WO2016057915A1 - Compositions d'acides gras et d'esters d'acides gras auto-micellisantes, ainsi que leur utilisation dans le traitement d'états pathologiques - Google Patents

Compositions d'acides gras et d'esters d'acides gras auto-micellisantes, ainsi que leur utilisation dans le traitement d'états pathologiques Download PDF

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WO2016057915A1
WO2016057915A1 PCT/US2015/054933 US2015054933W WO2016057915A1 WO 2016057915 A1 WO2016057915 A1 WO 2016057915A1 US 2015054933 W US2015054933 W US 2015054933W WO 2016057915 A1 WO2016057915 A1 WO 2016057915A1
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fatty acid
omega
composition according
pharmaceutical composition
disease
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PCT/US2015/054933
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English (en)
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Frederick D. Sancilio
Thorsteinn Thorsteinsson
Glynis DANIEL-ARCHIBALD
Miguel LOPEZ-TOLEDANO
Ahmed Abd Almalik Ahmed Mohammed DAAK
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Sancilio & Company, Inc.
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=54347886&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2016057915(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to BR112017007428A priority Critical patent/BR112017007428A2/pt
Priority to MX2017004324A priority patent/MX2017004324A/es
Priority to EP15784877.1A priority patent/EP3212236A1/fr
Priority to CA2963952A priority patent/CA2963952C/fr
Application filed by Sancilio & Company, Inc. filed Critical Sancilio & Company, Inc.
Publication of WO2016057915A1 publication Critical patent/WO2016057915A1/fr
Priority to US15/180,430 priority patent/US20160296492A1/en
Priority to ZA2017/02385A priority patent/ZA201702385B/en
Priority to US15/605,972 priority patent/US10898458B2/en
Priority to US16/655,643 priority patent/US10894027B2/en
Priority to US16/713,685 priority patent/US20200330422A1/en
Priority to US17/152,103 priority patent/US20210322359A1/en
Priority to US17/156,824 priority patent/US20210322360A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/32—Manganese; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • This invention relates to compositions including fatty acids, either in the triglyceride, ester, or free fatty acid forms, in combination with at least one surface active agent, and to the use of such compositions for the treatment of patients afflicted with various disease states.
  • this invention relates to self- micellizing compositions including at least one omega-3 fatty acid, which may be selected from the group consisting of hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, the omega-3 isomer of docosapentaenoic acid, also known as clupanodonic acid, docosahexaenoic acid, tetracosapentaenoic acid, and tetracosahexaenoic acid, in combination with a surface active agent composition effective to spontaneously form micelles with said fatty acids upon contact with an aqueous media.
  • omega-3 fatty acid which may be selected from the group consisting of hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic
  • the self-micellizing compositions may further contain an omega-6 fatty acid (either in the triglyceride, ester, or free fatty acid form), for example arachidonic acid (ARA), linoleic acid (LA), gamma-linolenic acid (GLA) or the omega-6 isomer of DPA, also known as osbond acid.
  • omega-6 fatty acid either in the triglyceride, ester, or free fatty acid form
  • ARA arachidonic acid
  • LA linoleic acid
  • GLA gamma-linolenic acid
  • DPA also known as osbond acid
  • the disease states may include (1) malabsorption syndromes, such as short bowel syndromes, which encompass a number of different clinical entities that may result in chronic diarrhea, abdominal distention, and failure to thrive; (2) primary sclerosing cholangitis (PSC), which is a chronic cholestatic liver disease characterized by progressive inflammatory and fibrotic destruction of the intrahepatic and/or extrahepatic bile ducts; (3) non-alcoholic fatty liver disease (NAFLD), which is characterized by increased hepatic fat accumulation in
  • neurodegenerative diseases contemplated for treatment by the present invention include, but are not limited to, Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease), Epilepsy, Bi-polar Syndrome, traumatic brain injury, peripheral PD
  • Malabsorption syndromes encompass a number of different clinical entities that result in chronic diarrhea, abdominal distention, and failure to thrive. Clinical malabsorption can be broken down into several distinct conditions, both congenital and acquired, that affect one or more of the different steps in the intestinal hydrolysis and subsequent transport of nutrients.
  • Malabsorption is caused by a disorder in the intestinal processes of digestion and/or transport of nutrients across the intestinal mucosa into the systemic circulation. Either a congenital abnormality in the digestive or absorptive processes or, more commonly, a secondarily acquired disorder of such processes may result in malabsorption.
  • pancreatic insufficiency is the principal condition that results in severe fat malabsorption. Pancreatitis, pancreatic cancer, pancreatic resection, cystic fibrosis, Shwachman-Diamond syndrome, Johnson- Blizzard syndrome, and Pearson syndrome can all result in pancreatic insufficiency. Significant obstructive biliary or cholestatic liver disease or extensive intestinal mucosal disease, such as occurs in celiac disease, may also result in severe steatorrhea.
  • Short-Bowel Syndrome a disorder clinically defined by a failure to properly absorb nutrients (malabsorption), frequently accompanied by diarrhea, steatorrhea, fluid and electrolyte disturbances, edema, dehydration and malnutrition.
  • Short-bowel syndrome has numerous causes, both congenital and acquired, but a common etiologic factor is the functional or anatomic loss of extensive segments of small intestine leading to a severe decrease in intestinal absorptive capacity.
  • Adult human intestines have a normal length range of 260-88 cm. If disease, accident, or any other cause results in a loss of 50% of the small intestine or leaves less than 200 cm of viable length, a patient is at high risk of SBS.
  • Whether or not a patient who has lost a significant amount of small intestine will develop SBS depends on a number of factors. Important cofactors that help to determine whether the syndrome will develop or not include the premorbid length of the small intestine, how much intestine is lost, the age of the patient, the remaining length of small intestine and colon, the functional quality of the residual bowel, and the presence or absence of the ileocecal valve.
  • Treatment of malabsorption syndromes is mainly aimed at supplying the nutrients and vitamins that patients lack. It may include (a) a high- calorie diet that includes vitamins, minerals, carbohydrates, proteins, and fats; (b) injections of vitamins and minerals; (c) administration of drugs that slow down the normal movement of the small intestine; and (d) feeding through a vein (Total Parenteral Nutrition (TPN)).
  • a high- calorie diet that includes vitamins, minerals, carbohydrates, proteins, and fats
  • injections of vitamins and minerals include injections of vitamins and minerals; and (c) administration of drugs that slow down the normal movement of the small intestine; and (d) feeding through a vein (Total Parenteral Nutrition (TPN)).
  • TPN Total Parenteral Nutrition
  • the present invention it is possible to significantly decrease this treatment-related morbidity by administering substantially pure DHA in combination with at least one surface active agent, as described herein, effective to spontaneously form a plurality of stable micelles having a particle size within a range of about 1 ⁇ to about 10 ⁇ upon contact with an aqueous medium, or alternatively, by administering pre-formed micelles produced therefrom, because the DHA avoids the first pass effect, the fatty acid is in the less toxic chylomicron form in blood, and there is no IV fistula issue.
  • TPN-associated liver disease PNALD
  • PNALD TPN-associated liver disease
  • inflammation that is related to the type of intravenous lipid emulsion used.
  • These fat emulsions cannot be eliminated from PN because to do so would lead to the development of essential fatty acid deficiency and its concomitant complications.
  • Recent data has shown that the replacement of omega-6 soybean oil lipid emulsions with those comprised primarily of omega-3 fatty acids may lead to reduction or avoidance of PNALD without predisposing the patient to essential fatty acid deficiency.
  • such medications should provide the necessary and the essential fatty acids and fat calories for proper growth, development and maintenance of bodily functions in humans of all ages, but especially in neonates, and reduce or even avoid PNALD.
  • PSC Primary sclerosing cholangitis
  • liver cells die and are replaced with scar tissue.
  • Neonatal Sclerosing Cholangitis NSC
  • children in neonates
  • PSC is referred to as Neonatal Sclerosing Cholangitis (NSC)
  • NSC Neonatal Sclerosing Cholangitis
  • the diagnosis is based on characteristic findings in combination with clinical, biochemical and histological features. Many patients are asymptomatic at presentation, but symptoms develop over time. Symptoms include itch, lethargy, steatorrhea and vitamin deficiencies, metabolic bone disease, bleeding peristomal varices, bacterial cholangitis, dominant biliary strictures, and in advanced cases cholangiocarcinoma.
  • Ursodeoxycholic acid has been studied and may improve the liver function profile, but a high number of adverse events are associated with this treatment and there is debate about its effectiveness.
  • CFTR cystic fibrosis transmembrane conductance regulator protein
  • CFTR dysfunction is associated with (1) decreased chloride secretions into the bile canaliculi with subsequent decrease in osmotic extrusion of water into the lumen, resulting in hyperconcentration and acidification of bile leading to obstruction of intrahepatic bile ductules, secondary inflammation and eventual focal biliary cirrhosis; (2) innate immune defects and leads to an excessive host inflammatory response; (3) fatty acid alterations, specifically a decrease in docosahexaenoic acid (DHA) and an increase in arachidonic acid (AA).
  • DHA docosahexaenoic acid
  • AA arachidonic acid
  • Omega-3 fatty acids are known to have anti-inflammatory effects.
  • Non- Alcoholic Fatty Liver Disease is a common, often "silent" liver disease and resembles alcoholic liver disease, but occurs in people who drink little or no alcohol.
  • the major feature of NAFLD is excess fat in the liver, along with inflammation and damage. Most people with this disease feel well and are not aware that they have a liver problem. Nevertheless, the condition can be severe and can lead to cirrhosis, in which the liver is permanently damaged and scarred and no longer able to function properly.
  • Non-alcoholic fatty liver disease is characterized by increased hepatic fat accumulation in individuals not consuming excessive alcohol and represents a spectrum of disease ranging from 'simple' steatosis to non-alcoholic steatohepatitis.
  • NAFLD is associated with the metabolic syndrome and is defined by the presence of >5% hepatic steatosis. Risk factors for the development of NAFLD include central obesity, type II diabetes, dyslipidemia, and hypertension. In Western populations, the prevalence of NAFLD may exceed 30%, and can be as high as 88% in the obese. NAFLD is the most common liver disease in children. Given the increasing prevalence and incidence of these conditions, the global burden of
  • NAFLD is expected to increase.
  • NASH and NAFLD are under diagnosed due to poor disease awareness, the insufficiency of non-invasive diagnostic tools and the lack of effective approved therapies.
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • the primary treatment for NAFLD is weight loss by lifestyle therapy involving diet and exercise. Weight loss has been shown to improve liver enzymes, decrease plasma triglycerides and improve liver fatness. Bariatric surgery is an extreme option for reducing weight and the resulting improvements in liver pathology. However, bariatric surgery is not feasible for the large number of patients having this disease.
  • Non-alcoholic steatohepatitis is a fibrotic manifestation, which progresses from NAFLD.
  • NASH is usually a silent disease with few or no symptoms and occurs in people who drink little or no alcohol.
  • the major feature in NASH is fat in the liver, along with inflammation and damage.
  • Most people with NASH feel well and are not aware that they have a liver problem. Nevertheless, NASH can be severe and can predispose the individual to hepatic fibrosis, cirrhosis, and subsequent end-stage liver disease and hepatocellular carcinoma. Not ever person with NASH develops cirrhosis, but once serious scarring or cirrhosis is present, few treatments can halt the progression.
  • NASH ranks as one of the major causes of cirrhosis in the United States, behind hepatitis C and alcoholic liver disease.
  • Weight loss is the first recommendation for NASH patients and is associated with a significant improvement in steatosis and overall severity of NASH. However, such improvement is only statistically significant when patients are able to reduce more than 7% of their body weight over a sustained period of 48 weeks, which occurs in less than 50% of NASH patients.
  • Products utilized off label in the management of NASH comorbidities include vitamin E, insulin sensitizers such as metformin and pioglitazone, which are used for diabetic patients, and anti-hyperlipidemic agents, pentoxifylline, and ursodiol.
  • Vitamin E has been shown in a clinical study of non-diabetic patients to reduce inflammation but not fibrosis. Vitamin E is not recommended for NASH patients with type-2 diabetes due to lack of data, therefore the use of vitamin E is limited. While other off-label pharmacotherapies demonstrate inconsistent benefits or are associated with significant side effects. Bariatric surgery is believed to impact NASH through dramatic weight loss, but it has significant complications and drawbacks. These include a host of perioperative risk factors, the need to adhere to post-surgical diet and nutritional regimens and high costs. A relatively small number of these procedures are performed annually on NASH patients compared to the overall NASH population, which we believe is due to the complications and drawbacks of bariatric surgery relative to NASH patient numbers.
  • NASH While NAFLD occurs in people of all ages, NASH most often occurs in people who are middle aged and overweight or obese. Affected individuals may also have elevated levels of blood lipids (such as cholesterol and triglycerides) and many have diabetes. N ASH affects 2 to 5 percent of Americans. Both NASH and NAFLD are becoming more common, possibly because of the greater number of Americans with obesity. In the past 10 years, the rate of obesity has doubled in adults and tripled in children. Obesity also contributes to diabetes and high blood cholesterol, which can further complicate the health of a patient with NASH.
  • blood lipids such as cholesterol and triglycerides
  • Sickle cell disease also known as sickle-cell anaemia (SCA) and drepanocytosis, is a group of hereditary blood disorders that affects hemoglobin, the molecule that delivers oxygen throughout the body via red blood cells.
  • Sickle cell disease is caused by mutations in the HbA gene and is inherited in an autosomal recessive pattern (a single point mutation in the sixth codon of the ⁇ -globin gene).
  • HbSS SCD - hemoglobin SS
  • HbS betaO-thalassemia hemoglobin SC
  • HbS beta+-thalassemia HbS beta+-thalassemia.
  • Sickle cell disease is a serious disease that significantly compromises the quality of patients' lives and reduces life expectancy significantly. Signs and symptoms of sickle cell disease usually begin in early childhood. The severity of symptoms varies from person to person and it has been postulated that clinical manifestations result from complex combinations of genetic, cellular and
  • Sickle cells have a shorter lifespan than normal red blood cells. Sickle cells also deliver less oxygen to the body's tissues. As a result, patents with sickle cell disease frequently develop anemia. Sickle cell anemia is a common manifestation of sickle cell disease. Patients with anemia experience fatigue, weakness, shortness of breath, dizziness, headaches, and coldness in the hands and feet. Anemia can also cause delayed growth and development in children. The rapid breakdown of red blood cells may also cause jaundice.
  • Sickle cells are rigid and prone to adhesive interactions with each other, leukocytes, platelets, plasma and vessel walls. These adhesive interactions lead to vaso-occlusion in small blood vessels, with the sickle cells either intact or in pieces.
  • Vaso- occlusion cuts down even more on the amount of oxygen flowing to body tissues.
  • Acute vaso-occlusive events are known as crises. Crises can last from hours to days. Some patients have one episode every few years while others have many episodes each year. Crises can be severe enough to require hospitalization and can be fatal.
  • Vaso-occlusive events in sickle cell disease are believed to be influenced by multiple factors, including leucocyte adhesion molecules, inflammatory factors, endothelial cell interactions, haemorheology and erythrocyte heterogeneity.
  • sickle cell patients are often in a near- continuous state of inflammation. They have elevated states of markers of inflammation such as C-reactive protein, fibrinogen and interleukin. Sickle cell patients also often have near continuous thrombotic activity, low level most of the time but spiking during crises.
  • compositions to nearer to normal levels will create a significant decrease in the inflammation and thus diminish the morbidity of sickle cell disease.
  • a reference to “sickle cell disease” or “sickle cell condition” or “sickle cell disease condition” refers to each and all of the disease states and/or effects and/or conditions of sickle cell disease as described herein or as otherwise known by the ordinarily skilled artisan in the relevant art.
  • a reference to “at least one sickle cell condition” refers to one or more of the conditions related to sickle cell disease as described herein or as otherwise known to such ordinarily skilled artisan.
  • Antibiotics are frequently prescribed to treat the bacterial infections that are common in sickle cell patients.
  • Sickle cell patients are often advised to take folic acid supplements because folic acid aids in the production of new red blood cells.
  • Hydroxyurea (tradename DROXIA) is approved to reduce the number of pain episodes (including chest pain and breathing problems) and blood transfusions in patients with recurring moderate to severe crises but is a cytotoxic molecule with teratogenic and carcinogenic effects.
  • DROXIA Hydroxyurea
  • hydroxyurea is uncertain. It has been found that besides the damage caused by sickle cells themselves, the inflammatory response that occurs in sickle cell disease patients could potentially play a significant role in the occurrence of painful episodes or pain crises. Sickle cell patients experience relief of symptoms when treated with a variety of anti-inflammatory agents.
  • omega-3 fatty acids decrease the hemolysis of mammalian red blood cells. It also has been found that sickle cell patients have abnormal blood fatty acids. These findings have led to the hypothesis that omega-3 fatty acids may be useful in the treatment of sickle cell disease. As early as 2001, small human clinical trials showed that omega-3 fatty acids could reduce pain episodes in sickle cell patients, perhaps by reducing prothrombotic activity. Other studies have shown that omega-3 fatty acids can increase hemoglobin levels, and reduce pain episodes, vaso-occlusive episodes, anemia, organ damage and other disease complications in sickle cell patients.
  • Vaso-occlusive events are the source of a number of problematic symptoms in patients with sickle disease and can occur through platelet aggregation as well as red blood cell aggregation and white blood cell aggregation. Some vaso-occlusive events are the result of thrombosis, which is initiated by thromboxane A2 (TXA2).
  • TXA2 thromboxane A2
  • Omega-3 DPA has been shown to be a potent inhibitor of COX-1 activity (the enzyme involved in synthesis of TXA2), thus omega-3 DPA can inhibit the pathways through which vaso-occlusive events occur.
  • omega-3 fatty acids can delay or even prevent some of the damaging effects of inflammation in sickle cell patients.
  • any new therapy that reduces the frequency or severity of inflammation, anemia and/or vaso-occlusive crises in patients is likely to play a useful role in the treatment of sickle cell disease.
  • omega-3 fatty acids may be useful in the treatment of sickle cell disease and improving or protecting cell health
  • new formulations, particularly those with a demonstrable increase in absorption and blood levels of omega-3 and other fatty acids in the treatment of sickle cell disease are warranted.
  • Age-related macular degeneration is a condition that results in a loss of vision in the center of the visual field (the macula). It is a progressive disease and is the leading cause of severe vision loss in people over age 60. It occurs in “dry” and “wet” forms and causes damage to the macula, a small spot near the center of the retina and the part of the eye needed for sharp, central vision, which lets us see objects that are straight ahead.
  • the macula is the part of the retina that receives most of the direct light in the eye; is very sensitive to light, with higher concentrations of rods and cones, and is needed for accurate central vision.
  • the retina is a network of visual receptors and nerves that lies on the choroid; a layer of blood vessels that provides blood to the macula, and the retinal pigment epithelium (RPE).
