the second alternative aspect of the present invention, the pharmaceutical composition is 10% or less by dry weight or weight of the pharmaceutical composition, for example, 5% or less by dry weight or weight of the pharmaceutical composition, 1% or less by dry weight or weight of the pharmaceutical composition, 0.5% or less by dry weight or weight of the pharmaceutical composition, 0.1% or less by dry weight or weight of the pharmaceutical composition, 0.01% or less by dry weight or weight of the pharmaceutical composition, or 0.001% or less by dry weight or weight of the pharmaceutical composition of a compound of general formula 10 (wherein R 2 is OH and R 4 is O-CO-(CH 2 ) 12 ).

[0186] In one embodiment according to the second alternative aspect of the present invention, the pharmaceutical composition is 10% or less by dry weight or weight of the pharmaceutical composition, for example, 5% or less by dry weight or weight of the pharmaceutical composition, 1% or less by dry weight or weight of the pharmaceutical composition, 0.5% or less by dry weight or weight of the pharmaceutical composition, 0.1% or less by dry weight or weight of the pharmaceutical composition, 0.01% or less by dry weight or weight of the pharmaceutical composition, or 0.001% or less by dry weight or weight of the pharmaceutical composition of a compound of general formula 10 (wherein R 2 is OH and R 4 is O-CO-(CH 2 ) 14 ).

[0187] In one embodiment according to the second alternative aspect of the present invention, the pharmaceutical composition is 10% or less by dry weight or weight of the pharmaceutical composition, for example, 5% or less by dry weight or weight of the pharmaceutical composition, 1% or less by dry weight or weight of the pharmaceutical composition, 0.5% or less by dry weight or weight of the pharmaceutical composition, 0.1% or less by dry weight or weight of the pharmaceutical composition, 0.01% or less by dry weight or weight of the pharmaceutical composition, or 0.001% or less by dry weight or weight of the pharmaceutical composition of a compound of general formula 10 (wherein R 2 is OH and R 4 is O-CO-(CH 2 ) 16 ).

Chemical Formula

[0188] In one embodiment according to the second alternative aspect of the present invention, O-CO-(CH 2 ) 12 -CH 3 The content of the LPC molecule in which the moiety is bound to the glycerol backbone of the LPC molecule is less than 10% of the LPC molecule in the pharmaceutical composition on a molar basis, for example, less than 5% of the LPC molecule, less than 1% of the LPC molecule, less than 0.5% of the LPC molecule, less than 0.1% of the LPC molecule, or less than 0.01% of the LPC molecule.

[0189] In one embodiment according to the second alternative aspect of the present invention, O-CO-(CH 2 ) 14 -CH 3 The content of the LPC molecule in which the moiety is bound to the glycerol backbone of the LPC molecule is less than 10% of the LPC molecule in the pharmaceutical composition on a molar basis, for example, less than 5% of the LPC molecule, less than 1% of the LPC molecule, less than 0.5% of the LPC molecule, less than 0.1% of the LPC molecule, or less than 0.01% of the LPC molecule.

[0190] In one embodiment according to the second alternative aspect of the present invention, O-CO-(CH 2 ) 16 -CH 3 The content of the LPC molecule in which the moiety is bound to the glycerol backbone of the LPC molecule is less than 10% of the LPC molecule in the pharmaceutical composition on a molar basis, for example, less than 5% of the LPC molecule, less than 1% of the LPC molecule, less than 0.5% of the LPC molecule, less than 0.1% of the LPC molecule, or less than 0.01% of the LPC molecule.

[0191] In one embodiment according to the second alternative aspect of the present invention, the pharmaceutical composition further comprises phosphatidylcholine (PC). In one embodiment according to the second alternative aspect of the present invention, at least one of the fatty acid acyl moieties of the PC molecule is an omega-3 fatty acid acyl, and preferably both of the fatty acid acyl moieties are omega-3 fatty acid acyls. The omega-3 fatty acid acyl is preferably selected from the group consisting of DHA, EPA, DPA, and SDA.

[0192] In one embodiment, phosphatidylcholine (PC) constitutes 1 to 95 dry weight % or weight % of the pharmaceutical composition, for example, 5 to 80 dry weight % or weight % of the pharmaceutical composition, or 10 to 80 dry weight % or weight % of the pharmaceutical composition. In another embodiment, phosphatidylcholine (PC) constitutes 10 to 70 dry weight % or weight % of the pharmaceutical composition, for example, 10 to 50 dry weight % or weight % of the pharmaceutical composition, or 5 to 50 dry weight % or weight % of the pharmaceutical composition.

[0193] The PC molecule has a choline head group attached to one end of the glycerol backbone, and the other two positions on the glycerol backbone are occupied by fatty acid acyl moieties. Thus, there are two fatty acid acyl moieties per PC molecule, i.e., 2 moles of fatty acid acyl per mole of PC.

[0194] A composition containing 100 molecules of PC, - eight of the above PC molecules have two O-CO-(CH 2 ) 12 -CH 3 moieties attached to the glycerol backbone, - four of the above PC molecules have one O-CO-(CH 2 ) 12 -CH 3 moiety attached to the glycerol backbone, - eighty-eight of the above PC molecules have no O-CO-(CH 2 ) 12 -CH 3 moiety attached to the glycerol backbone, has a total of 200 fatty acid acyl groups, 20 of which are O-CO-(CH 2 ) 12 -CH 3 moieties. In such a composition, 10% on a molar basis of the fatty acid acyl moieties attached to the glycerol backbone of PC are O-CO-(CH 2 ) 12 -CH 3 moieties.

[0195] When the pharmaceutical composition of the second alternative embodiment of the present invention contains PC, less than 10% on a molar basis of the fatty acyl moiety bonded to the glycerol backbone of PC, for example, less than 5%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% is O-CO-(CH 2 ) 12 -CH 3 moiety is preferred.

[0196] When the pharmaceutical composition of the second alternative embodiment of the present invention contains PC, less than 10% on a molar basis of the fatty acyl moiety bonded to the glycerol backbone of PC, for example, less than 5%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% is O-CO-(CH 2 ) 14 -CH 3 moiety is preferred.

[0197] When the pharmaceutical composition of the second alternative embodiment of the present invention contains PC, less than 10% on a molar basis of the fatty acyl moiety bonded to the glycerol backbone of PC, for example, less than 5%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% is O-CO-(CH 2 ) 16 -CH 3 moiety is preferred.

[0198] In one embodiment according to the second alternative embodiment of the present invention, the pharmaceutical composition contains PC. In a preferred embodiment, less than 10% on a molar basis of the fatty acyl moiety bonded to the glycerol backbone of PC, for example, less than 5%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% is O-CO-(CH 2 ) 12 -CH 3 moiety.

[0199] In one embodiment according to the second alternative embodiment of the present invention, the pharmaceutical composition contains PC. In a preferred embodiment, less than 10% on a molar basis of the fatty acyl moiety bonded to the glycerol backbone of PC, for example, less than 5%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% is O-CO-(CH 2 )14 -CH 3 is a part.

[0200] In one embodiment according to the second alternative aspect of the present invention, the pharmaceutical composition comprises PC. In a preferred embodiment, less than 10% on a molar basis of the fatty acyl moieties attached to the glycerol backbone of PC, such as less than 5%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% is O-CO-(CH 2 ) 16 -CH 3 is a part.

[0201] In one embodiment according to the second alternative aspect of the present invention, the pharmaceutical composition does not contain any appreciable amount of free omega-3 fatty acids (e.g., contains no free omega-3 fatty acids at all).

[0202] In another embodiment according to the second alternative aspect of the present invention, the pharmaceutical composition contains less than 10% on the weight or dry weight of the pharmaceutical composition, such as less than 5%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, or less than 0.001% of free omega-3 fatty acids.

[0203] In another embodiment according to the second alternative aspect of the present invention, the pharmaceutical composition does not contain any appreciable amount of free fatty acids (e.g., contains no free fatty acids at all).

[0204] In another embodiment according to the second alternative aspect of the present invention, the pharmaceutical composition contains less than 10% on the weight or dry weight of the pharmaceutical composition, such as less than 5%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, or less than 0.001% of free fatty acids.

[0205] In another embodiment according to the second alternative aspect of the present invention, the pharmaceutical composition does not contain any appreciable amount of free myristic acid (e.g., contains no free myristic acid at all).

[0206] In another embodiment according to the second alternative aspect of the present invention, the pharmaceutical composition contains less than 10%, such as less than 5%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, or less than 0.001% free myristic acid, based on the weight or dry weight of the pharmaceutical composition.

[0207] In another embodiment according to the second alternative aspect of the present invention, the pharmaceutical composition does not contain any appreciable amount of free palmitic acid (e.g., contains no free palmitic acid at all).

[0208] In another embodiment according to the second alternative aspect of the present invention, the pharmaceutical composition contains less than 10%, such as less than 5%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, or less than 0.001% free palmitic acid, based on the weight or dry weight of the pharmaceutical composition.

[0209] In some embodiments, the pharmaceutical composition of the second alternative aspect of the present invention is provided for use in increasing the amount of EPA, DHA, DPA, and / or SDA in a target tissue or organ, such as the brain, by intravascular administration, such as intravenous administration.

[0210] A further aspect of the present invention relates to a pharmaceutical composition according to the second alternative aspect of the present invention for use as a medicament, wherein the pharmaceutical composition is administered by oral administration.

[0211] A further aspect of the present invention relates to a pharmaceutical composition according to the second alternative aspect of the present invention for use in prophylaxis and / or treatment, wherein the pharmaceutical composition is administered by oral administration.

[0212] A further aspect of the present invention relates to a pharmaceutical composition according to the second alternative aspect of the present invention for use in prophylaxis and / or treatment of a condition that may benefit from an increase in brain EPA and / or DHA levels, wherein the pharmaceutical composition is administered by oral administration.

[0213] In one embodiment, a condition that can benefit from an increase in brain DHA and / or EPA levels is a neurological condition such as depression, schizophrenia, Alzheimer's disease, Parkinson's disease, or traumatic brain injury.

[0214] In a preferred embodiment according to a fifth aspect of the present invention, a condition that can benefit from an increase in brain DHA level is traumatic brain injury.

[0215] In a preferred embodiment according to a fifth aspect of the present invention, a condition that can benefit from an increase in brain DHA level is traumatic brain injury, and the pharmaceutical composition is administered in combination with i) a progestogen or a prodrug thereof, and / or ii) an estrogen or a prodrug thereof.

