New Composition

Abstract

The present invention relates to novel compositions comprising a retinoid mixture of cis and trans isomers of retinyl esters, specifically retinyl acetate, with a cis / trans ratio of less than 0.03, and their use for the treatment, prevention and alleviation of diseases and conditions treatable with 5-HT2B serotonin receptor antagonists, including, but not limited to, diseases or conditions selected from migraine headaches, anxiety, ocular hypotension, valvular heart disease, irritable bowel syndrome, and MDMA (commonly referred to as "ecstasy") abuse.

Description

Detailed Description of the Invention

[0001] The present invention relates to novel compositions comprising a mixture of retinoids, the cis and trans isomers of retinyl esters, specifically retinyl acetate, with a cis / trans ratio of less than 0.03, and their use for the treatment, prevention and alleviation of symptoms of diseases and conditions treatable with 5-HT2B serotonin receptor antagonists, including diseases or conditions selected from, but not limited to, migraine headaches, anxiety, ocular hypotension, valvular heart disease, irritable bowel syndrome, and MDMA (commonly referred to as "ecstasy") abuse.

[0002] Serotonin 5-HT receptors, except for the 5-HT3 subtype, belong to the superfamily of G protein-coupled seven-transmembrane proteins. They belong to the ligand-dependent cationic superfamily of receptors. G protein-coupled receptors constitute one of the major signal transduction systems in eukaryotic cells. Serotonin 5-HT2 receptors are widely distributed in the central nervous system and peripheral tissues. The 5-HT2 receptor class preferentially couples to Gq / 11, increasing the hydrolysis of inositol phosphates and increasing cytosolic [Ca 2+ ], causing a response in the body. Serotonin 5-HT2B receptor antagonism is known to be useful in treating migraines.

[0003] Of the seven described 5-HT receptors, 5-HT2B is the only receptor that signals through the second messengers inositol trisphosphate and diacylglycerol, both of which activate protein kinase C. In rat models, it has been suggested that activation of protein kinase C gamma may increase susceptibility to chronic migraine syndromes. Protein kinase C gamma is a protein kinase C isoform that is highly expressed in neural tissues.

[0004] Serotonin receptor activity also plays an important role in anxiety and other illnesses, including irritable bowel syndrome, migraines, ocular hypotension, heart valve disease, and certain illegal drugs of abuse (MDMA, commonly known as "ecstasy").

[0005] Migraine syndrome is a primary headache disorder characterized by recurrent moderate to severe headaches. They usually affect one side of the head, are pulsating, and last from a few hours to three days. Associated symptoms include nausea, vomiting, and hypersensitivity to light, sound, or smell. The pain is generally aggravated by physical activity. Up to one-third of people also experience an aura, or visual disturbances, shortly before the headache appears. The underlying mechanism is not fully known or understood; it is thought to involve blood vessels and nerves to the brain. Triptans, such as sumatriptan, are not recommended for people with cardiovascular disease, but they are included in the conventional treatment of migraine syndrome. Other treatments address specific symptoms, such as pain and nausea. Serotonin 5-HT2B receptor antagonism is also useful in the treatment of migraine.

[0006] There appears to be no single cause for Irritable Bowel Syndrome (IBS), and there are many different reasons why patients develop the condition. The most common trigger for symptoms to begin is after a bout of food poisoning or gastroenteritis. Although the cause is unclear, there are many factors that can trigger the condition. Stress makes the condition worse for some people. For others, irregular eating habits or abnormal eating habits can be the cause. Some medications, especially when taken over a long period of time for chronic illnesses, can cause IBS-type symptoms such as diarrhea. Overall, there appears to be some interaction between the nervous system of the gut and the brain, the emotional state, and the immune system of the gut.

[0007] About one-third of IBS patients suffer from bouts of constipation, one-third suffer from diarrhea, and most others do not fit any single pattern. Serotonin receptor 5-HT2B antagonists are often used to improve symptoms.

[0008] Hypotension (also called intraocular hypotension) is defined as intraocular pressure below 5 mmHg. Hypotension can accelerate cataract formation and lead to maculopathy and discomfort. The 5-HT2B receptor is a key part of the pathway leading to the development of these conditions.

[0009] Problems with the functional integrity of the heart valves are also associated with the 5-HT2B receptor and can be treated with antagonists.

[0010] MDMA belongs to the phenethylamine family, which further includes amphetamines and other chemically related compounds that act as stimulants, hallucinogens, and / or entactogens. MDMA is commonly referred to as "Molly" or ecstasy. It acts by releasing serotonin (and to a lesser extent other neurotransmitters) from their neuroreceptors and / or inhibiting their reuptake, resulting in increased serotonin levels in the synaptic cleft. The excessive release of serotonin by MDMA is thought to be responsible for the mood-elevating effects experienced by users. However, the release of large amounts of serotonin by MDMA causes the brain to become severely depleted of this neurotransmitter, which contributes to the negative psychological aftereffects experienced for several days after taking MDMA. Administration of a mixture according to the present invention and / or a composition containing said mixture prevents the initial release of serotonin, thereby blunting or counteracting the mood-elevating experience and reducing the serotonin deficiency phase, thereby making the drug less appealing.

[0011] Unfortunately, most medications using known 5-HT2B antagonists are associated with adverse side effects and are not recommended for long-term treatment.

[0012] Therefore, alternative therapies are desirable to prevent, treat, and alleviate symptoms of migraine headaches, ocular hypotension, valvular heart disease, irritable bowel syndrome, and certain illicit drugs of abuse (MDMA, commonly known as "ecstasy"), i.e., symptoms associated with the 5-HT2B pathway.

[0013] Surprisingly, it has been found that a particular mixture of cis and trans retinyl esters, i.e., a retinoid mixture comprising cis and trans isomers of retinyl esters with a cis / trans ratio of less than about 0.03, specifically a mixture comprising a particular ratio of cis / trans retinyl acetate, is particularly suitable for binding to and antagonizing 5-HT2B serotonin receptors, and can therefore be used to treat, prevent, or alleviate symptoms of diseases associated with 5-HT2B overactivity, including migraine syndrome, anxiety, irritable bowel syndrome, ocular hypotension, valvular heart disease, and abuse of MDMA (commonly known as "ecstasy").