  • the RPE is another layer of specialized cells, which transports the nutrients from the blood vessels and clears waste products from the macula.
  • Dry AMD is an early stage of the disease and may result from the aging and thinning of macular tissues due to the degeneration or atrophy that occurs from cell death. It is characterized by the presence of yellow spots, called drusen, which form in and around the macula. It is believed these spots are deposits or debris from deteriorating tissue, which accumulates between the retina and the choroid due to the inability of the RPE to get rid of the waste and leads to the eventual deterioration of the photoreceptors.
  • Wet AMD refers to the growth of abnormal growth of blood vessels (angiogenesis) beneath the retina, also referred to as choroidal neovascularization. These blood vessels leak blood and fluid into the retina, causing distortion of vision that makes straight lines look wavy, as well as blind spots and loss of central vision. These abnormal blood vessels eventually scar, leading to permanent loss of central vision.
  • angiogenesis inhibitors such as for example, BEVACIZUMAB, RANIBIZUMAB, PEGAPTANIB, AND AFLIBERCEPT can be injected into one's eye to stop new blood vessels from growing.
  • Oxidative damage, resulting from excess production of reactive oxygen species (ROS) has been implicated in the progression AMD.
  • Retinal pigmented epithelial (RPE) cells are highly metabolically active and there is strong evidence that the RPE cells are extremely sensitive to oxidative stress. It has been reported that the pathophysiology of AMD is due to cumulative oxidative damage to RPE cells resulting from an imbalance between the generation of ROS and the ability of these cells to destroy and/or protect against ROS damage. Strategies for protecting RPE cells against oxidative damage may be particularly important in maintaining retinal function and both preventing and treating AMD.
  • AREDS was designed to evaluate the prevention and treatment effects of high doses of antioxidants and zinc on individuals with AMD.
  • AREDS2 was conducted to evaluate the effects on progression and treatment of AMD patients of a modified version of the AREDS formulation, including omega-3 fatty acids.
  • the study showed no AMD-related benefit from the introduction of the omega-3 fatty acids into the treatment regimen.
  • the AREDS2 formulation did not include formulas with self-micellizing properties, the AREDS2 study was unable to evaluate an efficacious bioavailability of the omega-3 fatty acids on AMD.
  • Neurodegenerative disease is an umbrella term for a range of conditions, which primarily affect the neurons in the human brain.
  • Examples of the more common neurodegenerative diseases include Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease), Epilepsy, and Multiple Sclerosis (MS).
  • PD Parkinson's Disease
  • AD Alzheimer's Disease
  • ALS Amyotrophic Lateral Sclerosis
  • MS Multiple Sclerosis
  • PD is a neurodegenerative disorder primarily characterized by motor symptoms but which also includes several other pathological features such as autonomic system failures, mood disorders, and cognitive deficits.
  • Conventional treatment may involve medication that is primarily aimed at increasing dopamine activity either by providing the precursor (raw material) in the form of levodopa (L- Dopa), or by stimulating dopamine receptors (essentially mimicking dopamine) through the use of a dopamine agonist drug.
  • drugs called COMT inhibitors which can help the levodopa to be more effective
  • MAO-B inhibitors which prevent dopamine from breaking down so the limited supply is longer lasting.
  • Other therapies may include physiotherapy, osteopathy, remedial movement, massage, speech therapy, psychological therapy and in some cases surgery (deep brain stimulation). Current pharmacological options for the disease are limited to symptom management and their long-term use leads to important side effects.
  • MS is a nervous system disease that affects your brain and spinal cord. It damages the myelin sheath, the material that surrounds and protects your nerve cells. This damage slows down or blocks messages between your brain and your body, leading to the symptoms of MS. They can include visual disturbances, muscle weakness, trouble with coordination and balance, sensations such as numbness, prickling, or "pins and needles", and thinking and memory problems.
  • myelin sheath the material that surrounds and protects your nerve cells. This damage slows down or blocks messages between your brain and your body, leading to the symptoms of MS. They can include visual disturbances, muscle weakness, trouble with coordination and balance, sensations such as numbness, prickling, or "pins and needles", and thinking and memory problems.
  • therapies have proven helpful. The primary aims of therapy are returning function after an attack, preventing new attacks, and preventing disability.
  • medications used in the management of MS have several adverse effects. Available management and/or treatment of the disease is dependent on the stage of the disease.
  • RRMS relapsing remitting multiple sclerosis
  • eight disease-modifying treatments have been approved by regulatory agencies for RRMS including: interferon beta- la, interferon beta- lb, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, teriflunomide' and dimethyl fumarate.
  • PPMS primary progressive MS
  • ALS is a rapidly progressive, neuromuscular disease. It attacks the motor neurons that transmit electrical impulses from the brain to the voluntary muscles in the body. When they fail to receive messages, the muscles lose strength, atrophy and die.
  • RILUZOLE which extends survival of ALS patients by several months, is currently the only treatment approved for improving survival, but does not reverse the damage already done to motor neurons.
  • BACLOFEN and DIAZEPAM are often prescribed to control the spasticity caused by ALS, and trihexyphenidyl or amitriptyline may be prescribed when ALS patients begin having trouble swallowing their saliva.
  • AD Alzheimer's disease
  • Dementia is the loss of cognitive functioning— thinking, remembering, and reasoning— and behavioral abilities, to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Four medications are approved by the U.S. Food and Drug Administration to treat
  • DONEPEZIL ARICEPT ®
  • RI V AS TIGMINE EXELON ®
  • GALANTAMINE RAZADYNE ®
  • NAMENDA ® is used to treat moderate to severe Alzheimer's. These drugs work by regulating neurotransmitters (the chemicals that transmit messages between neurons). They may help maintain thinking, memory, and speaking skills, and help with certain behavioral problems. However, these drugs don't change the underlying disease process, are effective for some but not all people, and may help only for a limited time.
  • Epilepsy is a group of neurological diseases characterized by epileptic seizures. Epileptic seizures are episodes that can vary from brief and nearly undetectable to long periods of vigorous shaking. In epilepsy, seizures tend to recur, and have no immediate underlying cause while seizures that occur due to a specific cause are not deemed to represent epilepsy. The cause of most cases of epilepsy is unknown, although some people develop epilepsy as the result of brain injury, stroke, brain tumor, and substance use disorders. Genetic mutations are linked to a small proportion of the disease. Epileptic seizures are bel ieved to be the result of excessive and abnormal cortical nerve cell activity in the brain. Seizures are controllable with medication in about 70% of cases.
  • omega- 3 polyunsaturated fatty acids may constitute therapeutic strategy for several disorders of the central nervous system, including PD, AD, ALS, Epilepsy, Bi-polar Syndrome, traumatic brain injury, peripheral neuropathy, and MS.
  • fatty acids found most commonly in certain fish and some plants, are known to help reduce inflammation and oxidative stress on cells. Both of these processes are known to damage nerve tissue.
  • vitamin D may play a significant role in eye health, specifically in the prevention of AMD.
  • a high correlation is known to exist between deficient vitamin D levels and AMD.
  • Vitamin D is believed to act through the vitamin's anti-inflammatory or anti-angiogenic properties. For this reason, vitamin D may be useful in the treatment of multiple inflammation related diseases, including AMD, sickle cell disease, Alzheimer's, and other diseases.
  • Zinc is one of the most abundant trace metals in the human body. Over 300 enzymes are known to utilize zinc in normal mammalian function. Zinc deficiency affects many functions that are directly or indirectly related to declining cognitive performance in aging individuals, including the progression of
  • Alzheimer's Because zinc use is so prolific throughout the body, zinc deficiency can be causally related to Alzheimer's disease through multiple pathways. For instance, zinc deficiency can induce insulin resistance, a risk factor for Alzheimer's. Furthermore, zinc is believed to be very important in the transport of lipids across the intestinal lining and therefore affect many diseases related to lipid deficiencies, including Alzheimer's.
  • Alzheimer's disease represents a major health problem in the US, estimated to be the third leading cause of death, yet the causes of Alzheimer's disease remain largely unknown and misunderstood.
  • recent research is beginning to demonstrate a clear link between the progression of the disease and certain changes in lipids, including fatty acids and fat soluble vitamins, as well as
  • Markers correlated with progression of Alzheimer's include changing fatty acid profiles of DHA, EPA, and arachidonic acid, as well as metabolic syndrome, chronic inflammation, hypo vitamino sis D, and zinc deficiency.
  • markers themselves may be correlated.
  • Treatment of these correlated conditions can be made through the introduction of lipids in the correct ratios or amounts.
  • the absorption of lipids by the digestive system requires a co-consumption of the dietary fats necessary to form naturally occurring micelles, the ability to properly dose patients is often a significant challenge. Further complicating matters, the over- introduction of certain lipids, such as the fat-soluble vitamins, can be harmful.
  • Magnesium contributes to more than three hundred chemical reactions in mammals, including every ATP-dependent reaction. Magnesium deficiency is most commonly associated with malabsorption diseases, including Crohn's disease, gluten- sensitive enteropathy (celiac disease), and regional enteritis. Resection or bypass of the small intestine, such as in short bowel disease, typically leads to malabsorption and magnesium loss.
  • the interaction of magnesium and vitamin D is particularly important across a plethora of pathways and body systems. For example, magnesium is required for both steps in the activation of vitamin D to calcitriol, the form of the vitamin necessary for calcium absorption. Magnesium is also required for calcitriol' s role in calcium absorption.
  • Mammals with low magnesium are deficient in both vitamin D and calcitriol, but the introduction of calcitriol alone does not improve calcium absorption. Magnesium deficits are correlated to type 2 diabetes and insulin resistance as a result of higher excretion of magnesium that results from increased glucose concentrations in the kidneys. Thus, a need exists to co-administer magnesium with lipids in the treatment or prevention of certain disease states.
  • Vitamins A, D, and K cooperate synergistically not only with each other, but also with essential minerals like magnesium and zinc, with dietary fats. Vitamins A, D, and K2 interact synergistically to support immune health, support bone and teeth strengthening, and protect soft tissues from calcification. The interaction of these fat-soluble vitamins with magnesium and zinc is important. Zinc supports the formation of vesicles involved in transporting lipids, including the fat-soluble vitamins, across the intestinal wall.
  • compositions comprising at least one omega-3 fatty acid composition (either in the triglyceride, ester, or free fatty acid form) and at least one surface active agent composition. These compositions, when combined in specific ratios, are
  • the LSTM 13 320 Laser Diffraction Particle Size Analyzer uses laser diffraction and a patented polarization intensity differential scattering (PIDS) technology to rapidly determine the particle size distribution of materials with an overall sizing range of 0.04 ⁇ to 2000 ⁇ in a single scan with no extrapolation. This is accomplished with high resolution and excellent reproducibility.
  • PIDS polarization intensity differential scattering
  • the sample was heated in its original container at 37 C for one hour. After mixing well, approximately 0.25 g of sample was diluted with 5 mL of deionized water. The dilution was manually shaken to form a homogenous mixture. The preparation was allowed to equilibrate to room temperature and was subsequently dispensed to the ALM sample vessel dropwise and analyzed for the particle size distribution (PSD), which was determined using the Fraunhofer optical model. The instrument analyzed the PSD from 0.040 ⁇ to 2,000 ⁇ .
  • PSD particle size distribution
  • the at least one omega-3 fatty acid (either in the triglyceride, ester, or free fatty acid form) is selected from the group consisting of hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, the omega-3 isomer of
  • self-micellizing compositions may further contain an omega-6 fatty acid (either in the triglyceride, ester, or free fatty acid form), for example arachidonic acid (ARA), linoleic acid (LA), Gamma- linolenic acid (GLA), and omega-6 docosapentaenoic acid (omega-6 DP A).
  • omega-6 fatty acid either in the triglyceride, ester, or free fatty acid form
  • ARA arachidonic acid
  • LA linoleic acid
  • GLA Gamma- linolenic acid
  • omega-6 docosapentaenoic acid omega-6 DP A
  • Certain embodiments provide for at least one surface active agent, a first omega-3 fatty acid (either in the triglyceride, ester, or free fatty acid form) and a second omega-3 fatty acid (either in the triglyceride, ester, or free fatty acid form), wherein the first and second omega-3 fatty acids are different and are selected from the group consisting of hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, the omega-3 isomer of docosapentaenoic acid, docosahexaenoic acid, tetracosapentaenoic acid, and tetracosahexaenoic acid.
  • compositions comprising at least one surface active agent and a first omega-3 fatty acid (either in the triglyceride, ester or free fatty acid ester form) and a second omega-3 fatty acid (in either the ester, triglyceride or free fatty acid form), wherein the first and second omega-3 fatty acids are different and wherein the ratio of the amount of the first omega-3 fatty acid to the second omega-3 fatty acid is 1:X where 0 ⁇ X ⁇ 1.
  • X can be, for example, 0.001, 0.0015, 0.002, 0.0025, 0.0055, 0.006, 0.0065, 0.007, 0.0075, 0.008, 0.0085, 0.009, 0.0095, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.1, 0.15, 0.2, 0.25, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, or, 0.95.
  • the compositions comprise at least one surface active agent and a first and second omega-3 fatty acid, wherein the first omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is docosahexaenoic acid (DHA) and the second omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is selected from the group consisting of hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, the omega-3 isomer of docosapentaenoic acid,
  • the compositions comprise at least one surface active agent and a first and second omega-3 fatty acid, wherein the first omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is eicosapentaenoic acid (EPA) and the second omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is selected from the group consisting of hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, heneicosapentaenoic acid, docosahexaenoic acid (DHA), the omega-3 isomer of docosapentaenoic acid (DP A), tetracosapentaenoic acid, and tetracosahexaenoic acid and combinations thereof.
  • EPA eicosapentaenoic acid
  • DHA docosahex
  • compositions comprise at least one surface active agent and a first and second omega-3 fatty acid, wherein the first omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is DHA and the second omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is EPA, wherein the ratio of the amount of DHA:EPA is 1 :X, where 0 ⁇ X ⁇ 1.
  • X can be, for example, 0.001, 0.0015, 0.002, 0.0025, 0.0055, 0.006, 0.0065, 0.007, 0.0075, 0.008, 0.0085, 0.009, 0.0095, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.1, 0.15, 0.2, 0.25, 0.55, 0.6, 0.65, 0.7, 0.75, or 0.8.
  • compositions comprise at least one surface active agent and a first and second omega-3 fatty acid, wherein the first omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is EPA and the second omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is DHA, wherein the ratio of the amount of EPA:DHA is 1:X, where 0 ⁇ X ⁇ 1.
  • X can be, for example, 0.001, 0.0015, 0.002, 0.0025, 0.0055, 0.006, 0.0065, 0.007, 0.0075, 0.008, 0.0085, 0.009, 0.0095, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.1, 0.15, 0.2, 0.25, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, or 0.95.
  • compositions described herein optionally comprise a third fatty acid (either in the triglyceride, ester, or free fatty acid form), wherein the third fatty acid is different from the first and second omega-3 fatty acids.
  • the ratio of the amount of the first omega-3 fatty acid to the second and third omega-3 fatty acids is 1 :X, where X is the combined amount of the second and third fatty acids and where 0 ⁇ X ⁇ 1.
  • the third omega-3 fatty acid may be selected from the group consisting of hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, heneicosapentaenoic acid, the omega-3 isomer of docosapentaenoic acid, tetracosapentaenoic acid, and tetracosahexaenoic acid.
  • the ratio of the amount of DHA:(EPA+ third omega-3 fatty acid) is 1:X, where X is the amount of EPA plus the amount of the third omega-3 fatty acid, and where 0 ⁇ X ⁇ 1.
  • X can be, for example, 0.001, 0.0015, 0.002, 0.0025, 0.0055, 0.006, 0.0065, 0.007, 0.0075, 0.008, 0.0085, 0.009, 0.0095, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, or 0.95.
  • the third fatty acid can be an omega-6 fatty acid such as arachidonic acid (ARA), linoleic acid (LA), gamma-linolenic acid (GLA) or the omega-6 isomer of DP A (either in the triglyceride, ester, or free fatty acid form).
  • omega-6 fatty acid such as arachidonic acid (ARA), linoleic acid (LA), gamma-linolenic acid (GLA) or the omega-6 isomer of DP A (either in the triglyceride, ester, or free fatty acid form).
  • the omega-3 fatty acids are substantially pure.
  • the omega-3 fatty acids are in the form of triglycerides.
  • the omega-3 fatty acids are in the form of esters.
  • the omega-3 fatty acid ester is the ethyl ester derivative.
  • the omega-3 fatty acids are in the form of free fatty acids.
  • compositions comprising the at least one surface active agent and the omega-3 fatty acids in either the triglyceride or ester forms are free of free fatty acid forms.
  • compositions are substantially free of active agents other than the omega-3 fatty acids (either in the triglyceride, ester, or free fatty acid form).
  • the omega-3 fatty acid or combinations of omega-3 fatty acids comprises, for example, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% (wt/wt) of the composition.
  • the compositions described herein comprise DHA at, for example, from 50% to 99% (wt/wt) of the compositions.
  • the DHA is present at 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% (wt/wt) of the compositions.
  • the DHA is present at least, for example, 90% (wt/wt) of the compositions described herein.
  • the DHA is present at least, for example, 95% (wt/wt) of the compositions described herein.
  • the compositions described herein comprise EPA at, for example, from 0% to 50% (wt/wt) of the compositions.
  • the EPA is present at ⁇ 1% (wt/wt) of said compositions.
  • the EPA can be present at, for example, 2%, 4%, 6%, 8%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46%, 48% or 50% (wt/wt) of said compositions.
  • the EPA can be present at ⁇ 5% (wt/wt) of said compositions.
  • the EPA can be present at 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, or 4.5% (wt/wt) of said compositions.
  • the compositions described herein comprise an omega-3 fatty acid other than DHA and EPA at, for example, from >0% to 10% (wt/wt) of said compositions.
  • said omega-3 fatty acid other than DHA and EPA can be present, in certain embodiments at 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, %, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5% or 10% (wt/wt) of said compositions.
  • the omega-3 fatty acid other than EPA and DHA can be selected from the group consisting of hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, heneicosapentaenoic acid, the omega-3 isomer of
  • docosapentaenoic acid docosapentaenoic acid, tetracosapentaenoic acid, and tetracosahexaenoic acid.
  • compositions described herein comprise 90%, 5%, and 5% (wt/wt) of said compositions DHA, ARA, and EPA respectively.
  • compositions described herein comprise 95%, 5%, and ⁇ 1% (wt/wt) of said compositions DHA, ARA, and EPA respectively.
  • the omega-3 fatty acid compositions described herein comprise at least one surface active agent selected from the group consisting of at least one nonionic surface active agents, cationic surface active agents, anionic surface active agents, zwitterionic surface active agents, and combinations thereof.
  • the surface active agent is selected from the group consisting of at least one anionic surface active agent, at least one non-ionic surface active agent, and a combination thereof.