[0216] In a preferred embodiment according to a fifth aspect of the present invention, a condition that can benefit from an increase in brain DHA level is traumatic brain injury, and the traumatic brain injury is derived from a closed head injury.

[0217] In one embodiment according to a fifth aspect of the present invention, a condition that can benefit from an increase in brain DHA level is post-traumatic stress disorder (PTSD) or anxiety.

[0218] In another embodiment, a condition that can benefit from an increase in brain DHA and / or EPA levels is a traumatic brain injury such as a traumatic brain injury derived from a closed head injury.

[0219] In one embodiment, a condition that can benefit from an increase in brain DHA and / or EPA levels is post-traumatic stress disorder (PTSD) or anxiety.

[0220] A further aspect of the present invention relates to a pharmaceutical composition according to a second alternative aspect of the present invention for use in treating, preventing, or improving cognitive and / or cognitive diseases, disorders, or dysfunctions (memory, concentration, learning (deficits)), or for treating or preventing neurodegenerative disorders, the pharmaceutical composition being administered by oral administration.

[0221] In some embodiments, the cognitive disorder, impairment, or dysfunction is selected from attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), autism / autism spectrum disorder (ASD) (dyslexia, age-related memory impairment and learning disorder, amnesia, mild cognitive impairment, cognitive impairment without dementia, pre-onset Alzheimer's disease, Alzheimer's disease, epilepsy, Pick's disease, Huntington's disease, Parkinson's disease, Lewy body dementia, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, spinocerebellar ataxia type 1, type 2, type 3, type 6, type 7, amyotrophic lateral sclerosis, familial spastic paraplegia, spinal muscular atrophy, bulbar spinal muscular atrophy, age-related cognitive decline, cognitive decline, moderate mental dysfunction, mental dysfunction as a result of aging, conditions affecting the intensity of brain waves and / or glucose utilization in the brain, stress, anxiety, concentration and attention dysfunction, mood deterioration, general cognitive and mental well-being disorder, neurodevelopmental disorder, neurodegenerative disorder, hormonal disorder, neurological disorder, or any combination thereof. In certain embodiments, the cognitive impairment is a memory impairment.

[0222] A further aspect of the invention relates to a pharmaceutical composition according to a second alternative aspect of the invention for use in the treatment or prevention of a cardiovascular disorder or metabolic syndrome, the pharmaceutical composition being administered by oral administration.

[0223] In some embodiments, the cardiovascular disorder is selected from atherosclerosis, arteriosclerosis, coronary heart disease (coronary artery disease) (CHD or CAD), acute coronary syndrome (or ACS), valvular heart disease, aortic and mitral valve disorders, arrhythmia / atrial fibrillation, cardiomyopathy and heart failure, angina pectoris, acute myocardial infarction (or AMI), hypertension, orthostatic hypotension, shock, embolism (pulmonary and venous), endocarditis, diseases of the arteries, aorta and its branches, peripheral vascular system disorders (peripheral artery disease or PAD), Kawasaki disease, congenital heart disease (cardiovascular disorder) and stroke (cerebrovascular disease), dyslipidemia, hypertriglyceridemia, hypertension, heart failure, cardiac arrhythmia, low HDL level, high LDL level, stable angina pectoris, coronary heart disease, acute myocardial infarction, secondary prevention of myocardial infarction, cardiomyopathy, endocarditis, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypercholesterolemia, stroke, hyperlipidemia, hyperlipoproteinemia, chronic kidney disease, intermittent claudication, hyperphosphatemia, omega-3 deficiency, phospholipid deficiency, atherosclerotic carotid artery disease, peripheral artery disease, diabetic nephropathy, hypercholesterolemia in HIV infection, acute coronary syndrome (ACS), non-alcoholic fatty liver disease / non-alcoholic steatohepatitis (NAFLD / NASH), arterial occlusive disease, cerebral atherosclerosis, arteriosclerosis, cerebrovascular disorder, myocardial ischemia, coagulation disorders leading to intravascular thrombosis, and diabetic autonomic neuropathy.

[0224] A further aspect of the invention relates to a pharmaceutical composition according to a second alternative aspect of the invention for use in inhibiting, preventing, or treating inflammation or an inflammatory disease, the pharmaceutical composition being administered by oral administration.

[0225] In some embodiments, the inflammation or inflammatory disease is organ transplant rejection; reperfusion injury resulting from organ transplantation including, but not limited to, transplantation of the following organs: heart, lung, liver, and kidney (see Grupp et al., J. Mol. Cell. Cardiol. 31:297-303 (1999)); chronic inflammatory joint diseases including arthritis, rheumatoid arthritis, osteoarthritis, and bone diseases associated with increased bone resorption; inflammatory bowel diseases (IBD) such as ileitis, ulcerative colitis (UC), Barrett's syndrome, and Crohn's disease (CD); inflammatory lung diseases such as asthma, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD); inflammatory eye diseases including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmia, and endophthalmitis; chronic inflammatory gum diseases including gingivitis and periodontitis; inflammatory kidney diseases including uremic complications, glomerulonephritis, and nephrosis; inflammatory skin diseases including sclerodermatitis, psoriasis, and eczema; chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, epilepsy, amyotrophic lateral sclerosis, and viral or autoimmune encephalitis, pregnancy-induced hypertensive nephropathy; central nervous system inflammatory diseases selected from chronic liver failure, brain and spinal cord trauma, and cancer. The inflammatory disease can also be a systemic inflammation of the body exemplified by, for example, gram-positive or gram-negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to inflammatory cytokines, for example, shock associated with inflammatory cytokines. Such shock can be induced, for example, by chemotherapeutic agents administered as cancer therapeutics. Other disorders include depression, obesity, allergic diseases, acute cardiovascular events, muscle wasting diseases, and cancer cachexia. Inflammation resulting from surgery and trauma can also be treated with the lipid compositions.

[0226] A further aspect of the invention relates to a pharmaceutical composition according to a second alternative aspect of the invention for use in the treatment of diseases or conditions associated with erythrocytes and cell membranes, particularly diseases or conditions associated with abnormalities of erythrocyte cell membranes, wherein the pharmaceutical composition is administered by oral administration.

[0227] In some embodiments, the condition or disease is sickle cell disease, sickle cell anemia, or the sickle cell trait. In some embodiments, the condition or disease is (alpha, beta, or delta) thalassemia, hemoglobinopathy (hemoglobin E, hemoglobin S, or hemoglobin C) - associated thalassemia, splenomegaly, or membrane abnormalities, such as acanthocytes or spur / spike cells, target red blood cells (target cells), echinocytes (burr cells), elliptocytes and ovalocytes, spherocytes, stomatocytes (mouth cells), and dacrocytes ("bite cells").

[0228] In one embodiment, the pharmaceutical composition is administered to a subject less than 10 years old, such as less than 1 year old, less than 1 month old, or a neonate.

[0229] In one embodiment, the pharmaceutical composition is administered to a subject over 60 years old, such as over 70 years old, over 80 years old, or an elderly subject.

[0230] In one embodiment, the pharmaceutical composition is administered to a subject who is about 10 - 20 years old, about 20 - 50 years old, about 50 - 100 years old, about 60 - 100 years old, or about 70 - 100 years old.

[0231] In one embodiment, the pharmaceutical composition is administered to a subject who is female.

[0232] In one embodiment, the pharmaceutical composition is administered to a subject who is male.

[0233] In one embodiment, the traumatic brain injury does not include brain injury induced by ischemia / reperfusion.

[0234] In some embodiments, the closed head injury is a concussion or a contusion. Subjects at risk of such injury can include, among others, subjects participating in a sports event associated with the occurrence of a concussion. Exemplary subjects in this category can include, among others, football players, boxers, and hockey players.

[0235] A further aspect of the invention relates to a pharmaceutical composition according to a second alternative aspect of the invention for use in the prevention and / or treatment of a condition that can benefit from an increase in the levels of EPA and / or DHA in the intestine, such as the intestinal mucosa, the pharmaceutical composition being administered by oral administration.

[0236] In one embodiment, the condition that can benefit from an increase in the levels of EPA and / or DHA in the intestine, such as the intestinal mucosa, is selected from the group consisting of inflammatory bowel diseases (IBD) such as ileitis, ulcerative colitis (UC), Barrett's syndrome, and Crohn's disease (CD).

[0237] A further aspect of the invention relates to a pharmaceutical composition according to a second alternative aspect of the invention for use in the prevention and / or treatment of a condition that can benefit from an increase in the levels of EPA and / or DHA in the eye, such as the retina of the eye, the pharmaceutical composition being administered by oral administration.

[0238] In one embodiment, the condition that can benefit from an increase in the levels of EPA and / or DHA in the eye, such as the retina of the eye, is selected from the group consisting of: i) degenerative diseases of the retina such as macular degeneration, particularly age-related macular degeneration (ARMD) and retinitis pigmentosa; ii) vascular diseases of the retina in diabetic patients such as proliferative retinopathy in diabetic patients, clinically significant macular edema in diabetic retinopathy patients; iii) cataracts such as age-related cataracts in all patients, diabetic patients, and ARMD patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0239]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10A

Figure 10B

Figure 11A

Figure 11B

Figure 12A

Figure 12B

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

[0240] [Definitions] Throughout the present disclosure, related terms should be understood in accordance with their ordinary meanings established in the relevant technical fields, namely, the technical fields of pharmaceutical chemistry, medicine, biology, biochemistry, and physiology. However, as described below, further explanations and descriptions are provided for specific terms. [Chemical formula]

[0241] The terms "2-lysoPC-DHA" and "2-LPC-DHA" are used interchangeably herein and refer to the compound according to formula 1 (wherein R 2 is OH).

[0242] The terms "2-lysoPC-EPA" and "2-LPC-EPA" are used interchangeably herein and refer to the compound of formula 2 (wherein R 2 is OH).

[0243] The terms "2-lysoPC-DPA" and "2-LPC-DPA" are used interchangeably herein and refer to the compound of formula 5 (wherein R 2 is OH).

[0244] The terms "2-lysoPC-SDA" and "2-LPC-SDA" are used interchangeably herein and refer to the compound of formula 6 (wherein R 2 is OH).

[0245] The terms "1-lysoPC-DHA" and "1-LPC-DHA" are used interchangeably herein and refer to the compound of formula 3 (wherein R 1 is OH).

[0246] The terms "1-lysoPC-EPA" and "1-LPC-EPA" are used interchangeably herein and refer to the compound of formula 4 (wherein R 1 is OH).