[0014] Thus, the present invention relates to retinoid mixtures comprising cis and trans retinyl esters, particularly cis and trans retinyl acetate, with a cis / trans ratio of less than 0.03, and particularly with a cis / trans ratio within the range of about 0.0025.

[0015] In particular, the present invention relates to a pharmaceutical, food, feed or cosmetic composition comprising said retinoid mixture comprising cis and trans isomers of retinyl esters, in particular cis / trans isomers of retinyl acetate, in a cis / trans ratio of less than 0.03, wherein the pharmaceutical, food, feed or cosmetic composition or composition comprising a retinoid mixture as defined herein comprises a retinyl acetate with a cis / trans ratio different from that of commercially available all-trans retinyl acetate, such as Dry Vitamin A-Acetate 500 (BASF) or Vitamin A Acetate Crystals (DSM).

[0016] As used herein, a "retinyl ester" refers to a compound of formula (I): [ka] (In the formula, R is an alkyl group having 2 to 18 carbon atoms, including ester carbonyl, preferably selected from methyl, ethyl, propyl, butyl, stearyl and palmityl. (without any indication of stereochemistry). In all embodiments of the present invention, it is most preferred that R is methyl, i.e. the compound of formula (I) is retinyl acetate.

[0017] The cis / trans ratios given herein refer to the weight percent ratio of the sum of all cis to all trans isomers of each respective retinoid, e.g., retinyl acetate, retinol, retinal, etc., as determined by known methods, e.g., HPLC, and assuming the same response factors for all isomers.

[0018] As used herein, a "retinoid mixture" includes retinyl ester isomers, specifically retinyl acetate isomers, such as cis and trans isomers, in the ratios defined herein. A retinoid mixture may include cis and / or trans isomers of retinol or retinal.

[0019] Cis / trans ratio as used herein, specifically the ratio of cis to trans isomer in a retinoid mixture containing retinyl acetate, retinol or retinal, more specifically the ratio of cis to trans retinyl acetate, or the ratio of cis to trans retinol, or the ratio of cis to trans retinal, all refer to the weight percentage of cis isomer compared to the weight percentage of corresponding trans isomer based on the total retinoid in the mixture.Thus, for retinyl acetate, a mixture with a cis / trans ratio of 0.03 is, for example, a mixture with 1% cis to trans retinyl acetate based on the total retinoid in the mixture and 33% trans retinyl acetate based on the total retinoid in the mixture. With respect to retinyl acetate, a cis / trans ratio of 0.03 would apply to a mixture of 2.95% by weight cis retinyl acetate and 94.15% by weight trans retinyl acetate, or a mixture of 2.99% by weight cis retinyl acetate and 99.6% by weight trans retinyl acetate, a mixture of 2.98% by weight cis retinyl acetate and 99.2% by weight trans retinyl acetate, or a mixture of 2.97% by weight cis retinyl acetate and 99.7% by weight trans retinyl acetate.

[0020] The terms "trans retinyl acetate", "trans retinol", "trans retinal" and the like used herein are known to those skilled in the art and refer to all double bonds in such retinyl acetate, retinol, retinal compounds, including compounds according to formula (I), in trans configuration in accordance with IUPAC-IUB nomenclature. The terms "trans retinyl ester", specifically "trans retinyl acetate", and "all-trans retinyl ester", specifically "all-trans retinyl acetate", are used interchangeably herein. Thus, if one of several double bonds is in cis configuration instead of trans configuration, such isomers are named herein, for example, as cis retinyl acetate or cis retinol or cis retinal.

[0021] The cis-configured retinoid isomers of interest in the present invention include 9-cis retinol, 11-cis retinol, 13-cis retinol, 9,13-di-cis retinol, 11,13-di-cis retinol, 13-cis-3,4-didehydroretinol, 9-cis-3,4-didehydroretinol, 9,13-di-cis-3,4-didehydroretinol, 13-cis retinal, 11-cis retinal, 11,13-di-cis retinal, 9,13-di-cis retinal, 9-cis retinal, 13-cis-3,4-didehydroretinal, 11,13-di-cis-3,4-didehydroretinal, and the respective cis forms of retinyl acetate (for reviews, see, e.g., Gundersen and (see Table 1 in Blomhoff, J. Chromatogr. A935:13-43, 2001) but are not limited to these.

[0022] In all embodiments of the present invention, the cis / trans ratio of the retinyl ester isomers described above, i.e., the weight percent of cis or trans retinyl esters, specifically retinyl acetate, based on the total retinoid in the mixture, is less than 0.03, preferably less than 0.0299, 0.028, 0.025, 0.02, 0.015, 0.01, 0.0099, 0.0095, 0.009, 0.0085, 0.008, 0.0075, 0.007, 0.0065, 0.0085, 0.0085, 0.0075, 0.0075, 0.0075, 0.0065, 0.0085, 0.0085, 0.0085, 0.007 ... , 0.006, 0.0055, 0.005, 0.0049, 0.0045, 0.0043, 0.004, 0.0035, 0.003, 0.0028, 0.0025, 0.0022, 0.002, 0.0018, 0.0015, 0.001, 0.0005 or less, for example, 0.0001 or less, and more preferably 0.0299 to 0.0001, 0.01 to 0.001, 0.02 to 0.0005, 0.0099 to 0.00 01, 0.008~0.001, 0.007~0.002, 0.009~0.0001, 0.008~0.0001, 0.005~0.001, 0.005~0.0001, 0.005~0.0005, 0.006~0.001, 0.02~0.0001, 0.01~0.0001, 0.006~0.0001, 0.0055~0.0001, 0.007~0.0001, 0.0045~0.0001, 0.005~0.002, 0.00 The cis / trans ratio is preferably in the range of 0.4 to 0.0001, 0.0035 to 0.0001, 0.003 to 0.0001, 0.005 to 0.0025, 0.025 to 0.0001, 0.006 to 0.0005, 0.006 to 0.0008, 0.006 to 0.0015, 0.006 to 0.002, 0.006 to 0.003, 0.006 to 0.0004, 0.006 to 0.0025, or 0.004 to 0.0005, and most preferably about 0.0025.