  • the at least one surface active agent has a hydrophilic-lipophilic balance (HLB) of 8.0.
  • HLB hydrophilic-lipophilic balance
  • the surface active agent can be a non-ionic surface active agent selected from the group consisting of at least one polysorbate, at least one poloxamer, and a combination thereof.
  • the at least one surface active agent comprises a polysorbate present from, for example, 15% (wt/wt) to 35% (wt/wt) of the composition.
  • the polysorbate is present at, for example, 31% (wt/wt) of the composition.
  • the polysorbate is polysorbate 80.
  • the at least one surface active agent comprises a poloxamer present from, for example, 0.1% (wt/wt) to 5% (wt/wt) of the composition.
  • the poloxamer is present at, for example, 0.7% (wt/wt) of the composition.
  • the poloxamer is Poloxamer 237, also known as Pluronic ® F87.
  • compositions described herein comprise a combination of polysorbate 80 and the Poloxamer 237 (Pluronic ® F87)
  • the combination of polysorbate and poloxamer comprise at least, for example, 25% (wt/wt) of said composition.
  • the composition further comprises at least one antioxidant.
  • the at least one antioxidant is selected from the group consisting of a tocopherol, a tocotrienol, and combinations thereof.
  • the tocopherol, tocotrienol and combinations thereof is present from, for example, from about 0.01% to about 5% by weight of the compositions.
  • the tocopherols, tocotrienols and combinations thereof can be present at, for example, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, or 6% (wt/wt) of the compositions.
  • the tocopherols, tocotrienols, and combinations thereof can be present at, for example, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, or 6% (wt/wt) of the compositions.
  • the antioxidant is d-gamma tocotrienol present at, for example, 3%, 3.35%, 4%, 4.35%, 5%, or 5.35% (wt/wt) of the composition. In certain embodiments further comprising at least one antioxidant, the antioxidant is a-tocopherol present at, for example, 2% (wt/wt) of the composition.
  • compositions comprising at least one terpene.
  • Said present can be present from, for example, 0.1% (wt/wt) to 5% (wt/wt).
  • the terpene is present at, for example, 0.01%, 0.05%, 0.1%,
  • the terpene can be d-limonene.
  • the d- limonene is from about, for example, 95% to about 98% pure.
  • the substantially pure d-limonene is at least, for example, 95%, 96%, 97% or 98%, 99% pure.
  • compositions comprising natural orange-oil.
  • the bioavailability of the omega-3 fatty acids (in either the triglyceride, ester, or free fatty acid form) included in the compositions described herein is substantially the same when administered with or without food,
  • compositions comprising at least one omega-3 fatty acid (either in the triglyceride, ester or free fatty acid ester form) and at least one surface active agent, which are present in an amount and a combination effective to cause said
  • compositions to self-micellize when in contact with an aqueous medium can be characterized by their ability to spontaneously form a plurality of stable micelles having a particle size within a range of about 1 ⁇ to about 10 ⁇ , upon contact with the aqueous medium.
  • the plurality of micelles produced in this manner demonstrate enhanced bioavailability of said at least one omega-3 fatty acid, while eliminating any food effect, and improving patient compliance due to the lowered dosage required to reach a similar bioavailability or AUC (e.g. 1 pill versus 6).
  • a method for treating AMD by administering the compositions described herein to a human in need of such administration.
  • the human can be an adult, a child, an adolescent, or and infant, such as for example a neonate.
  • a method is provided for treating Juvenile Macular Degeneration, which includes Stargardt's disease, Best disease, and juvenile retinoschisis by administering the compositions described herein to a human juvenile.
  • the compositions may comprise at least one omega-3 fatty acid, and at least one non-omega-3 fatty acid nutritional supplement agent, wherein the omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is docosahexaenoic acid (DHA) (in either the triglyceride, ester, or free fatty acid form) and wherein the non-omega-3 fatty acid active agent or non-omega-3 fatty acid nutritional supplement may be selected from the group consisting of vitamin C, vitamin E, beta-carotene, magnesium, zinc (including as zinc oxide), and copper (including as cupric oxide), and combinations thereof, and at least one surface active agent, in an amount and a combination effective to cause said compositions to spontaneously self-micellize when in contact with an aqueous medium, thereby forming a plurality of stable micelles having a particle size within a range of about 1 ⁇ to about 10 ⁇ .
  • DHA docosahexaenoic
  • the compositions comprise at least one surface active agent, at least one omega-3 fatty acid, and a non-omega-3 fatty acid active agent, wherein the omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is eicosapentaenoic acid (EPA) (in either the triglyceride, ester, or free fatty acid form) and wherein the non-omega-3 fatty acid active agent is selected from the group consisting of vitamin C, vitamin E, beta-carotene, magnesium, zinc (including as zinc oxide), and copper (including as cupric oxide), and combinations thereof.
  • EPA eicosapentaenoic acid
  • non-omega-3 fatty acid active agent is selected from the group consisting of vitamin C, vitamin E, beta-carotene, magnesium, zinc (including as zinc oxide), and copper (including as cupric oxide), and combinations thereof.
  • the compositions comprise at least one surface active agent, a first omega-3 fatty acid, a second omega-3 fatty acid, and a non- omega-3 fatty acid active agent, wherein the first omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is EPA and the second omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is DHA, wherein the ratio of the amount of EPA:DHA is 1:X, where 0 ⁇ X ⁇ 1 and wherein the non-omega-3 fatty acid active agent is selected from the group consisting of vitamin C, vitamin E, beta- carotene, magnesium, zinc (including as zinc oxide), and copper (including as cupric oxide), arachidonic acid (ARA), linoleic acid (LA), gamma-linolenic acid (GLA) or the omega-6 isomer of DP A and combinations thereof.
  • the first omega-3 fatty acid in either the triglyceride,
  • neovascularization can create severe vision problems.
  • Current treatments include the use of known anti-angiogenesis medications. While not wishing to be bound to any particular theories, it is believed that compositions comprising omega-3 DPA can prevent angiogenesis through the vascular endothelial growth factor (VEGF) pathway.
  • VEGF vascular endothelial growth factor
  • a method for treating AMD by administering, to a patient in need thereof, a therapeutically effective amount of a composition comprising omega-3 DPA fatty acid (either in the triglyceride, ester or free fatty acid ester form) and at least one surface active agent, in an amount and a combination effective to cause said compositions to spontaneously self-micellize when in contact with an aqueous medium, thereby forming a plurality of stable micelles having a particle size within a range of about 1 ⁇ to about 10 ⁇ .
  • a method for treating fat malabsorption syndromes by administering the compositions described herein to a human in need of such administration.
  • the human can be an adult, an adolescent, or and infant, such as for example a neonate.
  • a method for treating fat malabsorption syndrome by administering the compositions described herein to a human suffering from SBS or Barrett's Syndrome.
  • a method for treating sickle cell disease by administering the compositions described herein to a human in need of such administration.
  • the human can be an adult, a child, an adolescent, or and infant, such as for example a neonate.
  • a method for treating NAFLD and/or NASH by administering the compositions described herein to a human in need of such administration can be an adult, a child, an adolescent, or and infant, such as for example a neonate.
  • Parkinson's Disease PD
  • AD Alzheimer's Disease
  • MS Multiple Sclerosis
  • ALS Amyotrophic Lateral Sclerosis
  • the human can be an adult, a child, an adolescent, or and infant, such as for example a neonate.
  • a method for preventing or treating Alzheimer's disease by administering the compositions described herein to a subject in need of such administration, wherein said
  • compositions may include at least one fat-soluble vitamin, at least one omega-3 fatty acid (in triglyceride, ester, or free fatty acid form), one or more minerals, such as magnesium, manganese, zinc, copper, selenium, and combinations thereof, and at least one surface active agent in an amount and a combination effective to cause said compositions to spontaneously self-micellize when in contact with an aqueous medium, thereby forming a plurality of stable micelles having a particle size within a range of about 1 ⁇ to about 10 ⁇ .
  • omega-3 fatty acid in triglyceride, ester, or free fatty acid form
  • minerals such as magnesium, manganese, zinc, copper, selenium, and combinations thereof
  • surface active agent in an amount and a combination effective to cause said compositions to spontaneously self-micellize when in contact with an aqueous medium, thereby forming a plurality of stable micelles having a particle size within a range of about 1 ⁇ to about 10 ⁇ .
  • a method for preventing or treating age-related macular degeneration by administering the compositions described herein to a subject in need of such administration, wherein said compositions may include at least one fat-soluble vitamin, an omega-3 fatty acid (in triglyceride, ester, or free fatty acid form, and one or more minerals, such as magnesium, manganese, zinc, copper, selenium, and combinations thereof, and at least one surface active agent in an amount and a combination effective to cause said compositions to spontaneously self-micellize when in contact with an aqueous medium, thereby forming a plurality of stable micelles having a particle size within a range of about 1 ⁇ to about 10 ⁇ .
  • a method for preventing or treating diseases by administering the compositions described herein to a subject in need of such administration wherein said compositions may include at least one fat-soluble vitamin, an omega-3 fatty acid (in triglyceride, ester, or free fatty acid form), and one or more minerals, such as magnesium, manganese, zinc, copper, selenium, and combinations thereof, and at least one surface active agent in an amount and a combination effective to cause said compositions to spontaneously self-micellize when in contact with an aqueous medium, thereby forming a plurality of stable micelles having a particle size within a range of about 1 ⁇ to about 10 ⁇ .
  • said diseases may include one or more of metabolic syndrome, chronic inflammation, hypo vitamino sis D, zinc deficiency, Crohn's disease, diseases related to calcium deficiency, Alzheimer's disease, age-related macular degeneration, short bowel syndrome, sickle cell disease, irritable bowel syndrome
  • compositions described herein may include at least one fat-soluble vitamin, an omega-3 fatty acid (in triglyceride, ester, or free fatty acid form), and one or more minerals, such as magnesium, manganese, zinc, copper, selenium, and combinations thereof, and an omega-6 fatty acid (in
  • compositions described herein self-micellize in an aqueous medium.
  • the aqueous medium is water.
  • the aqueous medium has an acidic pH.
  • the aqueous medium is 0.1N HC1.
  • the compositions described herein self-micellize in an aqueous medium, wherein the micelles have a diameter from about 1 ⁇ to about 10 ⁇ . In certain embodiments, the compositions described herein self- micellizes in an aqueous medium having an acidic pH, wherein the micelles have a diameter from about 1 ⁇ to about 10 ⁇ . In certain other embodiments, the compositions described herein self-micellizes in 0.1N HCL, wherein the micelles have a diameter from about 1 ⁇ to about 10 ⁇ . In certain embodiments, the micelles may have an average diameter of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 ⁇ .
  • compositions described herein minimize or eliminate at least one side effect when compared to the administration of a
  • composition comprising omega-3 fatty acids known to one of skill in the art.
  • side effects include regurgitation, frequency of burping, gastroesophageal reflux disease (GERD), bloating, increased intestinal gas, fish taste, fishy breath, fish smell, nausea, diarrhea, or combinations thereof.
  • GEF gastroesophageal reflux disease
  • compositions described herein comprise d- limonene or natural orange oil.
  • Such compositions can minimize or eliminate at least one side effect from the administration of a composition of the present disclosure when compared to the administration of a composition comprising omega-3 fatty acids substantially free of d-limonene or natural orange oil.
  • Non-limiting examples of the side effects include regurgitation, frequency of burping, gastroesophageal reflux disease (GERD), bloating, increased intestinal gas, fish taste, fishy breath, fish smell, nausea, diarrhea, or combinations thereof.
  • compositions described herein can be administered to a human subject in need of such administration in conjunction with a non-omega-3 fatty acid nutritional supplement or a non-omega-3 fatty acid active agent for the treatment of macular degeneration.
  • non- omega-3 fatty acid nutritional supplements may include a combination of vitamin C, vitamin E, beta-carotene, zinc, copper, magnesium, manganese, calcium, vitamin A, vitamin D, vitamin K (includes Kl and/or K2), lutein and zeaxanthin.
  • compositions described herein can be administered to a human subject in need of such administration in conjunction with a non-omega-3 fatty acid active agent for the treatment of SBS.
  • non-omega-3 fatty acid active agents can include L-Glutamine
  • non-omega-3 fatty acid active agents may include conjugated bile acids or opium tincture.
  • compositions described herein can be administered to a human subject in need of such administration, either alone, or in conjunction with a non-omega-3 fatty acid nutritional supplement or a non-omega-3 fatty acid active agent.
  • a fat malabsorption syndrome e.g.
  • a composition within the purview of the present invention will include substantially pure DHA, or a combination of substantially pure DHA and arachidonic acid in combination with a surface active agent which is a combination including about 31% of Polysorbate 80 and about 0.7% Poloxamer 237;
  • a composition within the purview of the present invention will include a combination of EPA and DHA, or a composition including EPA and a therapeutically effective amount of one or more statins, in combination with a surface active agent which is a combination including about 31% of Polysorbate 80 and about 0.7% Poloxamer 237;
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • compositions described herein can be administered to a human subject in need of such administration in conjunction with a non-omega-3 fatty acid nutritional supplement or a non-omega-3 fatty acid active agent for the treatment of sickle cell disease.
  • non-omega-3 fatty acid active agents can include pain medications, antibiotics, a therapeutically effective amount of a non-steroidal anti-inflammatory medication, illustrated by, albeit not limited to a particular dosage of acetysalicylic acid (aspirin), hydroxyurea, and anti-inflammatory medications.
  • Non-limiting examples of non-omega-3 fatty acid nutritional supplements may include a combination of folic acid, vitamin C, vitamin E, beta-carotene, zinc, copper, magnesium, manganese, calcium, vitamin A, vitamin D, vitamin K (includes Kl and/or K2), lutein and zeaxanthin.
  • compositions described herein can be administered to a human subject in need of such administration in conjunction with a non-omega-3 fatty acid nutritional supplement or a non-omega-3 fatty acid active agent for the treatment of NAFLD and/or NASH.
  • non- omega-3 fatty acid active agents can include, lipid lowering or cholesterol lowering agents selected from the group consisting of cholesterol absorption inhibitors, bile acid sequestrants/resins, statins, niacin and derivatives, MTP inhibitors, fibrates and CETP inhibitors, insulin sensitizers, hypolipidemics , anti-inflammatory medications, and thiazolidinediones.
  • compositions described herein can be administered to a human subject in need of such administration in conjunction with a non-omega-3 fatty acid nutritional supplement or a non-omega-3 fatty acid active agent for the treatment of PSC or Alagille Syndrome.
  • Non-limiting examples of non- omega-3 fatty acid active agents can, upon approval by a respective regulatory agency, may include 6-alpha-ethylchenodeoxycholic acid and salts thereof, and/or (4R,5R)-l-[[4-[[4-[3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-l,l- dioxido- 1 -benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza- 1 - azoniabicyclo [2.2.2] octane chloride .
  • compositions described herein can be administered to a human subject in need of such administration in conjunction with a non-omega-3 fatty acid nutritional supplement or a non-omega-3 fatty acid active agent for the treatment of a neurodegenerative disease.
  • non-omega-3 fatty acid active agents can include medications generally approved by a health regulatory body and prescribed by physicians for a particular
  • neurodegenerative disease such as for example, PD, AD, MS, Epilepsy, and ALS.
  • compositions including substantially pure DHA in combination with at least one surface active agent, as described herein, effective to spontaneously form micelles, or alternatively, pre-formed micelles produced therefrom, are effective for the treatment of neurodevelopmental psychiatric disorders, such as Attention Deficit Disorder (ADD) and Attention Deficit
  • ADHD Hyperactivity Disorder
  • the compositions described herein can be manufactured in an oil-filled inert, non-reactive vessel, non-limiting examples of which include glass vials and Teflon® coated vials; with or without light penetrating inhibitors, including for example amber colored vials.
  • the composition in said oil- filled vial can be administered to an adult human, adolescent, or infant, in particular to a neonate, in need of such administration, by adding an appropriate amount of saline or other pharmaceutically acceptable solutions to said vial, thereby initiating the self-micellization process which results in the formation of the pre-formed micelles as defined herein.
  • the homogenous solution, containing the pre-formed micelles can then be either administered intravenously or added to infant formula for oral ingestion
  • the compositions described herein may be administered in the form of a gel or liquid filled capsule.
  • kits comprising compositions described herein as one or more unit dosage forms together with instructions on using the dosage forms.
  • the dosage forms described herein can be packaged as unit doses, such as for example, glass crimp or snap top vials with instructions for using the unit dosage forms.
  • the instructions can be provided as a package insert or directly on a label attached to the vial, which can be made of clear or amber glass.
  • the instructions can include, for example, dosing frequency recommendations, administration of the dosage forms with or without food, and the active ingredients comprising the dosage forms.
  • kits wherein certain dosage forms comprising the compositions described herein can be packaged together with other non-omega-3 fatty acid nutritional supplements or active agents for the treatment of AMD.
  • the kit(s) comprise one or more unit dosage forms of certain embodiments of the compositions described herein together with one or more unit dosage forms comprising the non-omega-3 fatty acid nutritional supplement or active agent for the treatment of AMD together with instructions on using the dosage forms.
  • Non- limiting examples of non-omega-3 fatty acid nutritional supplements include, for example, a combination of vitamin C, vitamin E, beta-carotene, zinc, copper, magnesium, manganese, calcium, vitamin A, vitamin D, vitamins Kl and/or K2, lutein and zeaxanthin.
  • Non-limiting examples of non-omega-3 fatty acid active agents include, for example, verteporfin; the antioxidant carotenoids crocin and crocetin, as found in, for example, Saffron (Crocus sativus); and inhibitors of angiogenesis, such as for example, BEVACIZUMAB (AVASTIN ® ),
  • Certain embodiments provide for a functional food(s) for treating AMD comprising the compositions described herein.
  • Certain embodiments provide methods of treating AMD by administering a functional food comprising the compositions described herein.
  • the instructions can include, for example, dosing frequency,
  • kits wherein certain dosage forms comprising the compositions described herein can be packaged together with other non-omega-3 fatty acid nutritional supplements for the treatment of a fat
  • kits comprise one or more unit dosage forms of certain embodiments of the compositions described herein together with one or more unit dosage forms comprising the non-omega-3 fatty acid nutritional supplements for the treatment of a fat malabsorption syndrome together with instructions on using the dosage forms.
  • Certain embodiments provide for a functional food(s) for treating a fat malabsorption syndrome comprising the compositions described herein.
  • Certain embodiments provide methods of treating a fat malabsorption syndrome by administering a functional food comprising the compositions described herein.
  • kits wherein certain dosage forms comprising the compositions described herein can be packaged together with other non-omega-3 fatty acid nutritional supplements or active agents for the treatment of sickle cell disease.
  • the kit(s) comprise one or more unit dosage forms of certain embodiments of the compositions described herein together with one or more unit dosage forms comprising the non-omega-3 fatty acid nutritional supplement or active agent for the treatment of sickle cell disease together with instructions on using the dosage forms.