[0247] The terms "1-lysoPC-DPA" and "1-LPC-DPA" are used interchangeably herein and refer to the compound of formula 7 (wherein R 1 is OH).

[0248] The terms "1-lysoPC-SDA" and "1-LPC-SDA" are used interchangeably herein and refer to the compound of formula 8 (wherein R 1 is OH).

[0249] The terms "lysoPC-DHA" and "LPC-DHA" are used interchangeably herein and include both 1-lysoPC-DHA and 2-lysoPC-DHA.

[0250] The terms "lysoPC-EPA" and "LPC-EPA" are used interchangeably herein and include both 1-lysoPC-EPA and 2-lysoPC-EPA.

[0251] The terms "lysoPC-DPA" and "LPC-DPA" are used interchangeably herein and include both 1-lysoPC-DPA and 2-lysoPC-DPA.

[0252] The terms "lysoPC-SDA" and "LPC-SDA" are used interchangeably herein and include both 1-lysoPC-SDA and 2-lysoPC-SDA.

[0253] The term "EPA" refers to eicosapentaenoic acid.

[0254] The term "DHA" refers to docosahexaenoic acid.

[0255] The term "DPA" refers to n3-docosapentaenoic acid. The term "n3" indicates that the compound is an omega-3 fatty acid.

[0256] The term "SDA" refers to stearidonic acid.

[0257] The term "brain EPA level" refers to the level of EPA in the brain.

[0258] The term "brain DHA level" refers to the level of DHA in the brain.

[0259] The term "brain DPA level" refers to the level of DPA in the brain.

[0260] The term "brain SDA level" refers to the level of SDA in the brain.

[0261] As used herein, the term "intravenous administration" refers to a mode of administration in which a liquid substance is delivered directly into a vein. The intravenous route of administration can be used for injection (using a syringe under high pressure) or infusion (usually using only the pressure provided by gravity).

[0262] The term "pharmaceutically acceptable excipient" is different from one or more active ingredients recited in the claims and refers to substances 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, tricaprylin, tricaprin, vitamin E, antioxidants, α-tocopherol, ascorbic acid, deferoxamine mesylate, thioglycolic acid, emulsifiers, lecithin, polysorbate 80, methylcellulose, gelatin, serum albumin, sorbitan laurate, sorbitan oleate, sorbitan trioleate, polyethylene glycol (PEG), PEG400, polyethylene glycol-modified phosphatidylethanolamine (PEG-PE), poloxamer, glycerin, sorbitol, xylitol, pH adjusters; sodium hydroxide, antibacterial agents EDTA, sodium benzoate, benzyl alcohol, and proteins such as albumin. Pharmaceutically acceptable excipients must be acceptable in the sense that they are compatible with the other components of the composition and not harmful to its recipient.

[0263] As used herein, the term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counterions well known in the art, and by way of example only, includes sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, and when the molecule contains a basic functional group, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. Suitable salts are those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of pharmaceutical salts properties, Selection, and Use; 2002.

[0264] As used herein, the term "prevention" means a treatment taken to prevent, rather than treat, a disease or condition.

[0265] As used herein, the term "prodrug" is a compound that is metabolized (i.e., converted in the body) to a pharmacologically active drug after administration.

[0266] As used herein, "traumatic brain injury" or "TBI" refers to acquired brain injury or head injury when trauma causes damage to the brain. The injury may be focal, i.e., limited to one area of the brain, or may be diffuse, affecting multiple areas of the brain.

[0267] As used herein, "closed head injury" refers to brain injury when the head suddenly hits an object violently but the object does not penetrate the skull.

DETAILED DESCRIPTION OF THE INVENTION

[0268] Unless otherwise specifically defined herein, all technical and scientific terms used have the same meaning as commonly understood by one of ordinary skill in the fields of medicine, pharmacology, pharmaceutical chemistry, biology, biochemistry, and physiology.

[0269] All methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, but the preferred methods and materials are described herein. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, this specification, including definitions, will control.

[0270] When numerical limits or ranges are described herein, endpoints are included. Also, all values and subranges within the numerical limits or ranges are specifically included as if explicitly written.

[0271] As noted above, there are many medical conditions, including neurological conditions (such as TBI), PTSD, and anxiety, that are either associated with low brain omega-3 levels or can benefit from an increase in brain omega-3 levels. DHA, EPA, DPA, and SDA are omega-3 fatty acids of particular interest in this regard.

[0272] Accordingly, there is a need for means to increase omega-3 fatty acid levels in the brain, particularly means for increasing the levels of DHA, EPA, DPA, and / or SDA in the brain.

[0273] Unlike other tissues, omega-3 uptake does not occur via lipoprotein receptors in the brain, and there is currently some debate regarding the molecular carriers of omega-3 to the brain. In prior studies in animals, it has been reported that DHA in the form of LPC crosses the BBB at a much faster rate than free fatty acids. On the other hand, recent kinetic studies by Chen et al. (Sci Rep. 2015;5:15791) suggested that free DHA in plasma is the major pool supplying the brain, but also reported that the uptake of LPC-DHA into the brain is higher than that of free DHA.

[0274] Therefore, since it seems that an increase in the level of omega-3 fatty acids in serum is a necessary condition for increasing the level of omega-3 fatty acids in the brain, there is a need for means to increase the level of omega-3 fatty acids in serum.

[0275] Since the form of omega-3 in serum can potentially affect the uptake of these fatty acids into the brain, it may be of utmost importance to identify an omega-3 carrier that can deliver the form of omega-3 that is efficiently taken up by the brain to serum. Based on the recent identification of a specific transporter (Mfsd2a) in the endothelial cells of the blood-brain barrier (BBB) that selectively transports LPC-type DHA across the BBB, there is a basis to assume that increasing the level of LPC-omega-3 in serum is an efficient way to increase the content of each omega-3 fatty acid in the brain.

[0276] Therefore, there is an urgent need for means to increase the level of LPC-omega-3 in serum.

[0277] Dietary DHA provided at the sn-1 position of phosphatidylcholine (PC) or in the form of LPC in the diet has already been suggested to be an effective way to increase the level of LPC-DHA in serum. However, in the case of neurological conditions such as TBI, the time from ingesting dietary DHA to increasing the level of LPC-DHA in serum can be of utmost importance.

[0278] Therefore, in the art, there is an urgent need for means to rapidly increase the level of LPC-DHA in serum.

[0279] Furthermore, LPC is known to promote the disruption of cell membranes at relatively high concentrations and is therefore only found in trace amounts in most animal tissues (US2016 / 0022711, PharmSciTech, Vol. 11, No. 4, December 2010).

[0280] Accordingly, there is a need in the art for means to increase the levels of LPC-omega-3 in serum without causing unacceptable levels of cell membrane disruption and other potential side effects, particularly means to increase the levels of LPC-DHA, LPC-EPA, LPC-DPA, and / or LPC-SDA in serum.

[0281] Another issue to consider is the need for a continuous supply of DHA to the brain. It is well known that administered drugs are typically removed from circulation by various excretion processes, and such processes for excreting LPC-omega-3 can, of course, potentially affect the long-term concentration of LPC-omega-3 in serum, which is also assumed to have a direct adverse effect on uptake into the brain.

[0282] Accordingly, there is an urgent need in the art for means to maintain high levels of LPC-omega-3 in serum over a long period, as this is considered a necessary condition for ensuring a continuous supply of omega-3 to the brain.

[0283] To explore solutions to the above needs, a significant amount of resources has been invested in oral intake of various forms of omega-3 fatty acids, including tests on oral intake of LPC-omega-3, particularly focusing on LPC-DHA and LPC-EPA (PCT / IB2018 / 0001588).

[0284] The results of that project (oral intake of LPC-DHA and LPC-EPA) were excellent with respect to uptake of omega-3 fatty acids into the brain, but there was continued discussion about ways to further improve uptake. Thorough discussions were held about alternative forms of omega-3 fatty acids, ways of formulating fatty acids, and also various encapsulation techniques. Also discussed was whether it would be of interest to investigate another way of administering omega-3 fatty acids.

[0285] Parenteral administration of omega-3 fatty acids, particularly intravascular administration such as intravenous administration, may rapidly increase the levels of omega-3 fatty acids in the serum, and as a result, the levels of omega-3 fatty acids entering the brain may rapidly increase. Furthermore, this may also be an effective way to avoid the adverse effects of digestive enzymes that occur via the oral route. However, it has been recognized that the rapid increase in serum LPC-omega-3 levels can cause unacceptable levels of cell membrane disruption, and there may be other potential side effects. Furthermore, LPC is found only in trace amounts in most animal tissues and is known to be associated with side effects (i.e., disruption of cell membranes) when present in large amounts in the serum. Therefore, there is also a high risk that there is an effective mechanism for excreting such compounds from the circulation, which is assumed to have an adverse effect on the long-term uptake of omega-3 into the brain. Furthermore, when transitioning from the oral route to the parenteral route, there are always patient compliance issues. Therefore, the effects of the parenteral route must be significantly superior to the oral route if it is to be of any commercial interest.

[0286] Despite the risks described above, it was decided to further investigate whether the intravascular administration of omega-3 fatty acids, particularly LPC-EPA and LPC-DHA, particularly intravenous administration, represents a promising strategy for increasing omega-3 fatty acid levels in the brain without causing unacceptable side effects.

[0287] Since it was already known that LPC is an effective carrier for transporting molecules across the BBB, LPC-omega-3 was used in this study. To enable measurement of the amount of omega-3 fatty acids transported to the brain, LPC-omega-3 in which the omega-3 fatty acids were labeled with a radioactive marker was used. Furthermore, to ensure that only non-oxidized fatty acids were measured, a radioactive marker was placed on the acyl carbon of the fatty acid moiety, i.e., carbon number 1 (Example 1 provides a diagram showing the location where the radioactive marker is located).

[0288] The Mfsd2a transporter of the BBB is known to specifically transport LPC-omega-3 but not free omega-3. Previous studies have suggested that the transport across the BBB is not specific with respect to the fatty acid bound to the LPC molecule, but there is evidence indicating that the fatty acid bound to LPC needs to be of a specific length in order to be transported across the BBB. It has been shown in the prior art that a length of 14 or more carbon atoms is essential for transport across the BBB by the Mfsd2a transporter. DHA, EPA, SDA, and DPA are considered to be extremely important for the positive effects on human health, and all of these have more than 14 carbon atoms. Therefore, based on the information we currently have, each of these fatty acids should be efficiently transported across the BBB when bound to LPC. Accordingly, LPC-DHA and LPC-EPA were selected as the model molecules for this study, but all the data provided herein regarding uptake into the brain also shows the expected uptake profiles of the other two omega-3 fatty acids mentioned above again, namely, SDA and DPA.