[0023] According to a further embodiment of the present invention, the cis / trans ratio of retinyl ester isomers, particularly the retinyl acetate isomers mentioned above, i.e., the weight percent of cis retinyl esters or trans retinyl esters, particularly retinyl acetate, based on the total retinoid in the mixture, is greater than 1:33.33, and preferably is greater than 1:35.72, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:66.67, 1:70, 1:75, 1:80, 1:90, 1:95, 1:100, 1:101.01 ,1:105.26,1:110,1:111.11,1:115,1:117.65,1:120,1:125,1:130,1:133.33,1:135,1:140,1:142.86,1:145,1:150,1:155,1:160,1:165,1:166.67,1:170,1:175,1:180,1:181.82,1:185,1:190,1:195,1:200,1:204.08,1:205,1:210,1:215,1:220,1:222.22,1 :225, 1:230, 1:232.56, 1:235, 1:240, 1:245, 1:250, 1:255, 1:260, 1:265, 1:270, 1:275, 1:280, 1:285, 1:285.71, 1:290, 1:295, 1:300, 1:305, 1:310, 1:315, 1:320, 1:325, 1:330, 1:333.33, 1:335, 1:340, 1:345, 1:350, 1:355, 1:357.14, 1:360, 1:365, 1:370, 1:375, The cis / trans ratio is 1:380, 1:385, 1:390, 1:395, 1:400, 1:405, 1:410, 1:420, 1:430, 1:440, 1:450, 1:500, or 1:1000 or less, more preferably 1:33 to 1:1000, 1:100 to 1:500, 1:100 to 1:1000, 1:125 to 1:1000, 1:200 to 1:1000, 1:200 to 1:500, or 1:200 to 1:400, and most preferably a cis / trans ratio of about 1:400.

[0024] The retinoid mixtures comprising cis and trans isomers of retinyl esters, in particular mixtures of cis and trans isomers of retinyl acetate, and / or pharmaceutical, food, feed or cosmetic compositions comprising said mixtures according to the present invention can be prepared by mixing one or more cis isomers obtained by chemical or biological processes with the respective all-trans isomers. Methods for preparing such all-trans and / or cis isomers are known to those skilled in the art. Alternatively, the mixtures can be prepared in the ratio of said isomers by adjusting the process accordingly.

[0025] Advantageously, in all embodiments of the present invention, retinoid mixtures containing retinyl esters, particularly retinyl acetate, are biologically produced through fermentation process.In this process, trans-retinyl esters, particularly trans-retinyl acetate, are produced by the action of certain enzymes, resulting in stable all-trans retinyl esters, preferably all-trans retinyl acetate.Trans-retinyl esters, preferably trans-retinyl acetate, can be treated with heat to form cis-retinyl esters, preferably cis-retinyl acetate, and can reach the above-mentioned appropriate level in all embodiments of the present invention (see, for example, McBee et al., JBC, Vol. 276, No. 51, pp. 48483-48493, 2001).

[0026] Advantageously, in all embodiments of the present invention, retinoid mixtures comprising cis and trans retinyl esters, specifically retinyl acetate, with a cis / trans ratio of less than 0.03, particularly retinoid mixtures having a cis / trans ratio in the range of about 0.0025, are produced biologically through a fermentation process, resulting in a retinoid mixture that is preferably yellowish in color.

[0027] As is known in the art, color can be expressed as XYZ, RGB, CYMK, or L. * a * b *(CIELAB according to EN ISO / CIE 11664-4:2019). The preferred method is L * a * b * A person skilled in the art knows which instruments to use according to different color measurement systems and how to measure the color of the mixtures described herein.

[0028] As used herein, a "yellowish" color is * a * b * It means a color defined by a color system, especially L * a * b * is (3 <L * <100, -25 * <30, 10 * <150), for example, L * is in the range of 50 to 100, and a * is in the range of -25 to 10, and b * is in the range of 40 to 150, and preferably, * is in the range of 80 to 100, and a * is in the range of -22 to 1, and b * is in the range of 40 to 85 or 100 to 140, and more preferably L * is in the range of 80 to 95, and a * is in the range of -17 to -1, and b * is in the range of 105 to 135, especially L * is about 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, and a * are approximately -24.9, -24, -23, -22, -21, -20, -19, -18, -17, -18, -17, -16, -15, -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, -4, -3, -2, -1, 0, and b * ​​is about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135.

[0029] In a particular embodiment, the retinoid mixture comprising cis and trans isomers of retinyl esters, specifically retinyl acetate, as defined herein, is produced in a fermentation process using suitable retinyl ester / retinyl acetate producing host cells, such as bacterial or fungal cells (see Sun et al, ACS Synth. Biol. 2019 Sep 20;8(9):2131-2140; Jang et al., Microbial Cell Factories 2011,10:59), where the cells express the respective enzymes, such as those involved in the biosynthesis of retinyl esters, specifically retinyl acetate, by conversion of retinol. In particular, ethanol, corn sugar, or corn oil, all derived from agricultural production, are used for the fermentation. The fermentation product, including retinyl esters, specifically retinyl acetate, can be extracted with the fat phase and then purified into a crystalline form by methods used in the art.

[0030] In some embodiments, a mixture of retinoids as defined herein, in particular a mixture comprising retinyl acetate with a specific cis / trans ratio according to the invention, is obtained in a fermentation process using a retinoid-producing host cell, in which beta-carotene is enzymatically converted to retinoids comprising retinal, retinol or retinyl acetate with a cis / trans ratio as defined herein, the cis / trans ratio of the invention being obtainable using one or more enzymes with oxygenase and isomerase functions (see, for example, Oberhauser et al., PNAS, vol 105, no. 48, 19003, 2008). In particular, the retinoid-producing host organism is capable of enzymatically converting beta-carotene to retinyl acetate via retinal and retinol.