  • Non-limiting examples of non-omega-3 fatty acid active agents and nutritional supplements that can be provided in the kits include pain medications, antibiotics, folic acid, hydroxyurea, and anti-inflammatory medications
  • Certain embodiments provide for a functional food(s) for treating sickle cell disease comprising the compositions described herein.
  • Certain embodiments provide methods of treating sickle cell disease by administering a functional food comprising the compositions described herein.
  • kits wherein certain dosage forms comprising the compositions described herein can be packaged together with other non-omega-3 fatty acid nutritional supplements or active agents for the treatment of NAFLD and/or NASH.
  • the kit(s) comprise one or more unit dosage forms of certain embodiments of the compositions described herein together with one or more unit dosage forms comprising the non-omega-3 fatty acid nutritional supplement or active agent for the treatment of NAFLD and/or NASH together with instructions on using the dosage forms.
  • Non-limiting examples of non-omega-3 fatty acid active agents that can be provided in the kits include, lipid lowering or cholesterol lowering agents selected from the group consisting of cholesterol absorption inhibitors, bile acid sequestrants/resins, statins, niacin and derivatives, MTP inhibitors, fibrates and CETP inhibitors, insulin sensitizers, hypolipidemics , anti-inflammatory medications, and thiazolidinediones.
  • Certain embodiments provide for a functional food(s) for treating NAFLD and/or NASH comprising the compositions described herein. Certain embodiments provide methods of treating NAFLD and/or NASH by administering a functional food comprising the compositions described herein.
  • kits wherein certain dosage forms comprising the compositions described herein can be packaged together with other non-omega-3 fatty acid nutritional supplements or active agents for the treatment of PSC.
  • the kit(s) comprise one or more unit dosage forms of certain embodiments of the compositions described herein together with one or more unit dosage forms comprising the non-omega-3 fatty acid nutritional supplement or active agent for the treatment of PSC together with instructions on using the dosage forms.
  • Non-limiting examples of non-omega-3 fatty acid active agents that can, upon approval by a respective regulatory agency, be provided in the kits include 6-alpha- ethylchenodeoxycholic and/ or (4R, 5 R)- 1 - [ [4- [[4- [3 , 3 -Dibutyl-7-(dimethylamino)- 2,3,4,5-tetrahydro-4-hydroxy- 1 , 1 -dioxido- 1 -benzothiepin-5- yl]phenoxy]methyl]phenyl]methyl]-4-aza-l-azoniabicyclo[2.2.2]octane Chloride.
  • Certain embodiments provide for a functional food(s) for treating PSC comprising the compositions described herein.
  • Certain embodiments provide methods of treating PSC by administering a functional food comprising the compositions described herein.
  • kits are provided, wherein certain dosage forms comprising the compositions described herein can be packaged together with other non-omega-3 fatty acid nutritional supplements or active agents for the treatment of neurodegenerative disease.
  • the kit(s) comprise one or more unit dosage forms of certain embodiments of the compositions described herein together with one or more unit dosage forms comprising the non-omega-3 fatty acid nutritional supplement or active agent for the treatment of a neurodegenerative disease together with instructions on using the dosage forms.
  • Non-limiting examples of non-omega-3 fatty acid active agents that can be provided in the kits include medications generally approved by a health regulatory body and prescribed by physicians for a particular neurodegenerative disease.
  • Certain embodiments provide for a functional food(s) for treating neurodegenerative diseases, such as for example, PD, AD, MS, Epilepsy, or ALS, comprising the compositions described herein.
  • neurodegenerative diseases such as for example, PD, AD, MS, Epilepsy, or ALS
  • Certain embodiments provide methods of treating neurodegenerative diseases, such as for example, PD, AD, MS, Epilepsy, or ALS, by administering a functional food comprising the compositions described herein.
  • Figures 1A-1D illustrate plasma fatty acid profiles (mol%) in the SBS treatment group (dark gray) versus Control (light gray) groups.
  • DFIA plasma fatty acid profiles
  • FIGS 2A-2D illustrate intestinal morphology before and after surgical induction of SBS and DHA treatment.
  • SBS Short bowel syndrome
  • DHA DHA
  • Docosahexaenoic acid Black bars represent tissue morphometry from samples obtained at the time of surgery (Day 0); Striped bars represent tissue morphometry from samples obtained at the end of the study protocol (Final).
  • Figure 3 shows the mean body weight on the day of sacrifice of the mice between each of the Control, Second Treatment Group and Third Treatment Group.
  • Figure 4 shows a-SMA mRNA gene expression in mice in each of the control, NAFLD and NASH groups treated with either Vehicle or Composition 1 at the end of the treatment period.
  • Figure 5 shows plasma alanine transaminase (ALT) levels in mice between each of the control, NAFLD and NASH group treated with either Vehicle or Composition at the end of the treatment period.
  • Figure 6 shows the mean liver weight on the day of sacrifice of the mice between each of the treatment groups and the control.
  • Figure 7 shows the mean liver to body weight ratio on the day of sacrifice of the mice between each of the treatment groups and the control.
  • Figure 8 shows whole blood glucose in mice between each of the control, NAFLD and NASH group treated with either Vehicle or Composition at the end of the treatment period.
  • Figure 9 shows liver triglyceride levels in mice between each of the control, NAFLD and NASH.
  • Figures 10 A and 10B show the mean individual EPA (A) and DHA (B) total lipid concentration-time profiles (baseline-adjusted change) after a single dose of SC401 during fed and fasting conditions.
  • Figures 11 A and 1 IB show the mean individual EPA (A) and DHA (B) free fatty acid concentration-time profiles (baseline-adjusted change) after a single dose of SC401 during fed and fasting conditions.
  • Figure 12 shows mean EPA and DHA total lipid plasma concentration profiles ⁇ g/ml) (baseline-adjusted) after administration of a single dose (dose adjusted) of SC401 and Lovaza® in fasted conditions.
  • the various embodiments of the invention described herein may suitably comprise, consist essentially of, or consist of, at least one surface active agent, at least one omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form).
  • Certain embodiments of the invention may suitably comprise, consist essentially of, or consist of at least one surface active agent and a first and second omega-3 fatty acid, wherein the first omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is selected from the group consisting of
  • hexadecatrienoic acid a-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid,
  • docosahexaenoic acid tetracosapentaenoic acid, tetracosahexaenoic acid, and combinations thereof and the second omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is selected from the group consisting of
  • hexadecatrienoic acid a-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid,
  • docosahexaenoic acid docosahexaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, and combinations thereof, wherein the first and second omega-3 fatty acids (in either the triglyceride, ester, or free fatty acid form) are different and wherein the ratio of the first omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form):the second omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is 1:X, where 0 ⁇ X ⁇ 0.3 or 0.5 ⁇ X ⁇ 1.
  • Certain embodiments of the invention may suitably comprise, consist essentially of, or consist of at least one surface active agent and a first and second omega-3 fatty acid, wherein the first omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is DHA and the second omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is selected from the group consisting of hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid,
  • tetracosapentaenoic acid tetracosahexaenoic acid, and combinations thereof, wherein the ratio of the amount of DHA to the second omega-3 fatty acid is 1:X, where 0 ⁇ X ⁇ 0.3 or 0.5 ⁇ X ⁇ l .
  • Certain embodiments of the invention may suitably comprise, consist essentially of, or consist of at least one surface active agent and a first and second omega-3 fatty acid, wherein the first omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is EPA and the second omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is selected from the group consisting of hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, heneicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid,
  • tetracosapentaenoic acid tetracosahexaenoic acid, and combinations thereof, wherein the ratio of the amount of EPA to the second omega-3 fatty acid is 1 :X, where 0 ⁇ X ⁇ 0.3 or 0.5 ⁇ X ⁇ l .
  • composition(s) or “formulation(s)” includes therapeutic and dietary compositions including, but not limited to, a dietary supplement, nutraceutical formulation, or pharmaceutical formulation. Further, the terms composition, dietary supplement, nutraceutical formulation, and
  • DHA DHA
  • DPA refers inclusively to docosapentaenoic acid (DP A), wherein “omega-3 DPA” refers to the omega-3 isomer all-cis- 7,10,13,16,19-docosapentaenoic acid (clupanodonic acid) and “omega-6 DPA” refers to the omega-6 isomer all-cis-4,7,10, 13,16-docosapentaenoic acid (osbond acid).
  • ARA refers inclusively to (5Z,8Z, 11Z, 142)- Icosa-5,8,1 1 ,14-tetraenoic acid or derivatives thereof, including alkyl esters, such as, for example, the ethyl ester.
  • LA linoleic acid
  • GLA refers inclusively to
  • micelle refers to an aggregate of molecules, that have assembled into a substantially spherical core/shell architecture, and are suspended in an aqueous phase.
  • a typical micelle in aqueous solution forms an aggregate with the hydrophilic "head” regions in contact with surrounding solvent and/or in contact with the polar region of one or more surface active agent(s), sequestering the hydrophobic regions in the micelle center.
  • Micelles are approximately spherical in shape.
  • self-micellizes or “self-micellization” as used herein refers to the process in which micelles are formed in an aqueous medium without the introduction of energy, including agitation or shearing.
  • aqueous medium refers to any solution or suspension, that comprises in part or in whole water, including for example, without limitation, water by itself; phosphate buffered saline at about pH 7.4, soft-drinks, illustrated by, albeit not limited to Sprite®, apple juice, G-2 ® fruit punch, infant formula or any equivalent mammalian mother's milk substitutes or analogues, intravenous fluid, and milk and milk products, including chocolate milk.
  • an aqueous medium comprises at least one fluid having at least one fatty acid, carbohydrate, lipid, sugar, or combinations thereof.
  • an aqueous medium comprises at least one fluid having an acidic pH.
  • an aqueous medium comprises a biological fluid such as, for example and without limitation, stomach acid.
  • the aqueous medium comprises simulated stomach acid comprising 0.1N HC1.
  • free fatty acid refers to one or more
  • esters refers to the replacement of the hydrogen in the carboxylic acid group of a polyunsaturated fatty acid molecule with another substituent.
  • Typical esters are known to those in the art, a discussion of which is provided by Higuchi, T. et al., Pro-drugs as Novel Delivery Systems, Vol. 14, A.C.S. Symposium Series, Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, Amer. Pharma. Assoc., Pergamon Press (1987), and Protective Groups in Organic Chemistry, McOmie ed., Plenum Press, New York (1973), each of which is incorporated herein by reference in their entirety.
  • esters examples include methyl, ethyl, trichloroethyl, propyl, butyl, pentyl, tert-butyl, benzyl, nitrobenzyl, methoxybenzyl, benzhydryl, monoglyceride, diglyceride, triglyceride.
  • the term “monoglyceride” refers to a fatty acid chain, such as DHA or EPA molecule, covalently bonded to a glycerol molecule through an ester linkage.
  • diglyceride refers to a fatty acid chain such as DHA or EPA, covalently bonded to a glycerol molecule through an ester linkage, wherein the glycerol molecule is further bonded to one additional fatty acid chain, which may or may not be DHA or EPA, through one additional ester linkage.
  • triglyceride refers to a fatty acid chain, such as DHA or EPA, covalently bonded to a glycerol molecule through an ester linkage, wherein the glycerol molecule is further bonded to two additional fatty acid chains, either or both of which may or may not be DHA or EPA, through two additional ester linkages.
  • terpene refers to the large and diverse class of organic compounds produced by a variety of plants, particularly conifers. When terpenes are modified chemically, such as by oxidation or rearrangement of the carbon skeleton, the resulting compounds are generally referred to as “terpenoids” (e.g., carvone). Terpenes and terpenoids are the primary constituents of the essential oils of many types of plants and flowers.
  • tocopherol and “tocotrienol”, and “vitamin E” refer to a set of fat-soluble vitamins with antioxidant properties.
  • tocotrienol refers to the family of tocotrienols “alpha-tocotrienol”, “beta- tocotrienol”, “gamma-tocotrienol” and “delta-tocotrienol”.
  • tocopherol refers to the family of tocopherols “alpha-tocopherol”, “beta- tocopherol”, “gamma-tocopherol” and “delta-tocopherol”.
  • antioxidant refers to a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When the chain reaction occurs in a cell, it can cause damage or death to the cell. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions. They do this by being oxidized themselves, so antioxidants are often reducing agents such as thiols, ascorbic acid, or polyphenols.
  • antioxidants include rosemary oil, ascorbic acid (vitamin C), glutathione, lipoic acid, uric acid, carotenes, melatonin, ubiquinol (coenzyme Q), a-tocopherol (vitamin E), acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, and potassium metabisulfite.
  • a "pharmaceutically acceptable carrier” refers to any nontoxic amount of any substance suitable as a vehicle for delivering a molecule or composition to a suitable in vivo site of absorption.
  • examples of such carriers include, but are not limited to water, phosphate buffered saline (PBS), Ringer's solution, dextrose solution, serum- containing solutions, Hank's solution and other aqueous physiologically-balanced solutions.
  • a "pharmaceutically acceptable preservative” includes but is not limited to a non-toxic amount of potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quarternary compounds such as benzalkonium chloride.
  • a “coloring agent” provides coloration to the composition or dosage form.
  • coloring agents include, for example, food grade dyes.
  • the term "subject” refers to a mammal, including but not limited to a dog, cat, horse, cow, pig, sheep, goat, chicken, rodent, primate or human.
  • Subjects include animals such as house pets (e.g., dogs, cats, and the like), agricultural stock subjects (e.g., cows, horses, pigs, chickens, etc.), laboratory subjects (e.g., mice, rats, rabbits, etc.), but are not so limited.
  • the human subject may be a pediatric, such as for example neonate, adult, or a geriatric subject.
  • the human subject may be of either gender.
  • an "effective amount” or “therapeutically effective amount” of a composition as described in some embodiments herein can be a quantity sufficient to achieve a desired therapeutic and/or prophylactic effect, for example, an amount which results in the prevention of, or a decrease in the symptoms associated with, a disease that is being treated.
  • the amount of composition administered to the subject, particularly one in need of the composition can depend on the type and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. A person skilled in the art will be able to determine appropriate dosages depending on these and other factors.
  • an effective amount of the compositions described herein can be sufficient for achieving a therapeutic or prophylactic effect.
  • a "therapeutically effective amount" of a particular modality it is within the purview of the present invention to determine the presence of such a "therapeutically effective amount” by determining a quantity of a composition as described in some embodiments herein to modulate biomarkers related to a particular disease state.
  • biomarkers may form a basis for surrogate endpoints for clinical trials, provide a basis for elucidating a better understanding of disease pathogenesis, and for quantifying the effectiveness of a therapeutic modality to down-regulate an inflammatory response, thereby quantifying disease progression.
  • compositions of the present invention may include: SCD
  • D-Dimer to assess the coagulation rate, Total white blood cells and platelets, markers of inflammatory state, Lactate dehydrogenase (LDH), marker of intravascular hemolysis, Dense red blood cell fraction, marker of red blood cell sickling, Endothelin-1 (ET-1), soluble- VC AM- 1 (sVCAM-1), soluble P-selectin (sP- selectin), markers of endothelial activation, interleukins (IL2, IL3, IL6, IL8 and IL10), urinary cysteinyl leucotriene E4 (28), and serum levels of prostaglandin-E2, CA 15-3, soluble CD40 ligand, HSP-70, ferritin, angiopoietin 1 and 2, stromal derived factor 1, tumor necrosis factor-a and tumor necrosis factor receptor- 1.
  • LDH Lactate dehydrogenase
  • E Endothelin-1
  • sVCAM-1 soluble- VC AM- 1
  • CK18 M30 marker of NAFLD severity, IL-6, inflammatory state, Urine isoprostane, Oxidative stress, Livers spectroscopy, Fatty liver assessment
  • Calprotectin, Alkaline phosphatase - an elevated ALP is the most common biochemical abnormality in PSC, which often prompts clinicians to establish a diagnosis, reduction of ALP over time is associated with a favorable prognosis, Aspartate to alanine aminotransferase ratio: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are markers of hepatocellular injury or necrosis, and elevation of AST or ALT is present in case of liver damage,
  • Bilirubin Bilirubin is routinely used in clinical practice as a measure of extrahepatic obstruction
  • Immunoglobulin G4 Measure of inflammation,, inflammation results in fibrosis and deposition of connective tissue. PSC patients with elevated IgG4 have been shown to have a high prevalence of cirrhosis, and a shorter time to liver transplant, suggesting a more severe liver disease course.
  • dose unit refers to a portion of a composition that contains an effective amount of an active suitable for a single administration to provide, or contribute to, a therapeutic effect.
  • dosage units may be administered one to a plurality (i.e., 1 to about 10, 1 to about 8, 1 to about 6, 1 to about 4 or 1 to about 2) of times per day, or as many times as needed to elicit a therapeutic response.
  • the term "food effect,” as used herein, refers to a relative difference in AUC (area under the curve), C max (maximum plasma concentration), and/or T max (time to maximum concentration) of an active substance, when said substance or a composition thereof, such as a tablet, a capsule or a liquid, is administered orally to a subject concomitantly with food or in a fed state as compared to the same values when the same composition is administered in a fasted state.
  • the food effect, F is calculated as:
  • F (Yfed-Yfasted)/Yfasted wherein Y fed and Y fasted are the found values of AUC, C max , or T max in the fed and fasted state, respectively.
  • a food effect, F is generally established when F > 1.
  • the term "AUC" or "area under the plasma concentration-time curve” is related to the total amount of an active measurable in the systemic circulation following administration of a single dose.
  • the AUC is a mathematical and visual representation of the aggregate amount of the active in the systemic circulation over a given period of time. Changes in the AUC need not necessarily reflect changes in the total amount of the active absorbed but can reflect modifications in the kinetics of distribution, metabolism and excretion. Accordingly, the term AUC as used herein refers to the total amount of omega-3 fatty acids (in either the triglyceride, ester, or free fatty acid form) measurable in the systemic circulation following administration of a single dose of any of the compositions described herein.
  • T max or "time of peak concentration” refers to the period of time required to achieve peak plasma concentration of an active after administration of a single dose. Accordingly, the term T max as used herein refers to the period of time required to achieve peak plasma concentration of omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) after administration of a single dose of any of the compositions described herein.
  • C max or "peak concentration” is the highest concentration of an active achieved in the blood plasma. Accordingly, the term C max as used herein refers to the maximum concentration of omega-3 fatty acids (in either the
  • the bioavailability of the omega-3 fatty acids in either the triglyceride, ester, or free fatty acid form), as measured by the logarithm-transformed AUCo- ⁇ , is bioequivalent i.e., the 90% confidence interval should be within the acceptance range of 80% to 125% regardless of whether the compositions described herein are administered with or without food.
  • the pharmacological effects of administration of compositions described herein are substantially independent of a food effect.
  • reduced food effect refers to a substantial reduction in the effect of food upon the absorption, following oral administration, of any of the compositions described.
  • the compositions described herein have a reduced food effect.