[0289] In this study, since LPC-DHA and LPC-EPA were to be administered by intravenous injection, the active ingredients were mixed with one or more pharmaceutically acceptable excipients. Intralipid (IV) supplied by Sigma Aldrich was selected as one or more pharmaceutically acceptable excipients because it is compatible with oily substances. For details of the pharmaceutical composition used in this study, please refer to Example 1.

[0290] Sixteen male Sprague Dawley rats were each administered a single intravenous injection of either LPC-DHA or LPC-EPA. The dose was administered directly into the tail vein as a slow bolus over 30 seconds. One rat was euthanized by excessive intake of carbon dioxide gas at each of the following times: 0.5, 3, 8, 24, 72, 96, 168, and 336 hours after administration. Each cadaver was immediately frozen with a hexane / solid carbon dioxide mixture and then stored at approximately -20°C until further analysis.

[0291] As detailed in Example 2, frozen cadavers were subjected to quantitative whole-body autoradiography to examine the uptake of DHA and EPA into the brain at 0.5, 3, 8, 24, 72, 96, 168, and 336 hours after administration.

[0292] The final results for LPC-DHA are shown in Example 2, Table 1.1, and the data are also shown in Figures 1-4. The final results for LPC-EPA are shown in Example 2, Table 2.1, and the data are also shown in Figures 5-8.

[0293] The first results obtained were data regarding blood LPC-DHA levels (Figure 2). As expected, intravenous administration of LPC-DHA immediately increased blood LPC-DHA levels significantly. However, the levels of LPC-DHA also decreased very rapidly over time, clearly indicating the existence of an effective mechanism for excreting the compound from the blood. Since blood LPC-DHA levels may be very important regarding uptake into the brain, it was recognized that this could be the excretion problem to be solved in order to ensure continuous and high uptake of DHA into the brain.

[0294] The next results obtained were data regarding the uptake of LPC-DHA in the kidneys (Figure 3). As expected, the amount of LPC-DHA in the kidneys over time followed the trend seen in the blood. The LPC-DHA levels in the kidneys increased immediately at the time of administration but the LPC-DHA levels decreased very rapidly over time. Similar results were seen for the uptake of LPC-DHA into the spleen (Figure 4).

[0295] Based on the above results, similar to what was observed in blood, spleen, and kidney, the amount of LPC-DHA in the brain was expected to increase immediately after administration but also to rapidly decline over time. However, in contrast to what was expected, the results of the brain uptake study (Figure 1) surprisingly showed that the amount of LPC-DHA in the brain did not follow the trend seen in blood, kidney, and spleen. In contrast, intravenous administration of LPC-DHA immediately elevated the LPC-DHA level in the brain, and the LPC-DHA level continued to rise over time well beyond the point at which the blood LPC-DHA level had significantly decreased. These highly surprising results clearly indicate that intravenous administration of LPC-DHA can be an extremely effective way to rapidly increase DHA levels in the brain even after just a single injection and to maintain high levels of DHA in the brain for an extended period.

[0296] The results regarding LPC-DHA (Figures 1 - 4) are similar to those obtained with LPC-EPA (Figures 5 - 8), clearly indicating that intravenous administration of LPC-omega-3 can be an extremely effective way to rapidly increase omega-3 levels in the brain even after just a single injection and to maintain omega-3 levels in the brain for an extended period. Similar data may be obtained for other omega-3 fatty acids, but DHA, EPA, DPA, SDA, and perhaps also ALA are considered to be of particular interest in the present application.

[0297] The data presented herein regarding LPC-EPA are based on the measured amount of radioactivity present in the brain after intravenous administration of radiolabeled LPC-EPA. Therefore, it should be understood that the data presented herein do not necessarily reflect the fate of the EPA molecule itself. For example, if EPA is converted to DHA in the brain, the data presented herein may represent the amount of radiolabeled EPA + radiolabeled DHA. The same may be true for the data presented regarding LPC-DHA.

[0298] Considering the examples presented in this specification, it is asserted that all of the above-described needs in the art are met by the pharmaceutical composition of the claimed invention, particularly the pharmaceutical composition of the claimed invention for use as a medicament (this medicament is administered by intravascular administration, particularly intravenous administration).

[0299] Accordingly, a first aspect of the present invention relates to a pharmaceutical composition suitable for intravascular administration such as intravenous administration, the pharmaceutical composition comprising one or more active ingredients and one or more pharmaceutically acceptable excipients, wherein the one or more active ingredients are selected from the group consisting of a compound according to any one of Formulas 1 to 8, or a pharmaceutically acceptable salt thereof, and any combination thereof,

Chemical formula

[0300] In one embodiment according to the present invention, R 1 is OH and R 2 is OH.

[0301] An alternative aspect according to the present invention relates to the first aspect of the present invention wherein R 1 is OH or a protecting group and R 2 is OH or a protecting group. An example of a protecting group is O-CO-(CH 2 ) n -CH 3 wherein n is 0, 1 or 2.

[0302] The protecting group is preferably a group that does not interfere with the binding to the Mfsd2a transporter and at the same time blocks the translocation of omega-3 (i.e., DHA, EPA, SDA, and DPA) acyl groups. When the omega-3 fatty acid moiety (e.g., DHA moiety, EPA moiety, SDA moiety, and DPA moiety) is located at the sn-1 position of the glycerol backbone, the protecting group usually blocks the translocation of the omega-3 fatty acid moiety from the sn-1 position to the sn-2 position. When the omega-3 fatty acid moiety (e.g., DHA moiety) is located at the sn-2 position of the glycerol backbone, the protecting group usually blocks the translocation of the omega-3 fatty acid moiety from the sn-2 position to the sn-1 position.

[0303] Formulas 1 and 3 refer to compounds to which a DHA moiety is attached. Formulas 2 and 4 refer to compounds to which an EPA moiety is attached. Formulas 5 and 7 refer to compounds to which an n-3 DPA moiety is attached. Formulas 6 and 8 refer to compounds to which an SDA moiety is attached. In practice, the DHA, EPA, DPA, and SDA moieties can in principle be replaced by any omega-3 fatty acid as long as the omega-3 fatty acid has 14 or more C atoms in its chain. However, DHA, EPA, DPA, and SDA are considered to be the most relevant with respect to the health of the human brain.

[0304] An alternative embodiment according to the present invention relates to the first embodiment of the present invention, wherein the DHA, EPA, DPA, and SDA moieties are replaced by any omega-3 moiety that is at least i) any omega-3 moiety having 14 or more C atoms in its chain, or ii) any omega-3 moiety having a length corresponding to a chain length of 14 or more C atoms.

[0305] An alternative embodiment according to the present invention relates to the first embodiment of the present invention, wherein the DHA, EPA, DPA, and SDA moieties are replaced by DHA, EPA, DPA, ALA, and SDA moieties.

[0306] In one embodiment according to the present invention, the intravascular administration is intravenous administration. The intravenous administration can be performed by injection (e.g., using a syringe at high pressure) or infusion (e.g., using only the pressure exerted by gravity).

[0307] It has already been recognized that when transitioning from oral administration to intravenous administration, problems with patient compliance often occur, and with regard to intravascular administration, particularly intravenous administration, it is of course an advantage to minimize the number of injections as much as possible. The surprising results presented herein are based on a single injection.

[0308] Thus, in one embodiment according to the present invention, intravenous administration is performed by one or more injections, preferably less than 5 injections, more preferably less than 3 injections, and most preferably less than 2 injections, for example a single injection. The latter technical effect has already been demonstrated in Example 2 of this application.

[0309] One or more active ingredients (wherein R 1 is OH and R 2 is OH) mentioned in the first aspect of the present invention are all LPC molecules having any one of DHA, EPA, DPA, or SDA molecules bound to the triacylglycerol moiety of LPC. The technical effects of LPC-DHA and LPC-EPA have been demonstrated. Based on the data shown in WO2018162617 and WO2008068413, it is also considered that similar effects can be obtained for one or more active ingredients (wherein R 1 is O-CO-(CH 2 ) n -CH 3 and R 2 is O-CO-(CH 2 ) n -CH 3 and n is 0, 1 or 2, particularly n = 0) mentioned in the first aspect of the present invention.

[0310] The results shown in this specification are excellent. However, for example, by including a pharmaceutically acceptable carrier, the effect can be further improved. Liposomes can be a suitable carrier for the oily components of the present invention, for example, by providing a hydrophobic interior for oily substances and a hydrophilic exterior facing a hydrophilic environment. Furthermore, it is also known that LPC usually associates with proteins such as albumin in the blood to reduce the effective concentration of LPC. Therefore, in one embodiment according to the present invention, the pharmaceutical composition also contains a protein such as albumin suitable for reducing the effective concentration of one or more active ingredients when administered intravascularly or intravenously.

[0311] The pharmaceutical composition according to the present invention may or may not contain one or more solvents such as ethanol and / or water. When the composition contains one or more solvents, the amount of one or more active ingredients in the composition may be referred to as the dry weight percentage of the composition. However, when the composition does not contain one or more solvents, the amount of one or more active ingredients in the composition may be referred to as the weight percentage of the composition.

[0312] In one embodiment according to the present invention, the pharmaceutical composition may contain two or more combinations of one or more active ingredients. One of the active ingredients may have a DHA moiety bound to a glycerol backbone, and another active ingredient may have an EPA moiety bound to a glycerol backbone.

[0313] Accordingly, in one embodiment according to the present invention, the pharmaceutical composition comprises two or more combinations of one or more active ingredients. One of the active ingredients has a DHA moiety attached to a glycerol backbone, and the other active ingredient has an EPA moiety attached to a glycerol backbone. In a preferred embodiment, there is a specific molar ratio between the active ingredient having a DHA moiety attached to a glycerol backbone and the active ingredient having an EPA moiety attached to a glycerol backbone. The molar ratio of the active ingredient having a DHA moiety attached to a glycerol backbone to the active ingredient having an EPA moiety attached to a glycerol backbone is preferably in the range of 1:1 to 10:1, for example in the range of 1:1 to 7:1, or in the range of 1:1 to 5:1, or in the range of 1:1 to 3:1. In another embodiment according to the present invention, the molar ratio of the active ingredient having an EPA moiety attached to a glycerol backbone to the active ingredient having a DHA moiety attached to a glycerol backbone is preferably in the range of 1:1 to 10:1, for example, in the range of 1:1 to 7:1, or in the range of 1:1 to 5:1, or in the range of 1:1 to 3:1.