[0031] As used herein, the term "biologically produced" means that retinyl esters, particularly retinyl acetate, are produced with the aid of a biotechnological process, such as a fermentation process, comprising the cultivation of a suitable (carotenoid and / or retinoid producing) host cell expressing the respective enzymes involved in the conversion of a suitable carbon source to retinyl esters, particularly retinyl acetate, as defined herein, and the host cell may be selected from bacteria, fungi, particularly yeast, plants or algae, particularly fungal cells, such as Yarrowia or Saccharomyces, or bacterial cells, such as E. coli. It may further be selected from other suitable microorganisms known to produce retinoids. "Biogenic", "biogenically derived" and "biologically produced" or "bio-based" are used synonymously herein. Thus, the biologically produced retinoids, including retinyl esters, particularly retinyl acetate, are composed of carbon from atmospheric carbon dioxide (also referred to as carbon of atmospheric origin) that is converted by green plants into sugars and starches, and thus preferably sugars and starches composed of non-fossil fuel carbon.Also included is the use of isolated and / or immobilized enzymes in the process for producing mixtures of retinyl esters, particularly retinyl acetate, as defined herein, such as specific enzymes that can selectively catalyze the formation of specific trans / cis ratios of retinyl esters, particularly retinyl acetate, in the mixtures defined herein.

[0032] In one aspect, the retinoid mixture defined herein is produced by fermentation using a fungal host cell, such as an oleaginous yeast, in particular Yarrowia, which is cultured in the presence of a suitable carbon source and in the presence of a plant-derived second phase, such as a vegetable oil, e.g., corn oil, as a second phase solvent, and the retinoids accumulate in the second phase.

[0033] Suitable vegetable derived second phase solvents can be selected from any vegetable oil containing, but not limited to, oleic acid, palmitic acid, stearic acid or linoleic acid and glycerol, such as corn oil, olive oil, cottonseed oil, rapeseed oil, sesame oil, canola oil, safflower oil, sunflower oil, soybean oil, grapeseed oil or peanut oil, preferably corn oil.

[0034] The carbon source used in the present invention may be selected from linear alkanes, free fatty acids, ethanol, glucose, and / or mixtures thereof.

[0035] As used herein, a "bio-based" compound has a C-14 / C-12 isotope ratio ranging from 1:0 to greater than 0:1, as opposed to fossil-derived compounds having a C-14 / C-12 isotope ratio of 0:1. The bio-based content of a compound can be measured by known radiocarbon and isotope ratio mass spectrometry or accelerator mass spectrometry, for example, ASTM test methods D6866, such as D6866-05 or D6866-20, DIN SPEC 91236 (CEN / TS 16137), ISO 16620, or DIN EN 16785 / 1, which measures the C-14 / C-12 isotope ratio in a sample and indicates the percent bio-based content of the sample compared to a standard 100% bio-based material.

[0036] As used herein, "atmospheric carbon" refers to the carbon atoms of carbon dioxide molecules that have been liberated into the Earth's atmosphere over the last few decades. Such carbon mass is identifiable by the presence of certain radioisotopes as described herein. "Green carbon," "atmospheric carbon," "environmentally friendly carbon," "life cycle carbon," "non-fossil fuel carbon," "non-petroleum carbon," "atmospheric carbon," and "bio-based carbon" are used interchangeably herein.

[0037] In all embodiments of the present invention, advantageously, the retinoid mixtures including retinyl esters, particularly retinyl acetate, are produced solely from organic, renewable, bio-based feedstocks, particularly fermentation-produced, and such retinyl esters, particularly retinyl acetate, have a zero anthropogenic CO2 emission profile upon biodegradation, since all of the CO2 molecules released during degradation from such "fermentation-derived" or "fermentation-produced" retinyl esters, particularly retinyl acetate, have an atmospheric origin, thus resulting in zero net release of CO2 into the atmosphere.

[0038] Thus, the present invention particularly relates to a retinoid mixture comprising retinyl acetate, comprising cis and trans isomers as defined herein, with a cis / trans ratio (defined in weight % based on the total retinoid in the mixture) of less than 0.03, said mixture having at least about 20%, such as 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 98 or 100% bio-based carbon according to the definitions provided in the present application.

[0039] In particular, the present invention relates to a biodegradable composition comprising a mixture of retinyl acetates having a cis / trans ratio of less than 0.03 as defined herein, wherein the mixture of retinyl acetates in said composition has a zero anthropogenic CO2 emission profile upon biodegradation.

[0040] In a preferred embodiment, the retinoid mixture according to the present invention consists essentially of cis and trans retinyl esters, specifically cis and trans retinyl acetate, within the scope and with all the definitions and preferences set forth herein.

[0041] The term "consisting essentially of" as used in accordance with the present invention means that the total amounts of components in the mixture as defined herein ideally add up to 100% by weight. However, it is not excluded that small amounts of impurities or additives may be present in the mixture, provided that the total amount of such impurities is preferably less than about 5% by weight, more preferably less than about 3, 2, 1% by weight, e.g., introduced via the respective raw materials and / or processes used.

[0042] As used herein, the terms "impurities and additives" are used interchangeably herein and refer to co-ingredients in the mixture of the present invention, which are present in the mixture of the present invention in an amount of less than 5% by weight based on the total components present in the mixture.

[0043] If the retinoid mixture according to the present invention consists essentially of retinyl acetate having a cis / trans ratio as defined herein, the purity of said mixture, i.e. the (total) amount of cis and trans retinyl acetate, is preferably at least about 95%, more preferably at least about 96%, and most preferably at least about 98% or more, as measured by known methods such as, for example, HPLC, in particular reverse-phase C4 HPLC.

[0044] The term "purity" as used herein means the sum of cis and trans isomers by weight, for example, the sum of cis retinyl acetate and trans retinyl acetate as defined herein indicates the percent purity based on the total retinoids set at 100% purity. Thus, if a mixture essentially consists of 98.03% by weight of trans retinol and 0.25% by weight of cis retinol, said mixture has a purity of 98.28% with respect to retinol. According to all embodiments of the present invention, the retinoid mixture preferably contains less than 0.5% by weight of cis retinyl esters, specifically cis retinyl acetate, based on the total retinoids in said mixture.

[0045] In some embodiments, the retinoid mixture comprising cis and trans retinyl acetate in a cis / trans ratio as defined herein further comprises a small amount of an additive, such as a dihydroretinol, including dihydroretinol and / or dihydroretinyl acetate, specifically in a proportion of 0.2-0.01% by weight or less, such as 0.2, 0.18, 0.16, 0.15, 0.14, 0.12, 0.1, 0.05, 0.01% by weight or less, preferably 0.2-0.1, 0.17-0.06, 0.1-0.05, 0.04-0.01, more preferably 0.1% by weight or less, all based on the total retinoids. Also preferably, the proportion of dihydroretinyl acetate is about 0.05% by weight or less, especially about 0.01% by weight or less, based on the total retinoids in the mixture.