  • a subject such as a human subject, in need of treatment refers to a subject in need of treatment of a defined disease state or in need of preventative treatment (i.e., prophylaxis) of such a disease state.
  • the term "functional food” as used herein means any edible or drinkable foods or dietary components (e.g., infant formula, juices, milk, yogurt, butter, margarine, baking products) that are fortified or enhanced with any of the compositions described herein.
  • the functional food can be, e.g., solid, liquid, semisolid, or a combination thereof.
  • the term “functional food” also encompasses edible and drinkable nutritional supplements.
  • HLB hydrophilic-lipophilic balance
  • HLB values can be calculated based on methods and equations known to those of ordinary skill in the art, such as those described in United States Patent 5,585,192. Substances or compositions generally have an average HLB of about 6 to about 20. Hydrophilic-lipophilic balance values can be determined in a variety of the formulas or experimental methods provided, for example, in United States Patent 5,585,192.
  • substantially pure means at least 80% pure.
  • a composition comprising at least one omega-3 fatty acid and at least one surface active agent.
  • the at least one omega-3 fatty acid is selected from the group consisting of hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid,
  • docosapentaenoic acid docosahexaenoic acid, tetracosapentaenoic acid, and tetracosahexaenoic acid.
  • Certain embodiments comprise more than one omega-3 fatty acid, which can be selected from the group consisting of hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid,
  • omega-3 fatty acid components comprising the composition are present at, for example, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% (wt/wt) of the composition.
  • the omega-3 fatty acids used herein are typically in the form of an oil.
  • a composition comprising at least one isomer of docosapentaenoic acid (DP A) and at least one surface active agent, wherein the omega-3 DPA isomer is all-cis- 7,10,13,16,19-docosapentaenoic acid (clupanodonic acid) or the omega-6 DPA isomer is all-cis-4,7,10,13,16-docosapentaenoic acid (osbond acid).
  • DP A docosapentaenoic acid
  • clupanodonic acid or the omega-6 DPA isomer is all-cis-4,7,10,13,16-docosapentaenoic acid (osbond acid).
  • the compositions described herein comprise DHA at, for example, from 50% to 99% (wt/wt) of the compositions.
  • the DHA is present at 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% (wt/wt) of the compositions.
  • the DHA is present at at least, for example, 90% (wt/wt) of the compositions described herein.
  • the DHA is present at, at least, for example, 95% (wt/wt) of the compositions described herein.
  • the compositions described herein comprise EPA at, for example, from 0% to 50% (wt/wt) of the compositions.
  • the EPA is present at ⁇ 1% (wt/wt) of said compositions.
  • the EPA can be present at, for example, 2%, 4%, 6%, 8%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 42%, 44%, 46%, 48% or 50% (wt/wt) of said compositions.
  • the EPA can be present at ⁇ 5% (wt/wt) of said compositions.
  • the EPA can be present at 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, or 4.5% (wt/wt) of said compositions.
  • the compositions described herein comprise an omega-3 fatty acid other than DHA and EPA at, for example, from >0% to 10% (wt/wt) of said compositions.
  • said omega-3 fatty acid other than DHA and EPA can be present, in certain embodiments at 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5% or 10% (wt/wt) of said compositions.
  • the omega-3 fatty acid other than EPA and DHA can be selected from the group consisting of hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, heneicosapentaenoic acid, docosapentaenoic acid,
  • the third fatty acid other than DHA and EPA may be an omega-6 fatty acid, for example arachidonic acid (ARA), linoleic acid (LA), gamma-linolenic acid (GLA) or the omega-6 isomer of DPA.
  • ARA arachidonic acid
  • LA linoleic acid
  • GLA gamma-linolenic acid
  • DPA omega-6 isomer of DPA
  • compositions described herein comprise 90%, 5%, and 5% (wt/wt) of said compositions DHA, ARA, and EPA respectively.
  • compositions described herein comprise 95%, 5%, and ⁇ 1% (wt/wt) of said compositions DHA, ARA, and EPA respectively.
  • the omega-3 fatty acid oils used in the manufacture of the compositions described herein are substantially pure.
  • the omega-3 fatty acid oils are at least, for example, 90% pure; and the remainder of the omega-3 fatty acids in the oil can comprise a mixture of other omega-3 fatty acids of which one omega-3 fatty acid may predominate the mixture.
  • the DHA oil can be at least 90% DHA; and the remainder can comprise a mixture of omega-3 fatty acids, of which EPA can be the predominant omega-3 fatty acid and can be present at 5% of said composition.
  • the ratio of the amount of the substantially pure omega-3 fatty acid, the first omega-3 fatty acid, to the predominant omega-3 fatty acid in the remaining fraction of the oil, the second omega-3 fatty acid is 1:X, where 0 ⁇ X ⁇ 0.3 or 0.5 ⁇ X ⁇ 1.
  • X can be, for example, 0.001, 0.0015, 0.002, 0.0025, 0.0055, 0.006, 0.0065, 0.007, 0.0075, 0.008, 0.0085, 0.009, 0.0095, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.1, 0.15, 0.2, 0.25, 0.3, 0.55, 0.6, 0.65, 0.7, 0.75, or 0.8.
  • the composition described herein comprises at least one surface active agent and a first and second omega-3 fatty acid, wherein the first omega-3 fatty acid is DHA and the second omega-3 fatty acid EPA, wherein the ratio of the amount of DHA:EPA is 1 :X, where 0 ⁇ X ⁇ 0.3 or 0.5 ⁇ X ⁇ 1.
  • X can be, for example, 0.001, 0.0015, 0.002, 0.0025, 0.0055, 0.006, 0.0065, 0.007, 0.0075, 0.008, 0.0085, 0.009, 0.0095, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.1, 0.15, 0.2, 0.25, 0.55, 0.6, 0.65, 0.7, 0.75, or 0.8.
  • compositions described herein comprise at least one surface active agent and a first and second omega-3 fatty acid, wherein the first omega-3 fatty acid is EPA and the second omega-3 fatty acid is DHA, wherein the ratio of the amount of EPA: DHA is 1:X, where 0 ⁇ X ⁇ 0.3 or 0.5 ⁇ X ⁇ 1.
  • X can be, for example, 0.001, 0.0015, 0.002, 0.0025, 0.0055, 0.006, 0.0065, 0.007, 0.0075, 0.008, 0.0085, 0.009, 0.0095, 0.01, 0.015, 0.02, 0.025, 0.03, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.1, 0.15, 0.2, 0.25, 0.55, 0.6, 0.65, 0.7, 0.75, or 0.8.
  • compositions described herein can optionally comprise a third omega fatty acid (either in the triglyceride, ester, or free fatty acid form), wherein the third omega fatty acid is different from the first and second omega fatty acids.
  • the ratio of the amount of the first omega fatty acid to the second and third omega fatty acids is 1 :X, where X is the combined amount of the second and third omega fatty acids and X is 0 ⁇ X ⁇ 1.
  • a composition comprises DHA oil
  • the DHA oil can be at least, for example, 90% DHA (the first omega fatty acid); and the remaining 10% can comprise a mixture of omega fatty acids, of which EPA can be the predominant omega fatty acid (second omega fatty acid) and can be present at 5% of said composition.
  • the third omega fatty acid is selected from the group consisting of hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, heneicosapentaenoic acid, docosapentaenoic acid, tetracosapentaenoic acid, and tetracosahexaenoic acid.
  • the third omega acid may be an omega-6 fatty acid.
  • the first omega fatty acid is DHA and the second omega fatty acid is EPA
  • the ratio of the amount of DHA:(EPA+ third omega fatty acid) is 1:X, where X is the amount of EPA and the amount of the third omega fatty acid, and where 0 ⁇ X ⁇ 1.
  • X can be, for example, 0.001, 0.0015, 0.002, 0.0025, 0.0055, 0.006, 0.0065, 0.007, 0.0075, 0.008, 0.0085, 0.009, 0.0095, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, or 0.95.
  • the third fatty acid can be arachidonic acid (ARA) (either in the triglyceride, ester, or free fatty acid form).
  • the ARA is in the ethyl ester form.
  • the omega-3 or omega-6 fatty acid compositions described herein are in either the triglyceride, ester, or free fatty acid form.
  • the omega-3 or omega-6 fatty acid is in the ester form, particularly in the ethyl ester form.
  • the compositions comprise at least one surface active agent and a first and second omega-3 fatty acid, wherein the first omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is omega-3 docosapentaenoic acid (omega-3 DP A) and the second omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is selected from the group consisting of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid, tetracosapentaenoic acid, and tetracosahexaen
  • DHA docosa
  • the compositions comprise at least one surface active agent, an omega-6 fatty acid, and an omega-3 fatty acid, wherein the omega-6 fatty acid (in either the triglyceride, ester, or free fatty acid form) is for example arachidonic acid (ARA), linoleic acid (LA), gamma-linolenic acid (GLA) or the omega-6 isomer of DPA, and the second omega-3 fatty acid (in either the triglyceride, ester, or free fatty acid form) is selected from the group consisting of omega-3 docosapentaenoic acid (omega-3 DP A), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), hexadecatrienoic acid, a-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, hene
  • omega-3 fatty acid in either the triglyceride, ester, or free fatty acid form
  • a-linolenic acid may be included for its antiinflammatory properties.
  • compositions described herein are free of free fatty acids.
  • compositions described herein are free of a second medicament.
  • the at least one surface active agent is selected from the group consisting of nonionic surface active agents, cationic surface active agents, anionic surface active agents, zwitterionic surface active agents, or
  • the compositions include one or more non-ionic surface active agents.
  • Non-ionic surface active agents generally have a hydrophobic group and a reactive hydrogen atom, for example aliphatic alcohols, acids, amides and alkyl phenols, with alkylene oxides, especially ethylene oxide either alone or in combination with propylene oxide.
  • nonionic surfactant compounds include, but are not limited to, polyoxyethylene glycol sorbitan alkyl esters, block copolymers of polyethylene glycol and polypropylene glycol, ethylene glycol fatty acid esters, poly(ethylene glycol) fatty acid esters, propylene glycol fatty acid esters, poly(propylene glycol) fatty acid esters, glycol fatty acid esters, trimethylolpropane fatty acid esters, pentaerythritol fatty acid esters, glucoside derivatives, glycerin alkyl ether fatty acid esters, trimethylolpropane oxyethylene alkyl ethers, fatty acid amides, alkylolamides, alkylamine oxides, lanolin and its derivatives, castor oil derivatives, hardened castor oil derivatives, sterols and its derivatives, polyoxyethylene alkyl ethers, polyoxyethylene alkyl allyl ethers, polyoxyethylene alkyl
  • polyoxyethylene fatty acid amides polyoxyethylene alkylolamides, polyoxyethylene diethanolamine fatty acid esters, polyoxyethylene trimethylolpropane fatty acid esters, polyoxyethylene alkyl ether fatty acid esters, polyoxyethylene
  • polyoxypropylene glycols polyoxyethylene polyoxypropylene alkyl ethers, polyoxyethylene polyoxypropylene polyhydric alcohol ethers, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, sucrose fatty acid esters, or combinations thereof.
  • the surface active agents comprise
  • polyoxyethylene glycol sorbitan alkyl esters block copolymers of polyethylene glycol and polypropylene glycol, or combinations thereof.
  • polyoxyethylene glycol sorbitan alkyl esters are typically the polysorbates.
  • Polysorbates are a class of oily liquids derived from PEG-ylated sorbitan (a derivative of sorbitol) esterified with fatty acids. Common brand names for polysorbates include Tween ® . Tween ® -20, Tween ® -40, Tween ® -60 and Tween ® - 80, for example, are available from AkzoNobel (Strawinskylaan 2555 1077 ZZ, Amsterdam, the Netherlands).
  • Exemplary polysorbates include polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate ), polysorbate 60 (polyoxyethylene (20) sorbitan
  • polysorbate 80 polyoxyethylene (20) sorbitan monooleate
  • Examples of block copolymers of polyethylene glycol and polypropylene glycol include the poloxamers.
  • Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)).
  • Certain poloxamers, such as those listed herein, are also known by the trade names Pluronic® available from suppliers such as BASF AG (Ludwigshafen, Germany). Because the lengths of the polymer blocks can be customized, many different poloxamers exist that have slightly different properties.
  • Pluronic® poloxamers include, but are not limited to Pluronic® 10R5, Pluronic® 17R2, Pluronic® 17R4, Pluronic® 25R2, Pluronic® 25R4, Pluronic® 31R1, Pluronic® F 108 Cast Solid Surfacta, Pluronic® F 108 NF, Pluronic® F 108 Pastille, Pluronic® F 108 Prill, Pluronic® F 108NF Prill Poloxamer 338, Pluronic® F 127, Pluronic® F 127 Prill, Pluronic® F 127 NF, Pluronic® F 127 NF 500 BHT Prill, Pluronic® F 127 NF Prill Poloxamer 407, Pluronic® F 38, Pluronic® F 38 Pastille, Pluronic® F 68, Pluronic® F 68 Pastille, Pluronic® F 68 LF Pastille, Pluronic® F 68 NF, Pluronic® F 68 NF Prill Poloxa
  • the at least one surface active agent comprises a polysorbate present from, for example, 15% (wt/wt) to 35% (wt/wt) of the composition.
  • the polysorbate is present at, for example, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% (wt/wt) of said composition.
  • the polysorbate is present at, for example, 31% (wt/wt) of the composition.
  • the polysorbate is polysorbate 20, polysorbate 60, polysorbate 80 or a combination thereof. Typically, but not necessarily, the polysorbate is polysorbate 80.
  • the at least one surface active agent comprises a poloxamer present from, for example, 0.1% (wt/wt) to 5% (wt/wt) of the composition.
  • the poloxamer is present at, for example, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% (wt/wt) of said composition.
  • the poloxamer is present at, for example, 0.7% (wt/wt) of the composition.
  • the poloxamer is Pluronic® F87
  • compositions described herein comprise a combination of polysorbate 80 and the poloxamer Pluronic® F87
  • the at least one surface active agent comprises a combination of nonionic surfactants.
  • the combination of nonionic surfactants can comprise a combination of a polysorbate and a poloxamer totaling at least, for example, 30% (wt/wt) of said composition.
  • the polysorbate is polysorbate 80 and the poloxamer is poloxamer 237 (Pluronic® F87).
  • the polysorbate 80 is present at, about 31% (wt/wt) and the poloxamer 237 is present at, about 0.7% (wt/wt) of said composition.
  • the compositions include one or more anionic surface active agents.
  • anionic surface active agents include, but are not limited to, N-acyl-L-glutamic acid diethanolamine, N-acyl-L-glutamic acid triethanolamine, sodium N-acyl-L-glutamate, sodium alkanesulfonate, ammonium alkyl (C12, C14, C16) sulfate, alkyl (Cl l, C13, C15) sulfuric acid triethanolamine, alkyl (Cl l, C13, CI 5) sulfuric acid triethanolamine, alkyl (CI 2 to CI 4) sulfuric acid triethanolamine, liquid alkylsulfuric acid triethanolamine, sodium alkyl (CI 2, CI 3) sulfate, liquid sodium alkylsulfate, sodium isoethionate, sodium lacto-isostearate, disodium undecylenoylamido ethyl sulf
  • polyoxyethylene monooleylamido sulfosuccinate (2 E.O.), disodium polyoxyethylene lauroyl ethanolamide sulfosuccinate (5 E.O.), disodium lauryl sulfosuccinate, diethanolamide cetyl sulfate, sodium cetyl sulfate, soap base, sodium cetostearyl sulfate, triethanolamine tridecyl sulfate, potassium palmitate, sodium palmitate, palmitoyl methyltaurine sodium salt, liquid castor oil fatty acid sodium salt (30%), ammonium polyoxyethylene alkyl ether sulfate (3 E.O.), liquid diethanolamine polyoxyethylene alkyl (CI 2, CI 3) ether sulfate, liquid triethanolamine
  • polyoxyethylene lauryl sulfosuccinate sodium polyoxyethylene nonyl phenyl ether sulfate, sodium polyoxyethylene pentadecyl ether sulfate, triethanolamine
  • polyoxyethylene myristyl ether sulfate sodium polyoxyethylene myristyl ether sulfate, sodium polyoxyethylene myristyl ether sulfate (3 E.O.), liquid sodium polyoxyethylene lauryl ether acetate (16 E.O.), ammonium polyoxyethylene lauryl ether sulfate (2 E.O.), triethanolamine polyoxyethylene lauryl ether sulfate, sodium polyoxyethylene lauryl ether sulfate, diethanolamine myristyl sulfate, sodium myristyl sulfate, potassium myristyl sulfate, sodium N- myristoyl- L-glutamate, sodium myristoylmethylaminoacetate, liquid myristoyl methyl- -alanine sodium salt, myristoyl methyltaurine sodium salt, medicinal soaps, triethanolamine/magnesium coco alkyl sulfate, triethanolamine N-coconut oil fatty-acyl
  • said anionic surfactant(s) comprise from, for example, about 0.05% (wt/wt) to about 25% (wt/wt) of said composition. In certain embodiments, said anionic surfactant(s) comprise from, for example, about 0.05% (wt/wt) to about 15% (wt/wt) of said composition. In certain embodiments, said anionic surfactant(s) comprise, for example, 0.05% (wt/wt) to 5% (wt/wt) of said composition. In certain embodiments, said anionic surfactant(s) comprise, for example, 0.5% (wt/wt) to 3% (wt/wt) of said composition. In certain embodiments, said anionic surfactant(s) comprise, for example, 0.7% (wt/wt) of said composition. In certain embodiments, said anionic surfactant(s) comprise sodium lauryl sulfate.
  • the compositions include additional surface active agents such as the zwitterionic and cationic surface active agents.
  • additional surface active agents include, but are not limited to the bile acids (e.g., cholic acid, chenodeoxycholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, taurolithocholic acid, deoxycholic acid, lithocholic acid, and ursodeoxycholic acid and salts thereof, e.g., sodium, potassium, lithium), natural emulsifiers (e.g., cholic acid, chenodeoxycholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, taurolithocholic acid, deoxycholic acid, lithocholic acid, and ursodeoxycholic acid and salts thereof, e.g., sodium, potassium, lithium), natural emulsifiers (e.g.
  • acacia agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.
  • carboxymethylcellulose sodium powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose), polyoxyethylene esters (e.g. polyoxy ethylene monostearate [Myrj 45],
  • polyoxyethylene hydrogenated castor oil polyethoxylated castor oil
  • polyoxymethylene stearate and Solutol
  • sucrose fatty acid esters polyethylene glycol fatty acid esters (e.g. Cremophor)
  • polyoxyethylene ethers e.g.
  • polyoxyethylene lauryl ether [Brij 30]), poly( vinyl -pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium or combinations thereof.
  • compositions described herein will increase fatty acid absorption in patients with fat malabsorption syndromes and other disease states as described herein. This is because the compositions described herein comprising the omega-3 fatty acid(s) and the at least one surface active agent self-micellize in a manner similar to that in the body.