[0314] Please refer to the following example for explaining the method of calculating the molar ratio. When the composition contains 10 mol of LPC-DHA and 2 mol of LPC-EPA, the molar ratio of the active ingredient having a DHA moiety attached to a glycerol backbone to the active ingredient having an EPA moiety attached to a glycerol backbone is 10:2, i.e., 5:1. Unless otherwise specified, the number of moles of LPC-EPA is the number of moles of 1-LPC-EPA + the number of moles of 2-LPC-EPA, and the number of moles of LPC-DHA is the number of moles of 1-LPC-DHA + the number of moles of 2-LPC-DHA.

[0315] It has already been discussed that the position of the omega-3 fatty acid moiety on the glycerol backbone can affect the uptake of the fatty acid into the brain. Thus, in one embodiment according to the present invention, the described omega-3 fatty acid moiety is attached to the sn1 position of the glycerol backbone. In another embodiment according to the present invention, the described omega-3 fatty acid moiety is attached to the sn2 position of the glycerol backbone. In an alternative embodiment according to the present invention, there is a specific molar ratio of an active ingredient having an omega-3 fatty acid moiety attached to the sn1 position of the glycerol backbone to an active ingredient having an omega-3 fatty acid moiety attached to the sn1 position of the glycerol backbone. The molar ratio of the active ingredient having an omega-3 fatty acid moiety attached to the sn2 position of the glycerol backbone to the active ingredient having an omega-3 fatty acid moiety attached to the sn1 position of the glycerol backbone is preferably in the range of 1:8 to 18:1, for example, in the range of 1:8 to 15:1, or in the range of 1:8 to 10:1.

[0316] Please refer to the following example for explaining the method of calculating the molar ratio. When the composition contains 5 mol of 2-LPC-DHA, 5 mol of 2-LPC-EPA, and 2 mol of 1-LPC-DHA, the molar ratio of the active ingredient having an omega-3 fatty acid moiety attached to the sn1 position of the glycerol backbone to the active ingredient having an omega-3 fatty acid moiety attached to the sn2 position of the glycerol backbone is 10:2, that is, 5:1.

[0317] The second aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use as a medicament, and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0318] The third aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in prevention and / or treatment, and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0319] The fourth aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in the prevention and / or treatment of a condition that can benefit from an increase in brain EPA levels, and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0320] Depression is an example of an indication that can benefit from an increase in brain EPA levels.

[0321] According to the American Psychiatric Association, depression (major depressive disorder) is a common and serious medical illness that negatively affects how you feel, the way you think, and how you act. Depression causes feelings of sadness and / or a loss of interest in activities you once enjoyed. Depression can cause a variety of emotional and physical problems, and can decrease a person's ability to function at work and at home.

[0322] The symptoms of depression can vary from mild to severe and can include: - Feeling sad or having a depressed mood; - Loss of interest or pleasure in activities once enjoyed; - Changes in appetite - weight loss or gain unrelated to dieting; - Sleep disturbances or excessive sleeping; - Loss of energy or increased fatigue; - Increased purposeless physical activity (e.g., hand wringing or pacing) or slowed movements and speech (actions observable by others); - Feelings of worthlessness or guilt; - Difficulty thinking, concentrating, or making decisions; - Thoughts of death or suicide, and may include: A diagnosis of depression requires that the symptoms have been present for at least two weeks.

[0323] A fifth aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in the prevention and / or treatment of a condition that can benefit from an increase in brain DHA levels, the pharmaceutical composition being administered by intravascular administration such as intravenous administration.

[0324] In one embodiment according to the fifth aspect of the present invention, the condition that can benefit from an increase in brain DHA levels is a neurological condition.

[0325] In another embodiment according to the fifth aspect of the present invention, the neurological condition is depression, schizophrenia, Alzheimer's disease, Parkinson's disease, or traumatic brain injury.

[0326] According to the American Psychiatric Association, schizophrenia is a chronic brain disorder. When schizophrenia is active, symptoms can include delusions, hallucinations, problems with thinking and concentration, and lack of motivation. However, with treatment, most symptoms of schizophrenia can be significantly improved.

[0327] When the disease is active, the disease can be characterized by episodes in which the patient is unable to distinguish between real and unrealistic experiences. As with any other disease, the severity, duration, and frequency of symptoms can vary, but in people with schizophrenia, the incidence of severe psychotic symptoms often decreases over the patient's lifetime. Symptoms are classified into several categories: - Positive psychotic symptoms: Hallucinations such as auditory hallucinations, paranoid delusions, and excesses or distortions of cognition, beliefs, and behavior. - Negative symptoms: Loss or reduction in the ability to initiate plans, speak, express emotions, or discover pleasure. - Disorganization symptoms: Disordered and chaotic thinking and speech, problems with logical thinking, and sometimes strange behavior or abnormal movements. - Cognitive impairment: Problems related to decreased attention, concentration, memory, and educational achievement.

[0328] Parkinson's disease (PD) is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. As the disease worsens, non-motor symptoms become more common. Usually, symptoms develop slowly. The most obvious initial symptoms of the disease are tremors, rigidity, slowness of movement, and difficulty walking. Problems with thinking and behavior can also occur. Dementia is common in the advanced stages of the disease. Depression and anxiety are also common and occur in more than one-third of PD patients. Other symptoms include problems with sensation, sleep, and mood. The main motor symptoms are collectively referred to as "parkinsonism" or "Parkinson's syndrome."

[0329] In a preferred embodiment according to the fifth aspect of the present invention, a condition that can benefit from an increase in brain DHA level is traumatic brain injury.

[0330] Traumatic brain injury (TBI) is a head injury caused by trauma to the brain. The injury may be limited to one area of the brain (localized) or may involve multiple areas of the brain (diffuse). TBI can be mild, moderate, or severe. Some symptoms appear immediately, while others may not appear for days, weeks, months, or even years after the TBI event(s). Symptoms of mild TBI include headache, confusion, dizziness, blurred vision, mood changes, and dysfunction of cognitive functions such as memory, learning, and attention. Symptoms of moderate to severe TBI include, in addition to the symptoms observed in mild TBI, nausea, seizures or convulsions, inability to rotate the eyes, numbness of the extremities, and loss of coordinated movement.

[0331] The conventional concept of TBI also includes a primary injury stage and a secondary injury stage. The primary injury is represented by the moment of impact resulting from the application of kinetic energy and force vectors in either a linear acceleration-deceleration or rotational mode, or a combination of both. In addition to the movement of the brain within the cerebrospinal fluid space, contact of the brain with the irregular surface under the skull, establishment of micro-vacuum phenomena within the brain tissue, and traumatic and mechanical damage to nerve cells, particularly their processes, can result in both local and distal damage. At the clinical level, treatment attempts to minimize secondary injury by preventing or treating hypotension, hypoxia, and edema.

[0332] The tertiary stage of TBI includes what is currently recognized as progressive abnormalities in glucose utilization, cellular metabolism, and membrane fluidity, synaptic function, and structural integrity (Hovda, Crit Care Med. 35:663-4 (2007), Aoyama et al, Brain Res. 1230: 310-9 (2008) (Electronic publication on July 9, 2008). Generally, the axonal membrane is progressively damaged, ion leakage occurs, and axonal transport is disrupted. This concept is strengthened by the fact that recent autopsy findings in professional contact sports players show multiple and multi-region damage due to multiple concussions, with prominent tau antibody staining, indicating multifocal regions of damaged neurons and their processes (Omalu et al., Neurosurgery 57: 128-34 (2005), Omalu et al., Neurosurgery 59: 1086-92 (2006)).

[0333] Promising results of prophylactic treatment of TBI based on means suitable for increasing the level of DHA in the brain have been reported in the prior art (EP2488190).

[0334] In a preferred embodiment according to the fifth aspect of the present invention, the condition that can benefit from an increase in brain DHA level is traumatic brain injury, and the pharmaceutical composition is administered in combination with i) a progestogen or its prodrug, and / or ii) an estrogen or its prodrug.

[0335] In a preferred embodiment according to the fifth aspect of the present invention, the condition that can benefit from an increase in brain DHA level is traumatic brain injury, and the traumatic brain injury is derived from a closed head injury.

[0336] In one embodiment according to the fifth aspect of the present invention, the condition that can benefit from an increase in brain DHA level is post-traumatic stress disorder (PTSD) or anxiety.

[0337] The sixth aspect of the present invention relates to the pharmaceutical composition according to the first aspect of the present invention for use in the prevention and / or treatment of a condition that can benefit from an increase in brain DPA level, and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0338] The seventh aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in the prevention and / or treatment of a condition that can benefit from an increase in brain SDA level, and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0339] It should be understood that since at least a part of EPA in the brain can be converted to DPA, for example, a condition that can benefit from an increase in brain DHA level can be treated by increasing the brain EPA level.

[0340] The eighth aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in prevention and / or treatment (wherein R 1 and R 2 are OH), and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0341] The ninth aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in the prevention and / or treatment of a condition that can benefit from an increase in brain DHA level (wherein R 1 and R 2 are OH), and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0342] In one embodiment according to the ninth aspect of the present invention, the condition that can benefit from an increase in brain DHA level is a neurological condition, and the neurological condition is preferably traumatic brain injury.

[0343] In one embodiment according to the ninth aspect of the present invention, the condition that can benefit from an increase in brain DHA level is post-traumatic stress disorder (PTSD) or anxiety.

[0344] Post-traumatic stress disorder (PTSD) of the heart is a mental disorder that may develop after a person is exposed to a traumatic event such as sexual violence, war, traffic accidents, or other threats to human life. Symptoms may include disturbing thoughts, feelings, or dreams related to the event, mental or physical pain in response to triggers related to the trauma, attempts to avoid triggers related to the trauma, changes in ways of thinking and feeling, and increased fight-or-flight responses. These symptoms persist for more than one month after the event. Young children may be less likely to show distress but may instead express their memories through play. People with PTSD may have a relatively high risk of suicide and intentional self-harm.

[0345] In one embodiment according to any one of Aspects 2 to 9, the pharmaceutical composition is administered to a subject at risk of traumatic brain injury. To reduce the risk of the pathological effects of traumatic brain injury, it is preferable to administer the pharmaceutical composition in a prophylactically effective amount for a sufficient period before engaging in activities associated with a risk of traumatic brain injury. The traumatic head injury may be derived from a closed head injury.