[0046] In some embodiments, the retinoid mixture comprising cis and trans retinyl acetate in a cis / trans ratio as defined herein further comprises a small amount of an additive, such as, but not limited to, a retinol, including cis retinol, trans retinol, dihydroretinol, in an amount of 2% or less by weight, such as about 1.8, 1.7, 1.5, 1.2, 1.0, 0.8, 0.5, 0.3, 0.2, 0.1% or less by weight, preferably in the range of 2-0.1%, 2-1%, 1-0.1%, 1.5-0.1%, 0.5-0.2%, 0.4-0.2%, 1-0.2%, and most preferably in the range of 2-0.9% or 0.4-0.1% by weight of retinol, based on all total retinoids in the mixture.

[0047] In some embodiments, retinoid mixtures comprising cis and trans retinyl acetate in a cis / trans ratio as defined herein may contain small amounts of additives, such as retinals, including but not limited to 9-cis retinal, trans retinal, etc., in amounts of 1% or less by weight, such as about 0.8, 0.7, 0.5, 0.2, 0.1, 0.0, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, The composition further comprises retinal in a proportion of 8, 0.05, 0.03, 0.02, 0.01, 0.005% by weight or less, preferably 1 to 0.005% by weight, 0.5 to 0.01% by weight, 0.5 to 0.02% by weight, 0.05 to 0.01% by weight, 0.05 to 0.02% by weight, 0.04 to 0.1% by weight, 0-2 to 0.04% by weight, and most preferably 0.2 to 0.019% by weight or 0.04 to 0.01% by weight.

[0048] Another embodiment of the present invention is a method for treating or preventing a deleterious condition responsive to antagonism of the serotonin 5-HT2B receptor, comprising administering to a person in need thereof an effective amount of a retinoid mixture according to the present invention and / or a pharmaceutical, food, feed or cosmetic composition comprising said mixture, with all the definitions and priorities set out herein.Preferably, the deleterious condition is selected from the group consisting of migraine syndromes, anxiety disorders, ocular hypotension, valvular heart disease, irritable bowel syndrome and intoxication / abuse of one phenethylamine stimulant, in particular methylenedioxymethamphetamine (MDMA).

[0049] Another embodiment is the use of a retinoid mixture according to the present invention, with all the definitions and priorities described herein, and / or a pharmaceutical, food, feed or cosmetic composition comprising said mixture, for treating or preventing a deleterious pathology responsive to antagonism of the serotonin 5-HT2B receptor. Another embodiment of the present invention is the use of a retinoid mixture according to the present invention, with all the definitions and priorities described herein, and / or a pharmaceutical, food, feed, pharmaceutical or cosmetic product comprising a medicament for treating or preventing a deleterious pathology responsive to antagonism of the serotonin 5-HT2B receptor.

[0050] The present invention therefore relates to the use of a retinoid mixture having a specific cis / trans ratio of retinyl esters, in particular retinyl acetate, as defined herein, and / or a pharmaceutical, food, feed or cosmetic composition comprising said mixture, said mixture / composition being used as a 5-HT2B receptor antagonist, in particular for the treatment or prevention or alleviation of symptoms or adverse medical conditions associated with migraine syndrome, anxiety, ocular hypotension, valvular heart disease, irritable bowel syndrome, and addiction / abuse of one phenethylamine stimulant, in particular methylenedioxymethamphetamine (MDMA).

[0051] In all embodiments of the present invention, application can be topical or oral, with oral administration being preferred.

[0052] In all embodiments of the present invention, it is appreciated that adverse medical conditions may also include adverse skin conditions.

[0053] "Prevention" or "prophylaxis" includes not only complete prevention, but also delaying the onset of, reducing the severity of symptoms, and / or prolonging the time until recurrence of the condition.

[0054] Another embodiment of the present invention is a method for treating, preventing or alleviating the symptoms of migraine comprising administering a 5-HT2B receptor antagonizing amount of a retinoid mixture and / or a pharmaceutical, food, feed or cosmetic composition comprising said mixture according to the present invention having all definitions and priorities as set forth herein, preferably comprising the step of administering such mixture and / or composition to a person experiencing or at risk of experiencing a migraine.

[0055] A further embodiment is the use of a retinoid mixture according to the invention with all the definitions and priorities set out herein and / or a pharmaceutical, food, feed or cosmetic composition comprising said mixture for treating, preventing or reducing the severity of a migraine headache.

[0056] Another embodiment is the use of the retinoid mixture and / or pharmaceutical, food, feed or cosmetic composition comprising said mixture according to the present invention with all definitions and priorities given herein for the manufacture of a nutraceutical, nutritional product, pharmaceutical, feed product, food or cosmetic product comprising a medicament for treating, preventing or alleviating the symptoms of a migraine headache syndrome, in particular a migraine headache.

[0057] In another embodiment, the retinoid mixture and / or pharmaceutical, food, feed or cosmetic composition comprising said mixture according to the present invention having all the definitions and priorities set forth herein is used for treating, preventing or alleviating symptoms associated with anxiety.

[0058] Another embodiment of the present invention is a method for treating, preventing or alleviating symptoms of anxiety comprising administering a 5-HT2B receptor antagonizing amount of a retinoid mixture and / or a pharmaceutical, food, feed or cosmetic composition comprising said mixture according to the present invention having all definitions and priorities as set forth herein.

[0059] Another embodiment is the use of a retinoid mixture and / or a pharmaceutical, food, feed or cosmetic composition comprising said mixture according to the present invention with all definitions and priorities set forth herein for the manufacture of a nutraceutical, nutritional product, pharmaceutical, food, feed product or cosmetic product comprising an agent for treating, preventing or alleviating the symptoms of anxiety.

[0060] Another embodiment of the present invention is a method for treating, preventing or alleviating irritable bowel syndrome (IBS) symptoms comprising administering a 5-HT2B receptor-antagonizing amount of a retinoid mixture and / or a pharmaceutical, food, feed or cosmetic composition comprising said mixture according to the present invention having all definitions and priorities as set forth herein.