  • micelles When mammals eat, micelles are naturally formed around the fats ingested. These natural micelles form in the presence of bile regardless of the pH in the stomach or intestines. Natural micelles form around fats and digestive enzymes, entrapping both. Within the micelles, the enzymes quickly cleave the triglycerides or fatty acid esters into free fatty acids and monoglycerides.
  • Natural micelles fuse with the cell membrane when they come in contact with the brush barrier of the intestinal wall, delivering their cargo of free fatty acids and monoglycerides, among other components and compounds, into the cells lining the intestine and are absorbed. Natural micelles that form around omega-3 fatty acids have two characteristics that limit their effectiveness. Firstly, given the formation of natural micelles require the food-dependent release of bile salts, natural micelles form only when food is present.
  • Emulsion is a very broad term describing particles that may be amorphous, liquid-crystalline, bilayer, monolayer or any mixture of these structures.
  • An emulsion is a more general term that describes a dispersed phase in a continuous phase that is commonly seen as oil in water (o/w), water in oil (w/o) or even more complex mixtures such as water in oil in water (w/o/w).
  • Emulsion particle sizes can vary widely from 10 nanometers to 100 micrometers.
  • SEDDS self-emulsifying drug delivery systems
  • GI tract gastrointestinal tract
  • emulsions have the sole purpose of dispersing lipids, such as oils, into small droplets in order to increase the surface area available to interact with the body's natural bile salts, pancreatic lipases, co-lipase, and phospholipase A2.
  • SEDDS are formulated with mixtures of lipid vehicles, non-ionic surfactants and a drug in the absence of water, and are assumed to exist as
  • transparent isotropic solutions These systems have a unique property - they are able to self-emulsify rapidly in the gastrointestinal fluids, forming fine oil-in-water emulsions (droplet size diameter ⁇ 300 nm) under gentle agitation provided by gastrointestinal motion.
  • SEDDS are commonly suitable for oral delivery in soft and hard gelatin or hard hydroxypropyl methylcellulose (HPMC) capsules.
  • SMEDDS are defined as isotropic mixtures of an oil, surfactant, co- surfactant (or solubilizer) and a drug. Such systems form fine oil-in-water
  • SMEDDS are distinguished from SEDDS by smaller emulsion droplets produced on dilution, resulting in a transparent or translucent stable dispersion.
  • Mean droplet size after dilution is ⁇ 100 nm in the case of SMEDDS or ⁇ 300 nm in the case of SEDDS.
  • SMEDDS generally contain relatively high concentrations of surfactant (typically 30 to 60 %, m/m), and optionally also hydrophilic co-solvents (e.g., propylene glycol, polyethylene glycols). They are often described as microemulsion pre-concentrates because the microemulsion is formed on dilution in aqueous media.
  • SNEDDS are defined as self-nanoemulsifying drug delivery systems that spontaneously form transparent to opalescent oil-in-water dispersions of
  • SEDDS, SMEDDS, and SNEDDS leverage the body's natural process to be efficient, they also necessarily rely on the natural processes to be effective. This is particularly important because in order to form micelles, SEDDS, SMEDDS, and SNEDDS require the presence of bile salts. Since bile salts are emitted into the GI tract in mammals as a response to food consumption, then it follows that SEDDS SMEDDS, and SNEDDS are not able to use bile salts to form micelles in the GI tract unless food intake has induced the introduction of bile salts into the GI tract.
  • the present invention is directed toward a Self- Micellizing Drug Delivery System (SMDDS).
  • SEDDS Self- Micellizing Drug Delivery System
  • SEDDS Self- Micellizing Drug Delivery System
  • SMEDDS surface active agent
  • SNEDDS SNEDDS
  • surface active agent polysorbate and poloxamer 237
  • the present invention is able to deliver lipids through the intestinal wall by way of a plurality of spontaneously formed stable micelles.
  • the present invention encapsulates the lipids with surface active agents, thus bringing the lipids together, whereby predictable and repeatable enhancements in bioavailability are realized, absent any food effect. .
  • a micelle is a particle of colloidal dimensions that exists in equilibrium with molecules or ions in a solution from which it is formed.
  • Micelles are a particular type of particle (oil particle in water) which form a structure wherein the hydrophilic component is external and the hydrophobic component is internal. More specifically, micelles are usually formed from single chain lipids and surfactants, and a micelle is always a monolayer particle with the hydrophilic head facing the aqueous phase and the hydrophobic tail facing the oil phase.
  • BMR Basal Metabolic Rate
  • compositions or a plurality of micelles pre-formed therefrom described herein will lower a human's weight, if the human is overweight, to within the normal range as determined by the human's BMR.
  • compositions or a plurality of micelles pre-formed therefrom described herein will increase a human's weight, if the human is underweight, malnourished, or is suffering from a malabsorption syndrome, to within the normal range as determined by the human's BMR.
  • Omega-3 fatty acids are known to decrease circulating leptin levels. Accordingly, without being bound to any particular theory, it is believed that the enhanced absorption of omega-3 fatty acids provided by the compositions or a plurality of micelles pre-formed therefrom described herein will regulate leptin levels and signal a subject's brain accordingly to either decrease leptin levels if the subject is overweight or increase leptin levels if the subject is underweight, malnourished, or is suffering from a malabsorption syndrome. This increase or decrease in
  • a method for administering self-micellizing compositions described herein to facilitate a subject's weight gain, loss, or return to normal weight, or combinations thereof over time.
  • composition which can be used to increase the weight of a mammal, such as livestock.
  • Also disclosed herein in at least one embodiment of the invention is a method for administering a composition as provided herein to increase the weight of a mammal, such as livestock.
  • the compositions described herein comprising the omega-3 fatty acid(s) and the at least one surface active agent, for example the combination of polysorbate 80 and poloxamer 237, spontaneously form micelles when encountering aqueous liquids.
  • These micelles form regardless of the pH or the nature and concentration of other suspended materials in the liquid, do not require bile to form, and form micelles that remain stable almost indefinitely.
  • the micelles form whether or not food is present or whether food that is present is high or low in fat.
  • the micelles formed by the compositions described herein form around omega-3 fatty acids and entrap both fats and enzymes, allowing rapid digestion and the formation of free fatty acids and monoglycerides.
  • the micelles formed by the compositions described herein are similar in size to human micelles and share the ability to rupture at the intestinal brush barrier. Without being held to any one theory, it is believed that either by friction or a chemical reaction, the micelle ruptures and spills its contents onto the lining of the intestines and the intestines absorb the omega-3 fatty acids.
  • compositions described herein can overcome one of the primary challenges of malabsorption syndromes, such as SBS i.e., the delivery of adequate amount of free fatty acids to the bloodstream of patients suffering from the hepatic complications of SBS without exacerbating liver dysfunction, as does TPN treatment, or triggering fat malabsorption or dumping. This would also allow for more consistent dosing and thus produce more reliable results.
  • SBS malabsorption syndromes
  • the compositions described herein self-micellize in an aqueous medium.
  • the aqueous medium can include, for example, 0.1N HC1. It is well accepted that 0.1N HC1 (simulated gastric fluid) serves as a proxy for the acidity of stomach contents. Accordingly, and without being bound by theory, it is believed that the compositions described herein can self-micellize in situ in the stomach or small intestine. In certain embodiments, the compositions described herein more efficiently and effectively deliver omega-3 fatty acid esters through the intestinal tract when administered with or without food.
  • compositions comprising micelles are provided, wherein the micelles are formed by the addition of an aqueous medium to a composition of any one of the embodiments provided herein prior to administration of said composition to a subject in need of treatment.
  • micelles can also be formed when the compositions are added to an aqueous medium.
  • the micelles have a diameter of up to 10 ⁇ .
  • substantially all of the micelles have an average diameter of from 1 ⁇ to 10 ⁇ .
  • the micelles have an average diameter of, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 ⁇ .
  • said micelles are stable at ambient temperature and in certain other embodiments, said micelles are stable at about normal mammalian body
  • the surface active agents comprising the compositions suitable for self- micellization as described herein generally have an HLB from, for example, 12 to 18. In certain embodiments, said surface active agents have an HLB from, for example, 12.0 to 14.0. In certain embodiments, said surface active agents have an HLB from, for example, 13.0 to 14.0. In certain embodiments, said surface active agents have an HLB from, for example, 13.5 to 13.8.
  • the total HLB of all the surface active agents or surfactants used in the composition is generally from, for example, 12 to 18. In some embodiments, the total HLB of all surface active agents used in the composition is generally from, for example, 12 to 15. In some embodiments, the total HLB of all surface active agents or surfactants used in the composition is generally from , for example, 13 to 15.
  • the at least one surface active agent or surfactant has an HLB of at least, for example, 8.0.
  • said surface active agent(s) or surfactant(s) have a combined HLB in the range of from, for example, 13 to 15. As the HLB value of the surface active agent(s) or surfactant(s) increases, the amount of surface active agent or surfactant needs to be decreased.
  • compositions described herein can further comprise at least one antioxidant.
  • the antioxidant(s) suitable for use in the instant omega-3 fatty acid compositions include, but are not limited to tocopherols and/or tocotrienols and can be present from, for example, 0.01% to 5% (wt/wt) of the composition.
  • the tocopherols and/or tocotrienols can be present at, for example, 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% by weight of the compositions.
  • the antioxidant is a-tocopherol present at, for example, 2% by weight of the composition.
  • the composition further comprises a terpene.
  • the terpene is d-limonene.
  • the terpene is a cyclic terpene.
  • the terpene is d-limonene ((+)-limonene), which is the (R)-enantiomer.
  • the terpene is L-limonene, which is the (S)-enantiomer.
  • the terpene is racemic limonene, known as dipentene.
  • the terpene is a terpenoid. In another embodiment
  • the terpene or terpenes are derived from a natural oil (e.g., a citrus oil such as orange oil).
  • a natural oil e.g., a citrus oil such as orange oil.
  • Other terpenes are contemplated, such as monoterpenes (e.g., terpinenes, terpinolenes, phellandrenes, or menthol), having structures that are similar to d-limonene.
  • the compositions further comprise substantially pure d-limonene from, for example, 0.1% to 5% by weight of the composition.
  • the compositions further comprise natural orange oil from, for example, 0.1% to 5% by weight of the composition.
  • compositions comprising d-limonene or orange oil can aid in the elimination and/or minimization of side effects from the oral administration of the instant omega-3 fatty acid compositions.
  • side effects include regurgitation, frequency of belching, gastroesophageal reflux disease (GERD), bloating, increased intestinal gas, fish taste, fishy breath, fish smell, nausea, diarrhea, or combinations thereof.
  • GFD gastroesophageal reflux disease
  • Methods are provided of treating AMD in a subject in need of treatment, which method comprises administering to said subject a therapeutically effective amount of a composition of any one of the embodiments provided herein, or a preformed micelles according to the respective embodiments described herein.
  • the compositions described herein can be administered in conjunction with other medications and/or nutritional supplements prescribed for treating AMD.
  • non-limiting examples of non-omega-3 fatty acid nutritional supplements include, for example, a combination of vitamin C, vitamin E, beta- carotene, zinc, copper, magnesium, manganese, calcium, vitamin A, vitamin D, vitamin K2, lutein and zeaxanthin.
  • Non-limiting examples of non-omega-3 fatty acid active agents include, for example, verteporfin (VISUDYNE); the antioxidant carotenoids crocks and crocetin, as found in, for example, Saffron ⁇ Crocus sativus); and inhibitors of angiogenesis, such as for example, BEVACIZUMAB
  • compositions described herein can also be administered for treating Juvenile Macular Degeneration, which includes Stargardt's disease, Best disease, and juvenile retinoschisis by administering the compositions described herein to a human juvenile.
  • Juvenile Macular Degeneration which includes Stargardt's disease, Best disease, and juvenile retinoschisis
  • the amount of the non-omega-3 fatty acid active agents administered in conjunction with the compositions described herein can be reduced to avoid or minimize any side effects resulting from the non-omega-3 fatty acid active agents when such agents are administered alone at higher concentrations.
  • a method for treating AMD by administering, to a patient in need thereof, a therapeutically effective amount of a composition comprising omega-3 DPA fatty acid (either in the triglyceride, ester or free fatty acid ester form) and at least one surface active agent in an amount and a combination effective to cause said compositions to spontaneously self-micellize when in contact with an aqueous medium, thereby forming a plurality of stable micelles having a particle size within a range of about 1 ⁇ to about 10 ⁇ .
  • omega-3 DPA fatty acid either in the triglyceride, ester or free fatty acid ester form
  • Methods are provided for treating one or more fat malabsorption syndrome or disorder in a subject in need of treatment, which method comprises administering to said subject a therapeutically effective amount of a composition of any one of the embodiments provided herein, or a pre-formed micelle mixture of any one of the embodiments provided herein.
  • the fat malabsorption syndrome can be the result of a disorder in the intestinal processes of digestion and/or transport of nutrients across the intestinal mucosa into the systemic circulation.
  • the fat malabsorption syndrome can be either a congenital abnormality in the digestive or absorptive processes or a secondarily acquired disorder resulting from a disorder of the intestinal processes of digestion and/or transport of nutrients across the intestinal mucosa into the systemic circulation.
  • Exocrine pancreatic insufficiency can also result in a fat malabsorption syndrome or disorder.
  • Exocrine pancreatic insufficiency can be the result of pancreatitis, pancreatic cancer, pancreatic resection, cystic fibrosis, Shwachman- Diamond syndrome, Johnson-Blizzard syndrome, and Pearson syndrome.
  • compositions described herein can be used for the treatment of fat malabsorption syndrome resulting from exocrine pancreatic insufficiency.
  • compositions described herein can be administered to a human in need of such administration for the treatment of fat malabsorption resulting from obstructive biliary or cholestatic liver disease or extensive intestinal mucosal disease.
  • Fat malabsorption syndromes can be the result of functional or anatomic loss of extensive segments of small intestine leading to a severe decrease in intestinal absorptive capacity, often referred to as Short-Bowel Syndrome (SBS), which may be congenital or acquired as a result of surgery due to Crohn's Disease or necrotizing enterocolitis in infants or neonates.
  • SBS Short-Bowel Syndrome
  • the administration of the compositions described herein to a human, particularly a neonate, in need of such administration can treat fat malabsorption syndromes resulting from SBS or Crohn's Disease.
  • docosahexaenoic acid through enteral administration, a combination of fatty acids and surface active agents, specifically poloxamers and polysorbates, can be combined to form self-micellizing micelles.
  • Attempts to create artificial micelles have generally resulted in artificial micelles that are fragile and break easily, making it difficult for the particles to deliver adequate amounts of free fatty acids and monoglycerides to the intestinal lining for absorption.
  • creating micelles mimicking necessary characteristics of natural human micelles is important, especially having a size of about five microns in diameter to carry its cargo of dietary fats (or other lipophilic materials) to and through the intestinal cell wall is a novel means of creating bioavailable dietary fats for the treatment of malabsorption.
  • a novel formulation was utilized containing docosahexaenoic acid in combination with a blend of surface active agents including polysorbates and poloxamers, and a study was carried out in a porcine model of SBS.
  • the methodology and results of this experiment are set forth in Example 3.
  • compositions described herein can be administered in conjunction with a non-omega-3 fatty acid active agent for the treatment of SBS.
  • non-limiting examples of such non-omega-3 fatty acid active agents can include L-GLUTAMINE (NUTRESTORE®), RECOMBINANT SOMATOTROPIN (ZORBTIVE ® ), AND TEDUGLUTIDE (GATTEX®).
  • Other such non-omega-3 fatty acid active agents may include conjugated bile acids or opium tincture.
  • the amount of the non-omega-3 fatty acid active agent(s) administered in conjunction with the compositions described herein can be reduced to avoid or minimize any side effects resulting from the non-omega-3 fatty acid active agents when such agents are administered alone at higher
  • Methods are provided of treating NAFLD and/or NASH in a subject in need of treatment, which method comprises administering to said subject a therapeutically effective amount of a composition of any one of the embodiments provided herein, or pre-formed micelles according to the respective embodiments described herein.
  • compositions described herein can be administered concomitantly with other non-omega-3 fatty acid medications prescribed for treating NAFLD and/or NASH.
  • non-omega-3 fatty medications can include, lipid lowering or cholesterol lowering agents selected from the group consisting of cholesterol absorption inhibitors, bile acid sequestrants/resins, statins, niacin and derivatives, MTP inhibitors, fibrates and CETP inhibitors, insulin sensitizers, hypolipidemics , anti-inflammatory medications, and thiazolidinediones.
  • the amount of the non-omega-3 fatty acid active agent(s) administered in conjunction with the compositions described herein can be reduced to avoid or minimize any side effects resulting from the non-omega-3 fatty acid active agents when such agents are administered alone at higher concentrations.
  • compositions, or a plurality of micelles preformed therefrom, described herein provide for a method of treating a Non- Alcoholic Fatty acid Liver Disease (NAFLD) comprising the step of administering to a subject in need of such administration the compositions or a plurality of micelles pre-formed therefrom described herein.
  • NAFLD Non- Alcoholic Fatty acid Liver Disease
  • compositions, or a plurality of micelles preformed therefrom, described herein provide for a method of treating Non- Alcoholic Steatohepatitis (NASH) comprising the step of administering to a subject in need of such administration the compositions or a plurality of micelles pre-formed therefrom described herein.
  • NASH Non- Alcoholic Steatohepatitis
  • compositions, or a plurality of micelles preformed therefrom, described herein provide for a reduction in body weight (or weight loss) in a subject diagnosed with NAFLD and/or NASH.
  • compositions, or a plurality of micelles preformed therefrom, described herein provide for a method of reducing liver weight in a subject diagnosed with NASH.
  • compositions, or a plurality of micelles preformed therefrom, described herein provide for a method of reducing whole blood glucose in a subject diagnosed with NASH.
  • compositions, or a plurality of micelles preformed therefrom, described herein provide for a method of reducing liver triglyceride levels in a subject diagnosed with NAFLD and/or NASH.
  • compositions, or a plurality of micelles preformed therefrom, described herein provide for a method of reducing development of liver fibrosis in a subject diagnosed with NAFLD and/or NASH.
  • a nine- week preclinical study of certain embodiments of the present invention was conducted using a mouse model which progresses from NAFLD to NASH between 5 to 9 weeks of age. Within the disease progression of this animal model, the liver triglycerides reach a point around week 6 where the inflammation has progressed substantially over week 5.
  • the study contained three groups, a control group given a placebo from age five to nine weeks, and two trial groups, a first trial group administered a composition disclosed herein for 4 weeks, from five to nine weeks of age, and a second trial group administered the same said composition disclosed herein for 3 weeks, from six to nine weeks of age.
  • compositions disclosed herein can deliver polyunsaturated EPA and DHA fatty acids to mammals with NAFLD for incorporation into the cell membrane of erythrocytes, wherein said delivery can reduce the triglyceride level in the liver and thereby slow the disease's progression to NASH.