[0346] A tenth aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in treating, preventing, or improving cognitive and / or cognitive diseases, disorders, or dysfunctions (memory, concentration, learning (deficits)), or for treating or preventing neurodegenerative disorders, and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0347] In some embodiments, the cognitive disorder, impairment, or dysfunction is selected from attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), autism / autism spectrum disorder (ASD) (dyslexia, age-related memory impairment and learning disorder, amnesia, mild cognitive impairment, cognitive impairment without dementia, pre-onset Alzheimer's disease, Alzheimer's disease, epilepsy, Pick's disease, Huntington's disease, Parkinson's disease, Lewy body dementia, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, spinocerebellar ataxia type 1, 2, 3, 6, 7, amyotrophic lateral sclerosis, familial spastic paraplegia, spinal muscular atrophy, bulbar spinal muscular atrophy, age-related cognitive decline, cognitive decline, moderate mental dysfunction, mental dysfunction as a result of aging, conditions affecting the intensity of brain waves and / or glucose utilization in the brain, stress, anxiety, concentration and attention dysfunction, mood deterioration, general cognitive and mental well-being disorder, neurodevelopmental disorder, neurodegenerative disorder, hormonal disorder, neurological disorder, or any combination thereof. In certain embodiments, the cognitive disorder is a memory impairment.

[0348] The eleventh aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in the treatment or prevention of a cardiovascular disorder or metabolic syndrome, the pharmaceutical composition being administered by intravascular administration such as intravenous administration.

[0349] In some embodiments, the cardiovascular disorder is selected from atherosclerosis, arteriosclerosis, coronary heart disease (CHD or CAD), acute coronary syndrome (or ACS), valvular heart disease, aortic and mitral valve disorders, arrhythmia / atrial fibrillation, cardiomyopathy and heart failure, angina, acute myocardial infarction (or AMI), hypertension, orthostatic hypotension, shock, embolism (pulmonary and venous), endocarditis, diseases of arteries, aorta and its branches, peripheral vascular disorders (peripheral artery disease or PAD), Kawasaki disease, congenital heart disease (cardiovascular disorder) and stroke (cerebrovascular disease), dyslipidemia, hypertriglyceridemia, hypertension, heart failure, cardiac arrhythmia, low HDL level, high LDL level, stable angina, coronary heart disease, acute myocardial infarction, secondary prevention of myocardial infarction, cardiomyopathy, endocarditis, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypercholesterolemia, stroke, hyperlipidemia, hyperlipoproteinemia, chronic kidney disease, intermittent claudication, hyperphosphatemia, omega-3 deficiency, phospholipid deficiency, atherosclerotic carotid artery disease, peripheral artery disease, diabetic nephropathy, hypercholesterolemia in HIV infection, acute coronary syndrome (ACS), non-alcoholic fatty liver disease / non-alcoholic steatohepatitis (NAFLD / NASH), arterial occlusive disease, cerebral atherosclerosis, arteriosclerosis, cerebrovascular disorder, myocardial ischemia, coagulation disorders leading to intravascular thrombosis, and diabetic autonomic neuropathy.

[0350] A twelfth aspect of the invention relates to a pharmaceutical composition according to the first aspect of the invention for use in inhibiting, preventing or treating inflammation or an inflammatory disease, the pharmaceutical composition being administered by intravascular administration such as intravenous administration.

[0351] In some embodiments, the inflammation or inflammatory disease is organ transplant rejection; reperfusion injury resulting from organ transplantation including, but not limited to, transplantation of the following organs: heart, lung, liver, and kidney (see Grupp et al., J. Mol. Cell. Cardiol. 31:297-303 (1999)); chronic inflammatory joint diseases including arthritis, rheumatoid arthritis, osteoarthritis, and bone diseases associated with increased bone resorption; inflammatory bowel diseases (IBD) such as ileitis, ulcerative colitis (UC), Barrett's syndrome, and Crohn's disease (CD); inflammatory lung diseases such as asthma, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD); inflammatory eye diseases including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmia, and endophthalmitis; chronic inflammatory gum diseases including gingivitis and periodontitis; inflammatory kidney diseases including uremic complications, glomerulonephritis, and nephrosis; inflammatory skin diseases including sclerodermatitis, psoriasis, and eczema; chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, epilepsy, amyotrophic lateral sclerosis, and viral or autoimmune encephalitis, inflammatory diseases of the central nervous system including preeclamptic nephropathy; chronic liver failure, trauma to the brain and spinal cord, and cancer. The inflammatory disease can also be a systemic inflammation of the body exemplified by, for example, gram-positive or gram-negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to inflammatory cytokines, e.g., shock associated with inflammatory cytokines. Such shock can be induced, for example, by chemotherapeutic agents administered as a treatment for cancer. Other disorders include depression, obesity, allergic diseases, acute cardiovascular events, muscle wasting diseases, and cancer cachexia. Inflammation resulting from surgery and trauma can also be treated with the lipid compositions.

[0352] The thirteenth aspect of the present invention relates to a pharmaceutical composition according to the first aspect of the present invention for use in the treatment of diseases or conditions related to red blood cells and cell membranes, particularly diseases or conditions related to abnormalities of red blood cells in the cell membrane, and the pharmaceutical composition is administered by intravascular administration such as intravenous administration.

[0353] In some embodiments, the condition or disease is sickle cell disease, sickle cell anemia, or sickle cell trait. In some embodiments, the condition or disease is (alpha, beta, or delta) thalassemia, abnormal hemoglobinopathy (hemoglobin E, hemoglobin S, or hemoglobin C) combined with thalassemia, splenomegaly, or membrane abnormalities such as acanthocytes or spur / spike cells, target red blood cells (target cells), echinocytes (crenated cells), elliptocytes and ovalocytes, spherocytes, stomatocytes (mouth cells), and degmacytes ("bite cells").

[0354] In one embodiment according to any one of Aspects 2 to 13, the pharmaceutical composition is administered to a subject under 10 years old, such as under 1 year old, under 1 month old, or a neonate.

[0355] In one embodiment according to any one of Aspects 2 to 13, the pharmaceutical composition is administered to a subject over 60 years old, such as over 70 years old, over 80 years old, or an elderly subject.

[0356] In one embodiment according to any one of Aspects 2 to 13, the pharmaceutical composition is administered to a subject who is about 10 - 20 years old, about 20 - 50 years old, about 50 - 100 years old, about 60 - 100 years old, or about 70 - 100 years old.

[0357] In one embodiment according to any one of Aspects 2 to 13, the pharmaceutical composition is administered to a subject who is female.

[0358] In one embodiment according to any one of Aspects 2 to 13, the pharmaceutical composition is administered to a subject who is male.

[0359] In one embodiment according to the present invention, traumatic brain injury does not include brain injury induced by ischemia / reperfusion.

[0360] In some embodiments, a closed head injury is a concussion or a contusion. Subjects at risk of such injury can include, among others, subjects participating in a sports event involving the occurrence of a concussion. Exemplary subjects in this category can include, among others, football players, boxers, and hockey players.

[0361] An alternative aspect of the present invention relates to a method for administering a pharmaceutical composition according to the first aspect of the present invention to a subject, the pharmaceutical composition being administered by intravascular administration such as intravenous administration.

[0362] A further alternative aspect of the present invention relates to a method for prophylactic or therapeutic treatment of a subject, the method comprising the following steps: - administering to the subject a pharmaceutical composition according to the first aspect of the present invention by intravascular administration such as intravenous administration.

[0363] A further alternative aspect of the present invention relates to a method for prophylactic or therapeutic treatment of a subject suffering from a condition that may benefit from an increase in brain EPA levels, the method comprising the following steps: - administering to the subject a pharmaceutical composition according to the first aspect of the present invention by intravascular administration such as intravenous administration.

[0364] In one embodiment, a condition that may benefit from an increase in brain EPA levels is depression.

[0365] A further alternative aspect of the present invention relates to a method for prophylactic or therapeutic treatment of a subject suffering from a condition that may benefit from an increase in brain DHA levels, the method comprising the following steps: - administering to the subject a pharmaceutical composition according to the first aspect of the present invention by intravascular administration such as intravenous administration.

[0366] In one embodiment, the condition that can benefit from an increase in brain DHA levels is a neurological condition. The neurological condition is preferably selected from the group consisting of depression, schizophrenia, Alzheimer's disease, Parkinson's disease, or traumatic brain injury, particularly traumatic brain injury.

[0367] In another embodiment, the condition that can benefit from an increase in brain DHA levels is post-traumatic stress disorder (PTSD) or anxiety.

[0368] In another embodiment, the pharmaceutical composition is administered in combination with i) a progestogen or a prodrug thereof, and / or ii) an estrogen or a prodrug thereof.

[0369] A further alternative aspect of the present invention relates to a method for reducing the risk of the pathological effects of TBI, the method comprising - administering a pharmaceutical composition according to the first aspect of the present invention to a subject at risk of TBI, wherein - the pharmaceutical composition is administered by intravascular administration, particularly intravenous administration, - the pharmaceutical composition is administered in a prophylactically effective amount for a sufficient period before engaging in an activity associated with a risk of TBI in order to reduce the risk of the pathological effects of TBI.

[0370] Although the present invention has been generally described, further understanding can be obtained by referring to specific examples provided herein for illustrative purposes only and not intended to be limiting unless otherwise specified.

Examples

[0371] Example 1: Preparation of an intravenous formulation Materials

Table 1

Table 2

Table 3

[0372] [14C]-LPC-DHA formulation (referred to as formulation A in this specification) The formulation to be administered intravenously later was prepared according to the following target specifications:

Table 4

[0373] As follows, 14 C]-LPC-DHA was mixed with an Intralipid formulation to obtain an administration formulation containing phospholipids at a final concentration of 190 mg / kg and [14C]-LPC-DHA at a concentration of approximately 1.5 mg / kg (155 μCi / kg).

[0374] 0.394 mL of ethanolic 14 C]-LPC-DHA (2361 μCi / mL) was dispensed into a 20 mL glass vial and concentrated to a final volume of approximately 0.30 mL under a nitrogen stream at ambient temperature. The concentrated ethanolic 14 C]-LPC-DHA solution was added to 5.70 mL of 20% Intralipid and gently vortexed to ensure homogeneity.