[0061] A further embodiment is the use of a retinoid mixture according to the present invention with all the definitions and priorities set forth herein and / or a pharmaceutical, food, feed or cosmetic composition comprising said mixture for treating, preventing or alleviating IBS. Another embodiment is the use of a retinoid mixture or composition according to the present invention with all the definitions and priorities set forth herein in the manufacture of a nutraceutical, nutritional, food, feed, pharmaceutical or cosmetic product comprising an agent for treating, preventing or alleviating the symptoms of IBS. A particularly preferred retinyl ester is retinyl acetate.

[0062] Another embodiment of the present invention is a method for treating, preventing or alleviating symptoms of ocular hypotony, including cataract formation, comprising administering a 5-HT2B receptor-antagonizing amount of a retinoid mixture having a specific cis / trans ratio according to the present invention having all definitions and priorities set forth herein and / or a pharmaceutical, food, feed or cosmetic composition comprising said mixture.

[0063] A further embodiment is the use of a retinoid mixture and / or a pharmaceutical, food, feed or cosmetic composition comprising said mixture according to the present invention with all the definitions and priorities set out herein for treating, preventing or alleviating symptoms of ocular hypotony, including cataracts.

[0064] A further embodiment is the use of a pharmaceutical, food, feed or cosmetic composition according to the present invention, with all definitions and priorities set forth herein, in the manufacture of a nutraceutical, nutritional, pharmaceutical, feed, food or cosmetic product comprising an agent for treating, preventing or alleviating symptoms of ocular hypotony, including cataracts.

[0065] Another embodiment of the present invention is a method for treating, preventing or alleviating symptoms of valvular heart disease, comprising administering a 5-HT2B receptor-antagonizing amount of a retinoid mixture and / or a pharmaceutical, food, feed or cosmetic composition comprising said mixture according to the present invention having all definitions and priorities as set forth herein.

[0066] A further embodiment is the use of a retinoid mixture as defined herein and / or a pharmaceutical, food, feed or cosmetic composition comprising said mixture for treating, preventing or alleviating the symptoms of valvular heart disease.

[0067] Another embodiment is the use of a retinoid mixture and / or a pharmaceutical, food, feed or cosmetic composition comprising said mixture according to the present invention with all definitions and priorities set forth herein for the manufacture of a nutraceutical, nutritional product, food, feed, pharmaceutical or cosmetic product comprising an agent for treating, preventing or alleviating the symptoms of valvular heart disease.

[0068] One embodiment of the present invention is a method for preventing, treating or alleviating symptoms associated with phenethylamine drug dependency, comprising administering a serotonin 5-HT2B antagonistic amount of a retinoid mixture and / or a pharmaceutical, food, feed or cosmetic composition comprising said mixture according to the present invention having all definitions and priorities as set forth herein to a person in need thereof or at risk of or abusing drugs that cause excessive release of serotonin, such as but not limited to phenethylamine drugs, preferably methylenedioxymethamphetamine (MDMA).

[0069] Another embodiment is the use of a pharmaceutical, food, feed or cosmetic composition according to the invention, with all the definitions and priorities set out herein, to reduce the attractiveness of phenylethylamine drugs to those who abuse them. In a preferred embodiment, the drug is MDMA.

[0070] Another embodiment is the use of the retinoid mixture and / or pharmaceutical, food, feed or cosmetic composition comprising said mixture according to the present invention with all definitions and priorities set forth herein for the manufacture of a nutraceutical, nutritional, pharmaceutical or cosmetic product comprising an agent for treating, preventing or reducing the abuse of phenylethylamine drugs. In a preferred embodiment, the drug is MDMA.

[0071] The retinoid mixture and / or pharmaceutical, food, feed or cosmetic composition comprising said mixture according to the present invention, with all definitions and priorities set out herein, may be combined with other active ingredients to produce a product with beneficial results. Examples of further active ingredients include vitamin E, water-soluble tomato extract, resveratrol, vitamin D, 25-hydroxyvitamin D3, hydroxytyrosolol, polyunsaturated fatty acids (PUFAs), human milk oligosaccharides, cannabinoids and mixtures thereof.

[0072] The products according to the invention are generally prepared by mixing the retinoid mixture according to the invention and / or the pharmaceutical, food, feed or cosmetic composition comprising said mixture with suitable carriers and / or excipients and / or diluents conventionally used in nutraceutical, pharmaceutical, nutritional or cosmetic products, and contain a sufficient amount of the recommended daily dose of the retinoid mixture comprising retinyl acetate having a cis / trans ratio of less than 0.03 as defined herein, in particular up to a maximum of 2 mg of retinyl acetate per day for an adult.

[0073] The term "cosmetic product" as used in this application refers to a composition as defined in the "Kosmetika" section of the Rompp Lexikon Chemie, 10th edition 1997, Georg Thieme Verlag Stuttgart, New York, and in A. Domsch, "Cosmetic Compositions", Verlag für chemische Industrie (ed. H. Ziolkowsky), 4 th This refers to the cosmetic compositions disclosed in the 1992 edition.

[0074] In the case of combinations of active ingredients, the dosage of the combined ingredients in a dietary supplement, nutritional product, pharmaceutical product, feed product, food or cosmetic product may be adjusted to be at least 0.1-10 mg / day, but preferably not to exceed 30 mg / day.

[0075] If desired, the daily dosage can be divided into two or more doses, such as two tablets per day.

[0076] For non-human animals, the above human dosages can be adjusted for the animal's body weight.