  • administration of compositions disclosed herein might provide a larger medicinal response when provided later in the disease progression from NAFLD to NASH.
  • Methods are provided of treating neurodegenerative disease in a subject in need of treatment, which method comprises administering to said subject a therapeutically effective amount of a composition of any one of the embodiments provided herein, or pre-formed micelles according to the respective embodiments described herein.
  • neurodegenerative diseases include PD, AD, MS, Epilepsy, and ALS.
  • compositions described herein can be administered concomitantly with other non-omega-3 fatty acid medications prescribed for treating
  • Non-limiting examples of medications can include medications generally approved by a health regulatory body and prescribed by physicians for a particular neurodegenerative disease.
  • the amount of the non-omega-3 fatty acid active agent(s) administered in conjunction with the compositions described herein can be reduced to avoid or minimize any side effects resulting from the non-omega-3 fatty acid active agents when such agents are administered alone at higher concentrations.
  • Methods are provided of treating PSC and or NSC in a subject in need of treatment, which method comprises administering to said subject, typically a human adult, infant, child or adolescent, a therapeutically effective amount of a composition of any one of the embodiments provided herein, or pre-formed micelles according to the respective embodiments described herein.
  • PSC which is a chronic cholestatic liver disease
  • the compositions described herein can be administered to a human in need of such administration for the treatment of fat malabsorption resulting from PSC.
  • compositions described herein can be administered in conjunction with non-omega-3 fatty acid active agents.
  • active agents can, upon approval by a respective regulatory agency, include 6- alpha-ethylchenodeoxycholic and/or (4R,5R)-l-[[4-[[4-[3,3-Dibutyl-7- (dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-l ,l-dioxido-l-benzothiepin-5- yl]phenoxy]methyl]phenyl]methyl]-4-aza-l-azoniabicyclo[2.2.2]octane chloride.
  • the amount of the non-omega-3 fatty acid active agents administered in conjunction with the compositions described herein can be reduced to avoid or minimize any side effects resulting from the non-omega-3 fatty acid active agents when such agents are administered alone at higher concentrations.
  • Methods are provided of treating sickle cell disease in a subject in need of treatment, which method comprises administering to said subject a therapeutically effective amount of a composition of any one of the embodiments provided herein, or pre-formed micelles according to the respective embodiments described herein.
  • compositions described herein can be administered concomitantly with other non-omega-3 fatty acid active agents and non-omega-3 nutritional supplements prescribed for treating sickle cell disease.
  • non-omega-3 active agents can include pain medications, antibiotics, hydroxyurea, anti-inflammatory medications, and aspirin, particularly a low-dose (70 - 81 mg) aspirin dosage form; while non-omega-3 nutritional supplements may include one or more of folic acid, magnesium, manganese, zinc, calcium, vitamin A, vitamin E, vitamin D, and vitamin K2.
  • the amount of the non-omega-3 fatty acid active agent(s) administered in conjunction with the compositions described herein can be reduced to avoid or minimize any side effects resulting from the non-omega-3 fatty acid active agents when such agents are administered alone at higher concentrations.
  • compositions comprising omega-3 DPA fatty acid (either in the triglyceride, ester or free fatty acid ester form) and at least one surface active agent in an amount and a combination effective to cause said compositions to self-micellize when in contact with an aqueous medium can be used to treat sickle cell disease symptoms, such as vaso-occlusive events, sequestration crisis, avascular necrosis, stroke, and sickle cell anemia, among other known maladies, by decreasing the aggregation of platelets, red blood cells, and/or white blood cells.
  • sickle cell disease symptoms such as vaso-occlusive events, sequestration crisis, avascular necrosis, stroke, and sickle cell anemia, among other known maladies, by decreasing the aggregation of platelets, red blood cells, and/or white blood cells.
  • n-3 fatty acids do not occur in large amounts in plants food and western human diet. Moreover, the alpha-linolenic acid (ALA) conversion process to EPA and DHA in humans is not efficient as only 5-10% are converted to EPA, and a mere 2-5% to DHA. N-3 fatty acids are abundantly present in fish and shellfish. In fact, fish-oil supplements typically contain 30-50% of n-3 FAs.
  • AI current adequate intake
  • AI for ALA issued by the Institute of Medicine of the National Academys, USA is 1.6g/day for men 19 ⁇ 47 years and 1.1 g/day for women 19 ⁇ 47 years.
  • the acceptable macronutrient distribution range (AMDR) for ALA is 0.6-1.2% of energy.
  • the lower boundary of the range meets the AI for ALA.
  • Approximately 10% of the AMDR for ALA can be consumed as EPA and/or DHA.
  • the dietary guidelines (2005) also note that consumption of approximately two servings of fish per week (approximately 224 g total) may reduce the risk of mortality from coronary heart disease.
  • the physiological potency of EPA and DFIA is greater than ALA and there has been a substantive increase in the evidence base about the health benefits of long chain omega-3 fatty acids.
  • n-3 and n-6 LCPUFA are vital structural and functional components of cell and sub-cellular components. Studies have shown that the balance between these two fatty acid families influences blood cell adhesion, aggregation, blood coagulation, cell deformability and inflammatory response.
  • the retroconversion of DHA to satisfy the omega-3 deficiencies at this cellular level results in a normalization of the cell membrane and alleviation of symptoms of the disease state.
  • the displacement of ARA during this process decreases systemic inflammation.
  • Sickle cell disease is associated with hyper-metabolism and a consequent shortage of substrates for normal growth and healthy immune response. Insufficient nutrition in general is associated with poor immune function and is consequently regarded as the most common cause of immunodeficiency worldwide.
  • Vitamin A 5,000 International Units (IU)
  • Vitamin C 60 mg
  • Vitamin E 30 IU
  • kits comprising the compositions described herein are contemplated.
  • the kits comprise the compositions described herein as unit dosage forms in a container made of an inert material, such as for example, a glass vial, which can be clear or colored.
  • the glass vial can be a crimp or snap top glass vial.
  • Included in the kits are instructions for using the dosage form to treat a subject having a disease or disorder responsive to treatment by administration of the dosage forms comprising the compositions described herein.
  • the packaged pharmaceutical kits provide prescribing information, over the counter medical use information, and/or nutritional information for the dosage form including, for example and without limitation, to a subject or health care provider, or as a label in a packaged pharmaceutical kit.
  • Information included in the kit may include, for example and without limitation, efficacy, dosage and
  • the dosage and administration information can include dosing frequency recommendations as well as administration of the compositions with or without food.
  • the dosage forms comprising the compositions provided herein are in the form of a liquid filled or gel filled capsules for oral administration, which are provided either as blister packages or in bottles together with over the counter or prescription medical use information and/or nutritional information.
  • the packaged pharmaceutical kits can comprise one or more of the omega-3 fatty acids comprising the compositions described herein as the only active ingredient.
  • one or more of the compositions described herein can be packaged in combination with one or more active agents other than a non- Omega 3 fatty acid, such as for example and without limitation, one or more other lipid lowering or cholesterol lowering agents selected from the group consisting of cholesterol absorption inhibitors, bile acid sequestrants/resins, statins, niacin and derivatives, MTP inhibitors, fibrates and CETP inhibitors, 6-alpha- ethylchenodeoxycholic and/ or (4R, 5 R)- 1 - [ [4- [[4- [3 , 3 -Dibutyl-7-(dimethylamino)- 2,3,4,5-tetrahydro-4-hydroxy- 1 , 1 -dioxido- 1 -benzothiepin-5- yl]phenoxy]methyl]phenyl]methyl]
  • thiazolidinediones pain medications, antibiotics, folic acid, hydroxyurea, and antiinflammatory medications.
  • such active agents can include medications generally approved by a health regulatory body and prescribed by physicians for a particular neurodegenerative disease.
  • compositions described herein can be packaged in combination with one or more nutritional supplements.
  • nutritional supplements include various minerals, such as calcium, magnesium, iron, and vitamins, particularly fat-soluble vitamins, as well protein supplements well known in the art.
  • omega fatty acid containing compositions provided herein can be provided as a pharmaceutical composition to be administered orally or
  • nutraceutical formulation or a dietary supplement.
  • compositions comprise at least one surface active agent, at least one fat-soluble vitamin, such as vitamin A, vitamin D, vitamin K, vitamin K2, among others, and an omega-3 fatty acid (in triglyceride, ester, or free fatty acid form).
  • at least one surface active agent is combined with at least one fat-soluble vitamin and an omega-3 fatty acid (in triglyceride, ester, or free fatty acid form) in relative concentrations sufficient to form micelles when added to an aqueous medium.
  • At least one surface active agent is combined with at least one fat-soluble vitamin, an omega-3 fatty acid (in triglyceride, ester, or free fatty acid form), and one or more minerals, such as magnesium, manganese, zinc, copper, selenium, and combinations thereof.
  • At least one surface active agent is combined with at least one fat-soluble vitamin, an omega-3 fatty acid (in triglyceride, ester, or free fatty acid form), and one or more minerals, such as magnesium, manganese, zinc, copper, selenium, and combinations thereof, such that when added to an aqueous medium, the composition forms micelles and wherein said micelles range in size from lum to lOum in diameter.
  • an omega-3 fatty acid in triglyceride, ester, or free fatty acid form
  • minerals such as magnesium, manganese, zinc, copper, selenium, and combinations thereof
  • compositions described herein may further include one or more pharmaceutically acceptable excipients.
  • Pharmaceutically acceptable excipients include, but are not limited to, carriers, preservatives, and/or coloring agents. General considerations in the composition and/or manufacture of
  • compositions may be found, for example, in Remington The Science and Practice of Pharmacy 21 st ed., Lippincott Williams & Wilkins, 2005.
  • the compositions described herein can be formulated as a liquid for oral administration.
  • Liquid compositions include solutions, suspensions and emulsions.
  • liquid pharmaceutical preparations include propylene glycol solutions and solutions containing sweeteners for oral solutions, suspensions and emulsions.
  • an aqueous medium such as for example an aqueous medium having an acidic environment, the composition forms micelles.
  • the dosage form comprises micelles which may be pre-formed prior to administration to a subject in need of such administration, and wherein said micelles range in size from lum to lOum in diameter.
  • Such pre-formed micelles are stable at room temperature.
  • compositions described herein can be formulated as a fill material for capsules, including for example, a soft gelatin capsule.
  • a soft gelatin capsule when the contents of the soft gelatin capsule comes into contact with an aqueous medium, the composition forms micelles upon disintegration of the capsule.
  • a capsule may be prepared, e.g., by placing the compositions described above inside a capsule shell.
  • a capsule is a dosage form administered in a special container or enclosure containing an active agent.
  • the compositions described herein can be filled into soft capsules.
  • a capsule shell may be made of methylcellulose, hydroxypropylmethyl cellulose, polyvinyl alcohols, or denatured gelatins or starch or other material. Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins.
  • the unit dosage form is a gel capsule.
  • the capsule shell is a glycerin capsule shell, for example product no.
  • the capsule is a bovine gelatin shell, for example SwissCaps product no. GSU0708.
  • suitable capsule shell materials include polyethylene, polypropylene, poly(methylmethacrylate), polyvinylchloride, polystyrene, polyurethanes, polytetrafluoroethylene, nylons, polyformaldehydes, polyesters, cellulose acetate, and nitrocellulose.
  • the capsule shell itself may contain small amounts of dyes, opaquing agents, plasticizers, and preservatives.
  • Gelatin capsule shells may be made also be made of tapioca, grass, vegetable derived or fish derived gelatin.
  • K-CAPS Capsuline, Inc. Pompano Beach, Fla.
  • Other vegetarian derived gelatin capsules may, be made of vegetable derived hydroxypropylmethyl cellulose
  • Capsules shells may also contain Modified Maize Starch, Glycerol, and Carrageenan as a gelling agent.
  • the capsule has a shell comprising the material of the rate-limiting membrane, including coating materials, and filled with the compositions described herein.
  • Capsule shells may be made of a porous or a pH- sensitive polymer made by a thermal forming process.
  • the capsule shell in the form of an asymmetric membrane; i.e., a membrane that has a thin skin on one surface and most of whose thickness is constituted of a highly permeable porous material.
  • a "swelling plug device” can be used.
  • the compositions described herein can be incorporated into a non-dissolving capsule-half of the device which is sealed at one end by a hydrogel plug.
  • This hydrogel plug swells in an aqueous environment, and, after swelling for a predetermined time, exits the capsule thus opening a port through which the active agent can leave the capsule and be delivered to the aqueous environment.
  • Preferred hydrogel-plugged capsules are those which exhibit substantially no release of active agent from the dosage form until the dosage form has exited the stomach and has resided in the small intestine for about 15 minutes or more, preferably about 30 minutes or more, thus assuring that minimal omega-3 fatty acid (either in the triglyceride, ester, or free fatty acid form) is released in the stomach or the small intestine.
  • Hydrogel-plugged capsules of this type have been described in patent application WO90/19168.
  • the dosage forms may contain a plasticizer, such as for example, in a capsule shell.
  • Suitable plasticizers include, e.g., polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, triethyl cellulose, triacetin, glycerin, sorbitol, sorbitan or combinations thereof.
  • compositions can be formulated as a liquid for parenteral administration, particularly for intravenous administration, added to infant formula, or injected into an intravenous bag comprising a saline or other pharmaceutically acceptable solution or a nutritional supplement.
  • compositions described herein can be formulated as one or more dosage units. In some embodiments, it can be advantageous to formulate oral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit forms described in some embodiments can refer to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active composition calculated to produce the desired therapeutic effect in association with the suitable pharmaceutical carrier.
  • the dosage form may optionally contain a flavorant such as orange oil, substantially pure d-limonene, and an antioxidant such as tocopherol, tocotrienol, ascorbyl palmitate or a combination of antioxidants.
  • a flavorant such as orange oil, substantially pure d-limonene
  • an antioxidant such as tocopherol, tocotrienol, ascorbyl palmitate or a combination of antioxidants.
  • compositions which contain at least one surface active agent and at least one omega-3 fatty acid (in triglyceride, ester, or free fatty acid form) in relative concentrations sufficient to form micelles when added to an aqueous medium, and wherein said micelles range in size from lum to lOum in diameter.
  • These functional foods may further contain one or more of (1) at least one fat-soluble vitamin, such as vitamin A, vitamin E, vitamin D, vitamin K, vitamin K2, among others, (2) one or more minerals, such as magnesium, manganese, zinc, copper, selenium, and combinations thereof, and (3) an omega-6, for example arachidonic acid (ARA), linoleic acid (LA), gamma-linolenic acid (GLA) or the omega-6 isomer of DP A.
  • ARA arachidonic acid
  • LA linoleic acid
  • GLA gamma-linolenic acid
  • DP A omega-6 isomer of DP A.
  • compositions described herein comprise micelles pre-formed prior to administration to a subject in need of such
  • Such pre-formed micelles are stable at room temperature.
  • such pre-formed micelles or said pre-micellized compositions in combination with a foodstuff are provided, and can then be consumed as part of a healthy diet for enriching a subject's omega-3 fatty acid levels or as a dietary treatment in addition to the oral/parenteral administration of the compositions described herein as prescribed by a health professional.
  • the functional food is in the form of edible or drinkable compositions, e.g., foodstuffs such as chewable or edible bars,
  • confectionary products e.g., chocolate bars
  • cookies juice drinks
  • baked or simulated baked goods e.g., brownies
  • biscuits lozenges or chewing gum.
  • Examples of chewable or edible bars include chocolate bars or energy bars. Such functional foods can be particularly useful to people participating in sports or other forms of exercise.
  • the functional foods may also be in the form of, for example, butter, margarine, bread, cake, milk shakes, ice cream, yogurt and other fermented milk product.
  • the functional food can also be in the form of a liquid to be sprayed on meats, salads or other foods.
  • Other forms of the functional foods can be baby food, breakfast cereals, such as for example, grain flakes, muesli, bran, oatmeal.
  • compositions described herein can be added directly to the drink, such as for example plain milk, flavored milk, fermented milk products or juices, or infant formula.
  • compositions will form micelles comprising the omega-3 fatty acids in the drinkable product.
  • the compositions described herein can be first added directly to a functional food or to an aqueous medium, wherein the composition will form micelles as described herein.
  • the aqueous medium comprising the micelles can subsequently be either sprayed onto the solid edible product or mixed into the ingredients when manufacturing the edible product.
  • At least one surface active agent and one or more omega-3 fatty acids are further combined with Protein: 50 g, Vitamin A: 5,000 International Units (IU); Vitamin C: 60 mg, Vitamin E: 30 IU, Beta carotene, Folate: 400 ⁇ g, Zinc: 15 mg, Manganese: 2 mg, Copper: 2 mg, and Selenium: 70 ⁇ g.
  • At least one surface active agent is combined with at least one fat-soluble vitamin and an omega-3 fatty acid (in triglyceride, ester, or free fatty acid form) in relative concentrations sufficient to form micelles when added to an aqueous medium.
  • at least one surface active agent is combined with at least one fat-soluble vitamin, an omega-3 fatty acid (in triglyceride, ester, or free fatty acid form), and one or more minerals, such as magnesium, manganese, zinc, copper, selenium, and combinations thereof.
  • the omega-3 oil may contain -2% a-tocopherol as an antioxidant.
  • ⁇ DHA comprises at least 90% of the DHA oil (678.9mg). The majority of the remaining no more than 10% is EPA (-5%, or up to 37.7 mg)
  • the Omega-3 oil may contain -2% a-tocopherol as an antioxidant.
  • ⁇ EPA comprises 383mg and 170mg DHA.
  • the self-micellizing compositions may further contain at least one additional omega-3 fatty acid (either in the triglyceride, ester, or free fatty acid form), for example EPA or other known omega-3 fatty acids as disclosed herein.
  • the self-micellizing compositions may further contain an anti-oxidant, such as tocopherol.
  • the self- micellizing compositions may further contain an omega-6 fatty acid (either in the triglyceride, ester, or free fatty acid form), for example arachidonic acid (ARA), linoleic acid (LA), gamma-linolenic acid (GLA) or the omega-6 isomer of DP A, also known as osbond acid.
  • omega-6 fatty acid either in the triglyceride, ester, or free fatty acid form
  • ARA arachidonic acid
  • LA linoleic acid
  • GLA gamma-linolenic acid
  • DP A also known as osbond acid
  • -45 cm of jejunum distal to the ligament of Treitz and -45 cm of ileum proximal to the ileocecal junction were measured using sterile silk ribbon placed along the antimesentric border of the gently stretched small intestine. Intestine not included in the measurement was removed via cauterization. Bowel continuity was restored using an end-to-end jejunoileal anastomosis.
  • the control group received a standard DHA ethyl ester preparation of substantially pure DHA ethyl ester (>90% DHA ethyl ester).