[0375] 14 [14C]-LPC-EPA formulation (referred to as formulation B in this specification) The formulation to be administered intravenously later was prepared according to the following target specifications:

Table 5

[0376] As follows, 14 C]-LPC-EPA was mixed with an Intralipid formulation to obtain a final concentration of 190 mg / kg of phospholipids and a concentration of approximately 1.5 mg / kg (155 μCi / kg) of 14 ​An administered preparation containing C]-LPC-EPA was obtained.

[0377] 0.394 mL of ethanolic 14 C]-LPC-EPA (2361 μCi / mL) was dispensed into a 20 mL glass vial and concentrated to a final volume of approximately 0.30 mL under a nitrogen stream at ambient temperature. The concentrated ethanolic 14 5.70 mL of 20% Intralipid was added to the C]-LPC-EPA solution and gently vortexed to ensure homogeneity.

[0378] Example 2: Uptake of LPC by Tissues - Intravenous Administration Sixteen male Sprague Dawley rats weighing in the range of 213 - 289 g and approximately 7 - 8 weeks old at the time of dosing were housed in polypropylene cages and maintained in the cages except for short periods during dosing. The room where the animals were placed was monitored with a thermostat, and data were continuously recorded (generally, the temperature range was 21 ± 2 °C and the humidity range was 55 ± 10%), and they were exposed to fluorescent lighting for 12 hours and darkness for 12 hours per day. The animals were acclimated under standard animal housing conditions for at least 3 days before use. Throughout this period, the health status of the animals was monitored, and the suitability of each animal for experimental use was confirmed before use.

[0379] Pelleted diet (RM1(E)SQC, Special Diets Services, Witham, Essex, UK) and water (from domestic supply) were freely available throughout the holding, acclimation, and post - dosing periods.

[0380] In accordance with the dosing specifications defined in Example 1, each of the 16 rats was given a single intravenous administration of either Formulation A or Formulation B (8 rats per formulation). The weight of each rat was measured before dosing, and the individual doses to be administered were calculated based on body weight and the defined dosing volume.

[0381] The dosing apparatus for intravenous administration consisted of a subcutaneous syringe and a needle. The dose was administered directly into the tail vein as a slow bolus over 30 seconds.

[0382] After a single intravenous administration of formulation A or B to 16 male rats, one rat was euthanized by carbon dioxide gas overdose at each of the following times: 0.5, 3, 8, 24, 72, 96, 168, and 336 hours after administration.

[0383] Each cadaver was immediately frozen with a hexane / solid carbon dioxide mixture and then stored at approximately -20 °C until analysis by QWBA (quantitative whole body autoradiography).

[0384] Using a procedure based on the study by Ullberg (Acta. Radiol. Suppl 118, 22 31, 1954), the frozen cadavers were subjected to QWBA. Sections were presented at up to five different levels of the rat body such that uptake into the brain, blood, kidney, and spleen included the 30 - 40 tissues disclosed herein (conditioned on the presence of sufficient radioactivity).

[0385] The freeze - dried whole body autoradiography sections were exposed to a phosphor storage imaging plate and incubated in the dark at ambient temperature for a minimum of 5 days.

[0386] A series of calibrated autoradiographs 14 C] microsales (nCi / g, Perkin Elmer) containing known amounts of radioactivity were exposed with the animal sections on each plate.

[0387] The distribution of radioactivity was determined in the tissues and microsales and quantified using a Fuji FLA - 5100 fluorescence image analysis system and the accompanying Tina (version 2.09) and SeeScan (version 2.0) software.

[0388] For each exposed plate used, representative background radioactivity measurements were made. The exact quantification limit was the lowest 14It was considered to be [C]. A standard curve was created from the microscale using Seescan, and the tissue concentration of radioactivity (nCi / g) was determined from it. To calculate the weight equivalent / g data, the nCi / g data was divided by the relevant specific activity (nCi / μg).

[0389] Table 1.1 14 shows the total amount of radioactivity in tissues (blood, brain, kidney, spleen) after a single intravenous administration of [C]-LPC-DHA to male albino rats at a target dose of 190 mg / kg. The results are also shown in Figures 1 - 4.

[0390] Table 1.2 14 shows the radioactivity concentration in all tissues (expressed as μg equivalent / g) after a single intravenous administration of [C]-LPC-DHA to male albino rats at a target dose of 190 mg / kg.

[0391] Table 2.1 14 shows the total amount of radioactivity in tissues (blood, brain, kidney, spleen) after a single intravenous administration of [C]-LPC-EPA to male albino rats at a target dose of 190 mg / kg. The results are also shown in Figures 5 - 8.

[0392] Table 2.2 14 shows the radioactivity concentration in all tissues (expressed as μg equivalent / g) after a single intravenous administration of [C]-LPC-EPA to male albino rats at a target dose of 190 mg / kg.

Table 6

Table 7-1

Table 7-2

Table 7-3

Table 8

Table 9-1

Table 9-2

[0393] Example 3: Pharmacokinetics of LPC - Intravenous Administration Ten male Sprague Dawley rats weighing in the range of 229 - 286 g and approximately 7 - 8 weeks old at the time of dosing were housed in polypropylene cages and maintained in the cages except for short periods during dosing. The room where the animals were placed was monitored with a thermostat, and data were continuously recorded (generally, the temperature range was 21 ± 2°C and the humidity range was 55 ± 10%), and they were exposed to fluorescent lighting for 12 hours and darkness for 12 hours per day. The animals were acclimated under standard animal housing conditions for at least 3 days before use. Throughout this period, the health status of the animals was monitored, and the suitability of each animal for experimental use was confirmed before use.

[0394] Pelleted diet (RM1(E)SQC, Special Diets Services, Witham, Essex, UK) and water (from domestic supply) were freely available throughout the holding, acclimation, and post - dosing periods.

[0395] According to the dosing specifications defined in Example 1, each of the ten male Sprague Dawley rats (two groups of 5 rats each) was given a single intravenous dose of either Formulation A or Formulation B (5 rats per formulation). The weight of each rat was measured before dosing, and the individual doses to be administered were calculated based on body weight and the specified dosing volume.

[0396] The dosing apparatus for intravenous administration consisted of a hypodermic syringe and a needle. The dose was administered directly into the tail vein as a slow bolus over 30 seconds.

[0397] Serial samples of whole blood (about 0.15 mL each for the first 24 hours and about 0.21 mL for subsequent samples) were collected from the tail vein of each animal at 0.2, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 24, 30, 48, 72, and 96 hours after administration. At 168 hours after administration, a final whole blood sample (about 6 - 8 mL) was obtained from each animal by cardiac puncture under isoflurane anesthesia. After the final blood collection, the animals were sacrificed by cervical dislocation.

[0398] Whole blood was collected into tubes containing lithium heparin as an anticoagulant. The samples were centrifuged as soon as possible after collection (+4°C, about 3000 G for 10 minutes), and the resulting plasma was transferred to plain tubes, discarding the blood cells. The remaining plasma samples were stored at about -20°C.

[0399] For pharmacokinetic investigation, individual radioactivity concentration data in plasma were entered into PCModfit v4.0. The relevant pharmacokinetic parameters were derived using non-compartmental analysis (linear / log trapezoidal). The calculated pharmacokinetic parameters (as required) are as follows: Cmax Maximum plasma concentration tmax Time point at which Cmax was observed t1 / 2 Half-life of the terminal elimination phase AUC0-t Area under the concentration-time curve from 0 hours to the final sample collection time AUC0-inf Area under the concentration-time curve extrapolated from 0 hours to infinite time

[0400] At a target dose level of 1.55 mg / kg (radiation dose about 1.5 μCi / rat) 14 In male Sprague Dawley rats selected for the pharmacokinetic study that received a single intravenous dose of [14C]-LPC-EPA, the maximum mean concentration of total radioactivity in plasma (10.6 μg equivalent / g) occurred at 0 hours after administration. Thereafter, the total radioactivity concentration decreased and was detectable at the final sample collection time (0.0403 μg equivalent / g; 168 hours).

[0401] The blood concentration reached the maximum average concentration of total radioactivity (6.15 μg equivalent / g) at 0 hours after administration. Thereafter, the total radioactivity concentration decreased and was detectable at the final sample collection time (0.0840 μg equivalent / g; 168 hours).

[0402] In Intralipid (190 mg / mL), male Sprague Dawley rats were given 14 a single intravenous dose of [¹⁴C]-LPC-EPA at an average dose of 1.5 mg / kg, and the pharmacokinetic parameters of the total radioactivity measured in plasma and whole blood are shown in Tables 3a and 3b, respectively. [Table 10] [Table 11]

[0403] At a target dose level of 1.55 mg / kg (radiation dose approximately 1.5 μCi / rat), 14 in male Sprague Dawley rats selected for the pharmacokinetic study that received a single intravenous dose of [¹⁴C]-LPC-DHA, the maximum average concentration of total radioactivity in plasma (5.08 μg equivalent / g) occurred at 0 hours after administration. Thereafter, the total radioactivity concentration decreased and was detectable at the final sample collection time (0.0611 μg equivalent / g; 168 hours).

[0404] The blood concentration reached the maximum average concentration of total radioactivity (2.46 μg equivalent / g) at 0 hours after administration. Thereafter, the total radioactivity concentration decreased and was detectable at the final sample collection time (0.115 μg equivalent / g; 168 hours).

[0405] In Intralipid (190 mg / mL), male Sprague Dawley rats were given 14 a single intravenous dose of [¹⁴C]-LPC-DHA at an average dose of 1.5 mg / kg, and the pharmacokinetic parameters of the total radioactivity measured in plasma and whole blood are shown in Tables 4a and 4b, respectively. [Table 12]

Table 13

[0406] Example 4: Pharmacokinetic modeling of LPC - intravenous administration compared to oral administration. Intravenously administered 14 C]-LPC-DHA and 14 C]-LPC-EPA were further analyzed by compartmental pharmacokinetic modeling. Plasma and blood concentration - time curves were described by a three - compartment terminal distribution and excretion model using up to three recirculation compartments all directly connected to the central (plasma) compartment. The general structure of the model is shown in Figure 9.

[0407] To allow for time - dependent outflow and inflow, the recirculation compartments were modeled with a Heaviside continuous step function. The complete matrix of the terminal (separated from the recirculation model) distribution model is shown in the following panel.

Number

[0408] To enable the simultaneous on - off of recirculation inflow and outflow without loss, the in - out from the central (plasma) compartment was regulated by three Heaviside functions set in parallel with the same function reversed as shown in the following panel.