[0077] The nutraceutical, nutritional, feed, food, pharmaceutical or cosmetic product, including the retinoid mixture and / or the pharmaceutical, food, feed or cosmetic composition comprising said mixture according to the present invention, with all definitions and priorities set out herein, may take any galenical form suitable for administration to the human or animal body, in particular any conventional suitable form for oral administration, for example in solid form, for example (additives / supplements) for food, or food or feed premixes, enriched food or feed, tablets, pills, granules, dragees, capsules and effervescent preparations, for example powders and tablets, or in liquid form, such as solutions, emulsions or suspensions, for example as beverages, pastes and oily suspensions. The pastes may be encapsulated in hard or soft shell capsules, which are characterized for example by a matrix of gelatin (fish, porcine, poultry, bovine), plant proteins or sulfonic acid lignin. Examples of other application forms are topical, transdermal, parenteral or injectable forms of administration. The nutraceutical, nutritional, pharmaceutical, food, feed or cosmetic product may be in the form of a controlled (delayed) release formulation. The nutraceutical, nutritional, pharmaceutical, food, feed or cosmetic product according to the invention may further comprise protective hydrocolloids (gums, proteins, modified starches), binders, film-forming agents, encapsulating agents / materials, wall / shell materials, matrix compounds, coatings, emulsifiers, surfactants, solubilizers (oils, fats, waxes, lecithin, etc.), adsorbents, carriers, fillers, co-compounds, dispersants, wetting agents, processing aids (solvents), flow agents, flavoring agents, bulking agents, jellifying agents, gel forming agents, antioxidants and antimicrobial agents.

[0078] Examples of food products suitable for containing the pharmaceutical, food, feed or cosmetic composition according to the present invention, with all definitions and priorities set forth herein, are cereal bars, dairy products such as yogurt, bakery products such as cakes and cookies. Examples of fortified foods are cereal bars and bakery products such as bread, bread rolls, bagels and cookies. Examples of dietary supplements are effervescent preparations in the form of tablets, pills, granules, sugar-coated pills, capsules, and non-alcoholic drinks, such as soft drinks, fruit juices, lemonades, water-like drinks, teas and milk-based drinks in the form of liquid foods, such as soups and dairy products (muesli drinks). Beverages are also suitable. Beverages include non-alcoholic and alcoholic drinks, as well as liquid formulations added to drinking water and liquid foods. Non-alcoholic drinks are, for example, soft drinks, sports drinks, fruit juices, vegetable juices (e.g., tomato juice), lemonades, teas and milk-based drinks. Liquid foods are, for example, soups and dairy products (muesli drinks).

[0079] In addition to the retinoid mixture and / or pharmaceutical, food, feed or cosmetic composition comprising said mixture according to the present invention with all definitions and priorities set forth herein, the nutraceutical, nutritional product, food, feed product, pharmaceutical product or cosmetic product according to the present invention may contain, but is not limited to, water, gelatin of any origin, vegetable gum, sulfonic acid lignin, talc, sugar, starch, gum arabic, vegetable oil, polyalkylene glycol, flavoring agent, preservative, stabilizer, emulsifier, buffer, lubricant, colorant, wetting agent, filler, and conventional additives and auxiliary agents, excipients or diluents used in the respective fields, such as, but not limited to, those used in the respective fields. The carrier material may be suitable for oral / parenteral / injection / topical administration.

[0080] The following embodiments (1) to (14) are particularly within the scope of the present invention: (1): A mixture of cis and trans isomers of retinyl esters, wherein the cis / trans ratio in said mixture is less than 0.03, preferably 0.0299, 0.028, 0.025, 0.02, 0.015, 0.01, 0.0099, 0.0095, 0.009, 0.0085, 0.008, 0.0075, 0.007, 0.0065, 0.006, 0.0055, 0.005, 0.0049, 0.0045, The cis / trans ratio is 0.0043, 0.004, 0.0035, 0.003, 0.0028, 0.0025, 0.0022, 0.002, 0.0018, 0.0015, 0.001, 0.0005 or less, for example, 0.0001 or less, more preferably 0.0299 to 0.0001, 0.01 to 0.001, 0.02 to 0.0005, 0.0099 to 0.0001, 0.008 to 0.001, 0.007 to 0.00 2, 0.009~0.0001, 0.008~0.0001, 0.005~0.001, 0.005~0.0001, 0.005~0.0005, 0.006~0.001, 0.02~0.0001, 0.01~0.0001, 0.006~0.0001, 0.0055~0.0001, 0.007~0.0001, 0.0045~0.0001, 0.005~0.002, 0.004~0.0001, 0.003 0.004-0.0005, and most preferably a mixture with a cis / trans ratio of about 0.0025. (2): A composition comprising the mixture of embodiment (1). (3): The mixture of embodiment (1) or the composition of embodiment (2), wherein the retinyl ester is retinyl acetate. (4): The mixture / composition of embodiment (1), (2), or (3), wherein the retinyl ester is of biological origin. (5): The mixture / composition of embodiment (1), (2), (3) or (4), wherein the mixture consists of at least about 95% retinyl acetate, based on all components in the mixture. (6): The mixture / composition of embodiment (1), (2), (3), (4) or (5), comprising up to about 2% retinol based on the total components in the mixture. (7): A method for preventing or treating an adverse condition responsive to antagonism of the serotonin 5-HT2B receptor, comprising administering to a person in need thereof an effective amount of the mixture / composition of embodiment (1), (2), (3), (4), (5) or (6). (8): The method of embodiment (7) for the prevention, treatment or alleviation of symptoms associated with migraine syndrome, anxiety, irritable bowel syndrome, ocular hypotension, valvular heart disease, and addiction / abuse of a phenethylamine stimulant. (9): Use of the mixture / composition of embodiment (1), (2), (3), (4), (5) or (6) as a serotonin 5-HT2B receptor antagonist. (10): Use according to embodiment (9), wherein the 5-HT2B receptor antagonist is used for the treatment or prevention of migraine syndrome, anxiety, irritable bowel syndrome, ocular hypotension, valvular heart disease, and addiction / abuse of a phenethylamine stimulant. (11): Use of a mixture or composition according to embodiment (1), (2), (3), (4), (5), (6), (9) or (10) in the treatment, alleviation or prevention of a condition selected from the group consisting of migraine headache syndromes, preferably migraine headaches, anxiety, irritable bowel syndrome, ocular hypotension, valvular heart disease and addiction / abuse of one phenethylamine stimulant, in the preparation of a dietary supplement, nutritional product, pharmaceutical or cosmetic composition or product, in particular in the preparation of a medicament. (12): A dietary supplement, nutritional product, pharmaceutical, or cosmetic composition or product comprising the mixture or composition of embodiment (1), (2), (3), (4), (5), or (6). (13): A composition or product according to embodiment (12) for the treatment or prevention of migraine syndrome, anxiety, irritable bowel syndrome, ocular hypotension, valvular heart disease, and addiction / abuse of one phenethylamine stimulant. (14): A composition or product according to embodiment (13) in a form suitable for oral administration.