  • the SBS-treatment group received an equivalent amount of DHA as the control group, based on animal weight as described herein, of a preferred embodiment of the present invention comprising, about 683.9 mg/g of substantially pure DHA ethyl esters (>90% DHA ethyl ester), 2.7 mg/g of alpha- tocopherol, 306.3g/mg of polysorbate 80, and 7.1mg/g of poloxamer 237.
  • SBS-treatment The control and SBS-treatment formulations, respectively, mixed in the enteral feeding at the respective dose and infused via the intragastric catheter at a dose of 1 g/kg*day for a period of 4 days after which time the animals were sacrificed.
  • Piglets were weighed every other day. In addition to calculating a change in weight by subtracting the starting weight at the time of randomization from the final weight, percent weight change and growth velocity (g/kg*d) were also calculated. Percent weight change was calculated by: [((final weight- starting weight)/starting weight) x 100]. Growth velocity was calculated by: [(weight change/starting weight)/4 days of treatment].
  • the primary outcome measure was a change in plasma DHA level in the SBS-treated group versus control group. Given the small number of piglets per group, appropriate small group statistical methods were used to evaluate differences in outcome variables. Variable summary statistics are expressed as median + interquartile range (IQR). The Wilcoxon Rank-Sum test, which is appropriate to compare two non-normal distributions as is common in small sample size, was used to compare outcome measures between groups; while the Wilcoxon signed-rank test, which is appropriate for repeated measurements within the same animal, was used to compare paired, before and after surgery outcome measures within groups.
  • IQR interquartile range
  • IQR Interquartile range
  • SI Small Intestine
  • Eicosapentaenoic acid (EPA), ARA, and Linoleic acid (LA) obtained at the time of surgery were similar between groups (2.0+0.04 vs 2.3+0.4; 0.2+0.06 vs 0.3+0.1 ; 11.0+0.3 vs 11.8+0.5; 18.1+2.3 vs 16.6+1.8, respectively) ( Figure 1).
  • Crypt depth was increased at the end of the experiment compared to baseline values in the proximal jejunum within both control and SBS-treatment groups (p ⁇ 0.05). There were no differences between groups in the baseline or final crypt depth measurements. Similar to the proximal jejunum, the crypt depth of the distal ileum was increased from baseline in the distal ileum within the control group (p ⁇ 0.05). In contrast, there were no changes in the baseline to final crypt depth in the distal ileum for the piglets in the SBS-treatment group. The final crypt depths in the distal ileum were not significantly different between the two groups.
  • the piglets in the SBS-treatment group appeared to have an accelerated adaptive response compared to the control group possibly due to the efficient bioavailability and intestinal absorption of DHA. This may be a clinically relevant observation during the critical, immediate postoperative period. Although increased jejunal crypt depth was seen in both groups after 4 days, the lack of change in the ileum selectively in the SBS-treatment group suggests that increased bioavailability of DHA is exerting an intestinal trophic effect. While not wishing to be bound to any particular theory, it is possible that DHA is modulating intestinal cell growth and differentiation through PPAR or other growth factors.
  • the omega-3 oil may contain -2% a-tocopherol as an antioxidant.
  • ⁇ DHA comprises at least 90% of the DHA oil (617.3mg). The majority of the remaining no more than 10% is EPA (-5%, or up to 34.3 mg)
  • sterile saline solution is added to the vial and mixed to homogeneity to form a milky solution, which can then be administered intravenously directly into a human in need of such administration, such as for example a neonate, added to infant formula, into an IV infusion bag, via a stomach feeding tube, or through a duodenal feeding tube.
  • Poloxamer 237 (Pluronic® F87) 7.1 0.71
  • the omega-3 oils may contain -2% a-tocopherol as an antioxidant.
  • ⁇ DHA comprises at least 90% of the DHA oil (586.3mg). The majority of the remaining no more than 10% is EPA (-5%, or up to 32.6 mg)
  • the omega-3 oil may contain -2% a-tocopherol as an antioxidant.
  • ⁇ DHA comprises at least 90% of the DHA oil (678.9mg). The majority of the remaining no more than 10% is EPA (-5%, or up to 37.7 mg) EXAMPLE 7
  • the omega-3 oil may contain -2% a-tocopherol as an antioxidant.
  • ⁇ EPA comprises 383mg and 170mg DHA.
  • SC410 is a composition consisting of about: 68.39% docosahexaenoic acid ethyl esters (DHA), 0.27% alpha-tocopherol, 30.63% polysorbate 80, and 0.71% poloxamer 237.
  • DHA docosahexaenoic acid ethyl esters
  • SC410 is preferably administered enterally to a mammal, such as a human, and delivered within a soft gelatin capsule although the routes of
  • NASH mice mouse model
  • NAFLD mice a mouse model
  • SC410 SC-specific neoplasm originating from 5 to 9 weeks of age.
  • NASH mice mice which progresses from NAFLD to NASH between 5 to 6 weeks of age. Within the disease progression of this animal model, the animals reach NASH around week 6.
  • Eight NASH mice were orally administered an olive oil vehicle in a volume of 2.5 mL/kg once daily from 5 to 9 weeks of age (Control Group).
  • a second group, the "Second Treatment Group,” also interchangeably referred to herein as NAFLD Group, composition 1-5 group, or composition 1-5 treatment, consisted of eight NASH mice which were orally administered said olive oil vehicle supplemented with SC410 once daily from 5 to 9 weeks of age.
  • a third group, the "Third Treatment Group,” also interchangeably referred to herein as NASH Group, composition 1-6 group or composition 1-6 treatment, consisted of eight NASH mice, which were orally administered said olive oil vehicle supplemented with SC410 once daily from 6 to 9 weeks of age.
  • Non- fasting blood glucose was measured in whole blood and ALT levels were measured from plasma.
  • Liver total lipid-extracts were obtained from right lobes by Folch's method.
  • Figure 3 shows the mean body weight on the day of sacrifice of the mice between each of the Control, Second Treatment Group and Third Treatment Group.
  • Figure 4 shows a-SMA mRNA gene expression in mice in each of the control, NAFLD and NASH groups treated with either Vehicle or Composition 1 at the end of the treatment period.
  • Figure 5 shows plasma alanine transaminase (ALT) levels in mice between each of the control, NAFLD and NASH group treated with either Vehicle or Composition at the end of the treatment period.
  • Figure 6 shows the mean liver weight on the day of sacrifice of the mice between each of the treatment groups and the control.
  • Figure 7 shows the mean liver to body weight ratio on the day of sacrifice of the mice between each of the treatment groups and the control.
  • Figure 8 shows whole blood glucose in mice between each of the control, NAFLD and NASH group treated with either Vehicle or Composition at the end of the treatment period.
  • Figure 9 shows liver triglyceride levels in mice between each of the control, NAFLD and NASH.
  • Figures 10 A and 10B show the mean individual EPA (A) and DHA (B) total lipid concentration-time profiles (baseline-adjusted change) after a single dose of SC401 during fed and fasting conditions.
  • Figures 1 1 A and 1 IB show the mean individual EPA (A) and DHA (B) free fatty acid concentration-time profiles (baseline-adjusted change) after a single dose of SC401 during fed and fasting conditions.
  • Figure 12 shows mean EPA and DHA total lipid plasma concentration profiles ⁇ g/ml) (baseline-adjusted) after administration of a single dose (dose adjusted) of SC401 and Lovaza® in fasted conditions.
  • a-SMA a marker of myofibroblast associated with the development of liver fibrosis
  • mRNA expression levels tended non- significantly to decrease in both treatment groups as compared with the Control Group.
  • Liver triglyceride contents tended to decrease in the First Treatment Group and significantly decreased in the Second Treatment Group compared with the Control Group.
  • embodiments of the present invention can improve lipid and glucose metabolism in the liver. These results also demonstrate that omega-3 fatty acids can improve lipid and glucose metabolism in the liver.
  • compositions disclosed herein can deliver polyunsaturated EPA and DHA fatty acids to mammals with NAFLD for incorporation into the cell membrane of erythrocytes, wherein said delivery can reduce the triglyceride level in the liver and thereby slow the disease's progression to NASH.
  • administration of compositions disclosed herein might provide a larger medicinal response when provided later in the disease progression from NAFLD to NASH.
  • the omega-3 oil may contain -2% a-tocopherol as an antioxidant.
  • ⁇ DHA comprises at least 90% of the DHA oil (678.9mg). The majority of the remaining no more than 10% is EPA (-5%, or up to 37.7 mg)
  • Poloxamer 237 (Pluronic® F87) 7.8 0.68
  • the omega-3 oil may contain -2% a-tocopherol as an antioxidant.
  • ⁇ EPA comprises 383mg and 170mg DHA.
  • the omega-3 oil may contain -2% a-tocopherol as an antioxidant.
  • ⁇ DHA comprises at least 90% of the DHA oil (678.9mg). The majority of the remaining no more than 10% is EPA (-5%, or up to 37.7 mg) EXAMPLE 12
  • the omega-3 oil may contain -2% a-tocopherol as an antioxidant.
  • ⁇ EPA comprises 383mg and 170mg DHA.
  • compositions described herein in a murine model of Primary Sclerosing Cholangitis (PSC). It is believed that treatment with the compositions described herein will be more effective in preventing and/or reversing bile duct injury in a mouse model of PSC.
  • PSC Primary Sclerosing Cholangitis
  • the study will utilize a mouse model of PSC induced by DSS & DDC.
  • the well established mouse model of PSC where exon 10 CFTR +/ ⁇ knockout mice (heterozygotes) will be exposed to oral Dextran Sodium Sulfate (DSS) followed by up to 28 days of the xenobiotic DDC dissolved in peptamen (Martin CR, Zaman MM, Ketwaroo GA, Bhutta AQ, Coronel E, Popov Y, Schuppan D, Freedman SD.
  • DSS Dextran Sodium Sulfate
  • peptamen Martin CR, Zaman MM, Ketwaroo GA, Bhutta AQ, Coronel E, Popov Y, Schuppan D, Freedman SD.
  • CFTR dysfunction predisposes to fibrotic liver disease in a murine model. Am J Physiol Gastrointest Liver Physiol 303: G474-G481, 2012).
  • the Cftr +I ⁇ mouse model of PSC consists of two phases: (1) induction of colitis with DSS for 10 days or until overt blood per rectum; and, (2) induction of liver inflammation and fibrosis with DDC for 28 days. The following protocol will begin using Cftr +I ⁇ mice at ⁇ age 35 days, or week 5. [000406] Induction of colitis with DSS for 10 days
  • mice 85 mg of DSS dissolved in 12ml of Peptamen by continuous vortexing.
  • the mice will be fed using a liquid feeder (Dyets Inc., Bethlehem, PA).
  • the mice will be monitored daily for onset of colitis by overt bleeding per rectum.
  • DSS Once overt bleeding is noted (typically day 8-10 of DSS), DSS will be discontinued and the mice will be fed peptamen alone for one day.
  • mice After overt colitis and one day of peptamen feeding alone, the mice will be treated for 28 days with 1.5mg DDC in 12 ml of Peptamen per day
  • Body weight will be measured at the start of the protocol, every 3 rd day, then at the end of the protocol. Percent weight change will be calculated as follows:
  • Fatty acid levels will be determined in plasma and liver.
  • Liver injury will be scored based on four criteria: (1) epithelial injury, intraepithelial inflammation, and mononuclear cell infiltration; (2) bile duct proliferation; (3) bile duct angulation; and (4) fibrosis. Each criterion receives a score between 0 and 3.
  • a scoring rubric is defined in the box below. Scoring as previously described in our AJP article, will be performed by two individuals blinded to the conditions
  • Bile duct proliferation will be scored at 5x magnification on slides stained with H&E.
  • Bile duct angulation will be scored at 20x magnification on slides stained with H&E.
  • Fibrosis will be scored on slides at 5x magnification stained with Sirius Red. All tissues will be held and processed at the same time for Sirius Red staining.
  • the omega-3 oil may contain -2% a-tocopherol as an antioxidant.
  • ⁇ DHA comprises at least 90% of the DHA oil (678.9mg). The majority of the remaining no more than 10% is EPA (-5%, or up to 37.7 mg)
  • the omega-3 oil may contain -2% a-tocopherol as an antioxidant.
  • ⁇ EPA comprises 383mg and 170mg DHA.
  • Test (T): One or more of the compositions described herein (n 30)
  • Phenotypic characteristic was confirmed with the use of cellulose acetate electrophoresis at pH 8.5.
  • the primary end point will be rates of clinical vaso-occlusive crisis and secondary end points will include number of hospitalizations, haemo lytic events, blood transfusion rate, school attendance, and blood count— will be analysed by intention-to-treat analysis and quality of life assessment.
  • Figure 10 shows mean EPA and DHA total lipid plasma concentration profiles ⁇ g/ml) (baseline-adjusted) after administration of a single dose (dose adjusted) of SC401 and Lovaza® in fasted conditions.

Abstract

L'invention concerne des compositions contenant au moins un acide gras oméga 3 (sous la forme de triglycéride, d'ester ou d'ester d'acide gras libre) et au moins un agent tensioactif ; les compositions formant des micelles lorsqu'elles sont en contact avec un milieu aqueux. L'invention concerne également des méthodes d'administration à un patient d'une composition contenant au moins un acide gras oméga 3 (sous la forme de triglycéride, d'ester ou d'ester d'acide gras libre) et au moins un agent tensioactif, les compositions formant des micelles lorsqu'elles sont en contact avec un milieu aqueux, la biodisponibilité de l'acide gras oméga 3 étant sensiblement indépendante d'un effet alimentaire. Les compositions selon l'invention sont utiles dans le traitement de certains états pathologiques pouvant comprendre les syndromes de malabsorption (1), la cholangite sclérosante primitive (CSP) (2), la stéatose hépatique non alcoolique (SHNA) (3), la drépanocytose (4), la dégénérescence maculaire liée à l'âge (DMLA) (5) et les maladies neurodégénératives (6), notamment la maladie de Parkinson (MP), la maladie d'Alzheimer (MA), la sclérose latérale amyotrophique (SLA ou maladie de Lou Gehrig), l'épilepsie, le syndrome bipolaire, les lésions cérébrales traumatiques, la neuropathie périphérique et la sclérose en plaques (SP). L'invention concerne également diverses formes galéniques pour l'administration des compositions, ainsi que l'utilisation de ces compositions dans des aliments fonctionnels. L'invention concerne encore des kits contenant des instructions d'administration de ces compositions.
PCT/US2015/054933 2012-03-30 2015-10-09 Compositions d'acides gras et d'esters d'acides gras auto-micellisantes, ainsi que leur utilisation dans le traitement d'états pathologiques WO2016057915A1 (fr)

Priority Applications (11)

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BR112017007428A BR112017007428A2 (pt) 2014-10-10 2015-10-09 composições de éster de ácido graxo e ácidos graxos autocomnizantes e suas utilizações no tratamento de estados da doença
MX2017004324A MX2017004324A (es) 2014-10-10 2015-10-09 Composiciones de ácidos grasos y éster de ácido graso autoformadores de micelas y su uso en el tratamiento de patologías.
EP15784877.1A EP3212236A1 (fr) 2014-10-10 2015-10-09 Compositions d'acides gras et d'esters d'acides gras auto-micellisantes, ainsi que leur utilisation dans le traitement d'états pathologiques
CA2963952A CA2963952C (fr) 2014-10-10 2015-10-09 Compositions d'acides gras et d'esters d'acides gras auto-micellisantes, ainsi que leur utilisation dans le traitement d'etats pathologiques
US15/180,430 US20160296492A1 (en) 2012-03-30 2016-06-13 Self-micellizing fatty acids and fatty acid ester compositions and their use in the treatment of disease states
ZA2017/02385A ZA201702385B (en) 2014-10-10 2017-04-04 Self-micellizing fatty acids and fatty acid ester compositions and their use in the treatment of disease states
US15/605,972 US10898458B2 (en) 2012-03-30 2017-05-26 Self-micellizing fatty acids and fatty acid ester compositions and their use in the treatment of disease states
US16/655,643 US10894027B2 (en) 2012-03-30 2019-10-17 Sickle cell disease treatment utilizing omega-3 fatty acids
US16/713,685 US20200330422A1 (en) 2014-10-10 2019-12-13 Formulations for Treating and/or Preventing Disease
US17/152,103 US20210322359A1 (en) 2012-03-30 2021-01-19 Sickle cell disease treatment utilizing omega-3 fatty acids
US17/156,824 US20210322360A1 (en) 2012-03-30 2021-01-25 Self-micellizing fatty acids and fatty acid ester compositions and their use in the treatment of disease states

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US201462062651P 2014-10-10 2014-10-10
US201462062643P 2014-10-10 2014-10-10
US201462062652P 2014-10-10 2014-10-10
US62/062,646 2014-10-10
US62/062,634 2014-10-10
US62/062,643 2014-10-10
US62/062,652 2014-10-10
US62/062,651 2014-10-10
US62/062,638 2014-10-10

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US14/808,876 Continuation-In-Part US9364562B2 (en) 2012-03-30 2015-07-24 Functional foods and kits containing stable micelles of fatty acid esters

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JP2019518738A (ja) * 2015-11-13 2019-07-04 シンセン ハイタイド バイオファーマシューティカル リミテッド 組成物、ならびにその適用および薬学的調製の方法
EP3456328A4 (fr) * 2016-05-10 2020-02-26 Shenzhen Hightide Biopharmaceutical., Ltd. Composition, et application et préparation pharmaceutique de cette dernière
IT201900007202A1 (it) * 2019-05-24 2020-11-24 Pavia Farm S R L Composizione a base di vitamine liposolubili ad elevato assorbimento enterico
WO2021028737A1 (fr) 2019-08-13 2021-02-18 Team Foods Colombia S.A. Composition lipidique qui comprend des antioxydants et des polyphénols naturels comme alternative non pharmacologique pour le traitement et la prévention de la nafld
CN113924001A (zh) * 2019-02-22 2022-01-11 米克罗皮公司 食品补充剂

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JP2019518738A (ja) * 2015-11-13 2019-07-04 シンセン ハイタイド バイオファーマシューティカル リミテッド 組成物、ならびにその適用および薬学的調製の方法
EP3456328A4 (fr) * 2016-05-10 2020-02-26 Shenzhen Hightide Biopharmaceutical., Ltd. Composition, et application et préparation pharmaceutique de cette dernière
WO2018027278A1 (fr) * 2016-08-12 2018-02-15 Pharmako Biotechnologies Pty Limited Compositions d'oméga-3 et méthodes associées
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CN113924001A (zh) * 2019-02-22 2022-01-11 米克罗皮公司 食品补充剂
IT201900007202A1 (it) * 2019-05-24 2020-11-24 Pavia Farm S R L Composizione a base di vitamine liposolubili ad elevato assorbimento enterico
WO2021028737A1 (fr) 2019-08-13 2021-02-18 Team Foods Colombia S.A. Composition lipidique qui comprend des antioxydants et des polyphénols naturels comme alternative non pharmacologique pour le traitement et la prévention de la nafld

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