TW201609085A - Pharmaceutical compositions and methods for treating non-alcoholic steatohepatitis - Google Patents

Abstract

The disclosure provides for a pharmaceutical composition and method for treating a fatty liver disease or disorder in a subject in need thereof, comprising selecting a subject having or suspected of having a fatty liver disease or disorder, wherein the subject is non diabetic, pre-diabetic, mildly diabetic; has normal or substantially normal biliary tract function; or has non or early stage hepatocyte apoptosis; and administering a therapeutically effective amount of a pharmaceutical composition comprising EPAs.

Description

Pharmaceutical composition and method for treating nonalcoholic steatohepatitis

It is known that severe alcohol use can lead to liver complications, including alcoholic hepatitis, which is usually characterized by fatty liver and inflammation. Alcoholic hepatitis can eventually lead to cirrhosis (scarring) and liver tissue sclerosis. However, it has also been found that individuals who do not consume excessive amounts of alcohol have liver disease complications. Nonalcoholic fatty liver disease (NAFLD) should be understood to cover a variety of liver diseases, including steatosis (simple fatty liver), nonalcoholic steatohepatitis (NASH), and advanced liver scar (hardening). Traditionally, NASH has been used to diagnose NASH to characterize liver histology, particularly with regard to inflammation, fibrosis, and steatosis (fat accumulation). NASH generally refers to liver biopsy based on patients with steatohepatitis and clinical findings that there is no significant alcohol consumption (Neuschwander-Tetri, B.A. and S.H. Caldwell (2003) Hepatology 37(5): 1202-1209).

In NASH, fat accumulation is found in varying degrees of inflammation (hepatitis) and can lead to more severe conditions involving scarring (fibrosis). Patients with NASH are also typically characterized by abnormal levels of liver enzymes such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Currently, very few therapies are used to slow or alter the progression of further disease progression in NASH. EPA-E had no significant effect on the histological features of NASH in Phase 2 trials (Sanyal, A. J. et al., (2014) Gastroenterology 147(2): 377-384). Therefore, effective NASH treatment is still needed.

The present disclosure provides a fatty liver disease or condition for treating an individual in need thereof Pharmaceutical compositions and methods comprising selecting an individual having or suspected of having a fatty liver disease or condition, wherein the system is free of diabetes, pre-diabetes or mild diabetes; or has normal or substantially normal biliary function; Or no hepatocyte apoptosis or having early hepatocyte apoptosis; and administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound selected from the group consisting of ethyl eicosapentaenoate (EPA-E) , eicosapentaenoic acid (EPA) and its pharmaceutically acceptable indoleamines, salts, esters and phospholipids. In some cases, the EPA-E or EPA present may comprise a total of at least 40% by weight of the fatty acid and its derivatives.

In some embodiments, the present invention provides a pharmaceutical composition and method for treating a fatty liver disease or condition in an individual in need thereof, the method comprising selecting an individual having or suspected of having a fatty liver disease or condition, wherein the The system is free of diabetes, pre-diabetic or mild diabetes and undergoes medical nutritional therapy and/or physical exercise; and administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound selected from the group consisting of eicosapentaenoic acid Ethyl ester (EPA-E), eicosapentaenoic acid (EPA) and its pharmaceutically acceptable indoleamines, salts, esters and phospholipids. In some cases, the EPA-E or EPA present may comprise a total of at least 40% by weight of the fatty acid and its derivatives.

In some embodiments, the invention provides a pharmaceutical composition and method for treating a fatty liver disease or condition in an individual in need thereof, the method comprising selecting an individual having or suspected of having a fatty liver disease or disorder, wherein the individual Serum hepatocyte apoptosis or early hepatocyte apoptosis or serum or plasma soluble Fas (sFas) or serum or plasma cytokeratin-18 fragment M30 (M30) associated with no hepatocyte apoptosis or early hepatocyte apoptosis Or it is considered to have a NASH risk score of 3.0 or lower; and a therapeutically effective amount of a pharmaceutical composition comprising at least one compound selected from the group consisting of ethyl eicosapentaenoate (EPA-E), Eicosapentaenoic acid (EPA) and its pharmaceutically acceptable indoleamines, salts, esters and phospholipids. In some cases, the EPA-E or EPA present may comprise a total of at least 40% by weight of the fatty acid and its derivatives.

In some embodiments, the disclosure provides a lipid for treating an individual in need thereof A pharmaceutical composition and method for a fatty liver disease or condition, the method comprising: selecting an individual having or suspected of having a fatty liver disease or condition, wherein the individual has a serum HbA1c content of 6.4% or less or an individual having a fasting serum glucose content equal to Or less than 125 mg/dl; and administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound selected from the group consisting of ethyl eicosapentaenoate (EPA-E), eicosapentaenoic acid ( EPA) and its pharmaceutically acceptable indoleamines, salts, esters and phospholipids. In some cases, the EPA-E or EPA present may comprise a total of at least 40% by weight of the fatty acid and its derivatives.