[0081] In order to better illustrate the present invention, the following non-limiting examples are presented.

[0082] [Example] Example 1: Antagonism of human serotonin 5-HT2B using IP1 functional assay A retinoid mixture containing retinyl acetate as defined herein can be produced as described in WO 2022 / 090549 (Example 1), where the retinoids are accumulated in the lipid phase and then isolated / extracted with ethanol or solvents known in the art.

[0083] Antagonism is determined using human 5-HT2B receptors expressed in transfected CHO cells by measuring the effect on agonist-induced inositol monophosphate (IP1) production using HTRF® detection (Porter et al., 1999, Brit. J. Pharmacol., 128:13-20; Trinquet et al., 2006, Analytical Biochemistry 358, 126-135).

[0084] CHO cells are suspended in a buffer containing 10 mM Hepes / NaOH (pH 7.4), 4.2 mM KCl, 146 mM NaCl, 1 mM CaCl2, 0.5 mM MgCl2, 5.5 mM glucose, and 50 mM LiCl, then distributed into microtiter plates at a density of about 20,000 cells / well and pre-incubated for 5 minutes at room temperature in the presence of buffer (basal control), a mixture of test compounds, i.e. reference samples, and retinyl acetate ("retAc") of the present invention (see Table 1), or the highly potent known reference antagonist SB-206553. The reference agonist 5-HT (serotonin) is then added at a final concentration of 30 nM. In the basal control measurement, individual assay wells do not contain 5-HT. After 30 min incubation at 37°C, cells are lysed and the fluorescence acceptor (D2-labeled IP1) and fluorescence donor (anti-IP1 antibody labeled with europium cryptate) are added. After 60 min at room temperature, the fluorescence transfer is measured at wavelengths Ex=337 nm and Em=620 and 665 nm using a microplate reader (Envision, PerkinElmer). IP1 concentrations can be determined by dividing the signal measured at 665 nm by the signal measured at 620 nm (ratio). Results are expressed as percent inhibition of the control response to 30 nM 5-HT. Means, standard deviations are calculated and IC50 values ​​are calculated using a dose-response model.

[0085] [Table 1]

[0086] The standard reference antagonist SB-206553 is tested at several concentrations in each experiment to generate a concentration-response curve. The dose-response curve is used to calculate IC50 values. The same procedure is performed for RetAc mix and Reference RetAc to obtain IC50 values. The results are shown in Table 2. When using the retinyl acetate mix according to the present invention, the IC50 values ​​are dramatically reduced, i.e., the antagonism is dramatically increased compared to Reference retAc.

[0087] [Table 2]

[0088] Example 2: Formulation Cosmetic formulations in the form of gels, emulsions, shampoos, hair creams, lotions, make-ups, toners, aftershaves, creams, and hand sanitizers are made according to methods known in the art. Unless otherwise indicated, the pH of the formulation is adjusted to a pH between 3 and 7.5 as deemed appropriate. In the formulations below, the term "novel ingredient" refers to retinyl acetate (RetAc mix) having the cis / trans ratio shown in Table 1.

[0089] [Table 3]

[0090] [Table 4] [Table 5] [Table 6]

[0091] [Table 7] [Table 8]

[0092] [Table 9] [Table 10]

[0093]

Table 11

[0094]

Table 12

[0095]

Table 13

[0096]

Table 14

[0097]

Table 15

[0098]

Table 16

[0099]

Table 17

[0100]

Table 18

[0101]

Table 19

[0102]

Table 20

[0103]

Table 21

Claims

1. A retinoid mixture comprising cis and trans isomers of retinyl esters, wherein the cis / trans ratio within said mixture is greater than 1:33.33, said ratio being calculated as the weight percentage of cis isomers compared to the weight percentage of trans isomers, based on the total retinoids in said mixture.

2. A retinoid mixture as described in claim 1, wherein the mixture contains less than 0.5% by weight of cis-retinyl esters based on total retinoids.

3. A retinoid mixture as described in claim 1, comprising cis and trans isomers of retinyl acetate in a ratio ranging from 1:33 to 1:1000.

4. 4. The retinoid mixture of claim 3, wherein the retinoid mixture comprises cis-retinyl acetate and trans-retinyl acetate in a ratio of 1:

400.

5. 5. The mixture according to claim 1, which contains up to 2% by weight of retinol based on total retinoids.

6. 5. The mixture of claim 1, comprising no more than 1% by weight of retinal based on total retinoids.

7. L ＊ is in the range of 50 to 100, and a ＊ is in the range of −25 to 10, and b ＊ 5. The mixture according to claim 1, wherein the color value is in the range of 40 to 150.

8. A pharmaceutical, food, feed or cosmetic composition comprising a mixture according to any one of claims 1 to 4, which is of biological origin.

9. The composition described in claim 8, wherein the mixture described in any one of claims 1 to 4, which is of biological origin, is biologically produced via a fermentation process.

10. The mixture according to any one of claims 1 to 4 is biodegradable and does not contain artificial CO ２ 10. The composition of claim 8, which has a zero emission profile.

11. 9. The composition according to claim 8, which is used as a serotonin 5-HT2B receptor antagonist.

12. 10. The composition of claim 8 in the preparation of a dietary supplement, nutritional product, pharmaceutical product, or cosmetic product, for use in the treatment, alleviation, or prevention of a condition selected from the group consisting of migraine syndrome, anxiety, irritable bowel syndrome, ocular hypotension, valvular heart disease, and addiction / abuse of one phenethylamine stimulant.

13. A nutraceutical, nutritional, pharmaceutical or cosmetic product comprising the mixture of any one of claims 1 to 4.

14. 9. The composition according to claim 8, for the treatment or prevention of migraine syndrome, anxiety, irritable bowel syndrome, ocular hypotension, valvular heart disease and addiction / abuse of one phenethylamine stimulant drug.

15. A method for the prevention, treatment or alleviation of symptoms associated with migraine syndrome, anxiety, irritable bowel syndrome, ocular hypotension, valvular heart disease, and addiction / abuse of one phenethylamine stimulant, comprising administering the composition of claim 8.