Number

[0409] The flow through the controlled step function is less lossy and is restricted to the terminal distribution phase and the first half of the discrete time interval before the elimination phase, so the microconstants of normal distribution and elimination (related to compartments q2, q3, and q4) can be solved for the corresponding macroconstants (the two distribution constants lambda2 and lambda3, and the terminal elimination constant lambda1 from which the corresponding half-lives can be calculated).

[0410] [Number]

[0411] This model was set up and solved using the compartment modeling software SAAM II version 2.3.1.1 (University of Washington and The Epsilon Group). Orally administered 14 [14C]-LPC-DHA and 14 [14C]-LPC-EPA, a model was provided that was similar except for including a delay model to regulate uptake from the intestine. The results show very similar kinetics independent of the dosing regimen.

[0412] Obtained from the animal experiments described in Example 2 14 [14C]-LPC-DHA and 14 [14C]-LPC-EPA plasma and blood profiles show some very unique characteristics, particularly rapid and extensive recirculation of mass from the central compartment. The estimated values of the model parameters are shown in the following panel together with the main parameters from non-compartmental statistical analysis. The panel also includes similar data for 14 [14C]-PC-DHA and 14 [14C]-PC-EPA for comparison purposes. (PC = phosphatidylcholine). [Table 14]

[0413] The data and models shown in the panel above exhibit distinct and consistent commonalities in their dynamics. The major determinants of the dynamics in the PC form are surprisingly similar between the two fatty acids.

[0414] Targeting and controlled delivery to deep tissues: Orally administered 14 C]-LPC-DHA, 14 C]-LPC-EPA, 14 C]-PC-DHA, and 14 C]-PC-EPA all show distinct and consistent variations between uptake and initial distribution, but clear differences in the variations seen in the first 24 hours after ingestion are revealed by plasma concentration-time data and compartment models, with LPC showing the greatest variation. However, the most distinct differences are in the intravenous administration of 14 C]-LPC-DHA and 14This is the difference between C]-LPC-EPA and other forms. Such a sharp variation in the concentration-time curve indicates that the injected LPC-EPA and LPC DHA are very well penetrated into specific organs, especially the organs that possess Mfsd2a of the EPA-LPC and DHA-LPC transporters, such as the brain, eye organs, liver, and intestinal mucosa, and are taken up very rapidly. The ability of the compartment model to faithfully describe the observed variations enables its use in simulating the effects of other dosing regimens. Figure 13 is a graphical representation of data and a model simulating the use of a long-term continuous infusion rather than a bolus injection. The simulation suggests that a constant and well-set dose of LPC-bound EPA and DHA can be supplied to highly penetrated tissues such as the brain. Therefore, this provides a means to supply therapeutic concentrations of EPA and DHA to such deep tissues (brain, spleen, retina, intestinal mucosa, bone marrow, white blood cells, liver, reproductive organs, skin (the list is not comprehensive)). Figure 13 shows how a careful continuous infusion of LPC-DHA (the same amount as a single bolus dose injected over 12 hours) over 48 hours can create a long-term stable plateau without still causing the same very sharp spike as the bolus. The bolus is given at the 0-hour time point, while the infusion starts at the 200-hour time point and continues until 248 hours.

[0415] Example 5: Effects of compositions containing a combination of LPC EPA and LPC DHA. This example provides data on the daily administration of various sardine oil lysophospholipid compositions containing LPC-EPA and LPC-DHA for 3 weeks. It was of interest to investigate whether the sardine oil lysophospholipid compositions caused an increase in LPC-DHA / EPA in plasma and an increase in the EPA and DHA content throughout the brain. The EPA, DHA, and total omega-3 content of these oils are shown in Table 5 below. The sardine oil lysophospholipid compositions of various purities and their production have been described in detail in the past (WO2019 / 123015).

Table 15

[0416] Twenty-four male rats were divided into six groups and subjected to daily oral gavage for three weeks containing the following: Group 1) olive oil (0 mg / kg / day EPA and 0 mg / kg / day DHA), Group 2) unrefined (27% LPC), low dose (185 mg / kg / day EPA and 108 mg / kg / day DHA), 3) unrefined (27% LPC), medium dose (370 mg / kg / day EPA and 217 mg / kg / day DHA), 4) unrefined (27% LPC), high dose (926 mg / kg / day EPA and 543 mg / kg / day DHA), 5) pure (89% LPC), medium dose (324 mg / kg / day EPA and 160 mg / kg / day DHA), 6) Superba Boost krill oil, medium dose (379 mg / kg / day EPA and 219 mg / kg / day DHA).

[0417] LPC-DHA and LPC-EPA were extracted from plasma using the Bligh-Dyer protocol and dissolved in ethanol prior to LC-MS / MS analysis. Samples were taken at baseline (T0), 10 days after oral gavage (T1), and 22 days after oral gavage (T2). The results are shown in Figures 14 and 15. Rats given the krill oil lysophospholipid composition showed an increase in LPC-DHA at T1 and an increase in LPC-EPA at T1 and T2 in plasma compared to the olive oil group, and furthermore showed a dose-dependent increase in LPC-EPA in plasma. In general, an increase in LPC-EPA / DHA plasma content indicates that more EPA and DHA are available for uptake into the brain via mfsd2a.

[0418] After homogenizing and lyophilizing the brain tissue, the FA of the whole brain was extracted by the Bligh-Dyer method, hydrolyzed, and analyzed by HPLC. As shown in Figure 16, there is a very strong dose-response relationship, and the higher the dose of EPA, the higher the brain EPA concentration (ng / mg). Surprisingly, there was no difference in brain EPA concentration between the "unrefined" krill oil lysophospholipid composition and the "pure" krill oil lysophospholipid composition at the same dose. However, rats given the krill oil lysophospholipid composition showed a higher brain EPA concentration than rats given Superba Boost krill oil at the same dose. This means that the uptake of EPA from the two krill oil lysophospholipid compositions into the brain is superior to that of Superba Boost krill oil, which is due to the relatively high content of LPC-EPA in the krill oil lysophospholipid composition.

[0419] The analysis of fatty acid methyl esters (FAME) by GC-FID was used to evaluate the brain DHA concentration in relation to total fatty acids (Figure 17) and arachidonic acid (ARA; 20:4n-6) (Figure 18). The results show that the DHA:total FA ratio is dose-dependent, with the high-dose unrefined oil showing the highest ratio, followed by the medium-dose unrefined oil. At the medium dose, rats given the unrefined oil showed a higher DHA:total FA ratio than rats given Superba Boost krill oil, which may be due to the higher amounts of LPC-DHA and LPC-EPA in the lysophospholipid product (and the subsequent increased uptake of DHA / EPA via Mfsd2a) compared to Superba Boost krill oil. Similarly, Figure 18 further shows a more favorable brain fatty acid profile for rats given the lysophospholipid composition. Here, the ARA:DHA ratio decreases dose-dependently, with the high-dose unrefined oil having the lowest ratio. Furthermore, comparing the unrefined oil and Superba Boost oil at the same dose, the data shows that the ARA:DHA ratio of the unrefined lysophospholipid composition is significantly reduced compared to Superba Boost krill oil.

Claims

1. A pharmaceutical composition for use in the prevention and / or treatment of traumatic brain injury, comprising: said pharmaceutical composition comprising one or more active ingredients and one or more pharma- ceutically acceptable excipients; the one or more active ingredients comprise a compound of formula 1 or a pharma- ceutically acceptable salt thereof and / or a compound of formula 3 or a pharma- ceutically acceptable salt thereof; - the pharmaceutical composition is administered by intravenous administration, 【Chemistry 1】 During the ceremony, R １ is OH or O-CO-(CH ２ ) ｎ -CH ３ and R ２ is OH or O-CO-(CH ２ ) ｎ -CH ３ and The pharmaceutical composition, wherein n is 0, 1 or 2.

2. The one or more pharma- ceutically acceptable excipients are one or more ingredients suitable for dissolving said one or more active ingredients, One or more ingredients having emulsifying properties, and One or more components to adjust tonicity to physiological conditions The pharmaceutical composition of claim 1, selected from the group consisting of:

3. The one or more pharma- ceutically acceptable excipients are containing one or more antioxidants, such as α-tocopherol, ascorbic acid, deferoxamine mesylate, or thioglycolic acid; A pharmaceutical composition according to any one of the preceding claims.

4. 2. The pharmaceutical composition of any one of the preceding claims, further comprising at least one pharma- ceutically acceptable lipid carrier, such as a liposome.

5. The one or more active ingredients further include a compound represented by formula 2 or a pharma- ceutically acceptable salt thereof, and / or a compound represented by formula 4 or a pharma- ceutically acceptable salt thereof: 【Chemistry 2】 During the ceremony, R １ is OH or O-CO-(CH ２ ) ｎ -CH ３ and R ２ is OH or O-CO-(CH ２ ) ｎ -CH ３ and The pharmaceutical composition of claim 1 , wherein n is 0, 1 or 2.

6. The pharmaceutical composition of claim 5, wherein the molar ratio of lyso-PC-DHA:lyso-PC-EPA is in the range of 1:1 to 10:

1.

7. The pharmaceutical composition of claim 5, wherein the one or more active ingredients are 10-99% by weight of the pharmaceutical composition.

8. 10. The pharmaceutical composition according to any one of the preceding claims, wherein the one or more active ingredients are 50-99% by weight of the pharmaceutical composition.

9. R １ is OH, R ２ 4. The pharmaceutical composition of any one of the preceding claims, wherein is OH.

10. 2. The pharmaceutical composition of any one of the preceding claims, wherein the traumatic brain injury results from a closed head injury.

11. 2. The pharmaceutical composition of any one of the preceding claims, wherein said intravenous administration is by one or more injections.

12. 2. The pharmaceutical composition of any one of the preceding claims, wherein the intravenous administration is performed in less than five injections.

13. 2. The pharmaceutical composition of any one of the preceding claims, wherein the intravenous administration is performed by infusion for more than 6 hours.

14. - the pharmaceutical composition is used for the prevention of traumatic brain injury, and - the pharmaceutical composition is administered in a prophylactically effective amount and for a period of time sufficient to reduce the risk of pathological consequences of traumatic brain injury prior to engaging in an activity that involves a risk of traumatic brain injury; A pharmaceutical composition according to any one of the preceding claims.

15. 20. The pharmaceutical composition of any one of the preceding claims, wherein the traumatic brain injury does not include ischemia / reperfusion induced brain injury.

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