In some embodiments: selecting an individual having or suspected of having a fatty liver disease or condition, wherein the individual exhibits no hepatocyte apoptosis or early hepatocyte apoptosis or sFas content equal to or less than 10.0, 9.9, 9.8, 9.7, 9.6, 9.5, 9.4, 9.3, 9.2, 9.1, 9.0, 8.9, 8.8, 8.7, 8.6, 8.5, 8.4, 8.3, 8.2, 8.1 or 8.0 ng/mL (preferably equal to or less than 9.5 ng/mL) and/or The M30 content is equal to or less than 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600 or 500 U/L (preferably equal to or less than 900 U/L, more preferably equal to or less than 500 U/L) or NASH risk A score equal to or less than 3.0, 2.9, 2.859, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1 or 2.0 (preferably equal to or less than 3.0), and administration of a therapeutically effective amount comprising eicosapentaenoic acid A pharmaceutical composition of ethyl ester (EPA-E), eicosapentaenoic acid (EPA), and pharmaceutically acceptable indoleamines, salts, esters, and phospholipids thereof. In some cases, the EPA-E or EPA present may comprise a total of at least 40% by weight of the fatty acid and its derivatives.

In some embodiments, the present disclosure provides pharmaceutical compositions and methods for treating a fatty liver disease or condition in an individual in need thereof, the method comprising: selecting an individual having or suspected of having a fatty liver disease or condition, wherein The individual exhibits no hepatocyte apoptosis or early hepatocyte apoptosis or sFas content equal to or less than 10.0, 9.9, 9.8, 9.7, 9.6, 9.5, 9.4, 9.3, 9.2, 9.1, 9.0, 8.9, 8.8, 8.7, 8.6, 8.5, 8.4, 8.3, 8.2, 8.1 or 8.0 ng/mL (preferably equal to or less than 9.5 ng/mL) and/or M30 content equal to or less than 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700 , 600 or 500 U/L (preferably equal to or less than 900 U/L, more preferably equal to or less than 500 U/L) or NASH risk score equal to or less than 3.0, 2.9, 2.859, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1 Or 2.0 (preferably equal to or less than 3.0), and administration of a therapeutically effective amount of ethyl eicosapentaenoate (EPA-E), eicosapentaenoic acid (EPA), and pharmaceutically acceptable salts thereof a pharmaceutical composition of an amine, a salt, an ester, and a phospholipid; (b) improving the steatosis and lobular inflammatory condition of the individual and the fibrosis stage score does not deteriorate; and (c) the individual exhibits a baseline content prior to treatment, There will be at least one of the following changes in labeling: ALT, AST, TG, TG/HDL ratio, free fatty acid, AA, MUFA, palmitoleic acid, oleic acid, oleic acid/stearic acid ratio, palmitoleic acid/palmitic acid ratio, Stearic acid/palmitic acid ratio, γ-linolenic acid/linolenic acid ratio, adrenal acid/AA ratio, ferritin, thioredoxin, TNFα, sTNF-R1, sTNF-R2, Hs-CRP, CTGF, sCD40, leptin, complement factor D, CK18 fragment, serum HMGB1, Fas, hyaluronic acid, type IV collagen (7s domain), procollagen III peptide or PAI-1 reduced to 1%; EPA or EPA/AA ratio increased by at least 5%; DPA, AA/high-γ-linoleic acid ratio or serum adiponectin increased by at least 1%; ALP, bilirubin, GGT, albumin, HDL-C , LDL-C, TC, non-HDL-C, HOMA-IR, HbA1c, glucose, fasting plasma glucose, postprandial plasma glucose, OGTT, platelet count or BMI will not worsen.

In some embodiments, the present disclosure provides pharmaceutical compositions and methods for treating fatty liver disease or disorder in an individual in need thereof, the method comprising: selecting at least one individual selected from the group consisting of: a group indicative of fatty liver disease : NAS score, steatosis score, lobular inflammatory score, air swell score and fibrosis stage; and wherein the individual exhibits no hepatocyte apoptosis or early hepatocyte apoptosis or sFas content equal to or less than 10.0, 9.9, 9.8, 9.7, 9.6, 9.5, 9.4, 9.3, 9.2, 9.1, 9.0, 8.9, 8.8, 8.7, 8.6, 8.5, 8.4, 8.3, 8.2, 8.1 or 8.0 ng/mL (preferably equal to or less than 9.5 ng/mL) and/or The M30 content is equal to or less than 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600 or 500 U/L (preferably equal to or less than 900 U/L, more preferably equal to or less than 500 U/L) or NASH risk score equal to or less than 3.0, 2.9, 2.859, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1 or 2.0 (preferably equal to or less than 3.0), and administration of a therapeutically effective amount A pharmaceutical composition comprising at least one compound selected from the group consisting of ethyl docosapentaenoate (EPA-E), eicosapentaenoic acid (EPA), and pharmaceutically acceptable indoleamines and salts thereof , esters and phospholipids. In some cases, the EPA-E or EPA present may comprise a total of at least 40% by weight of the fatty acid and its derivatives.

The present disclosure also provides pharmaceutical compositions and methods for treating fatty liver diseases or conditions in an individual in need thereof, the method comprising: selecting an individual having or suspected of having a fatty liver disease or condition, wherein the individual exhibits normal or Substantially normal biliary function or serum gamma glutamine thiotransferase (GGT) content is normal or substantially normal, and administration of a therapeutically effective amount of a pharmaceutical composition comprising at least one compound selected from the group consisting of: Ethyl pentenoate (EPA-E), eicosapentaenoic acid (EPA) and its pharmaceutically acceptable indoleamines, salts, esters and phospholipids. In some cases, the EPA-E or EPA present may comprise a total of at least 40% by weight of the fatty acid and its derivatives.

In some embodiments, the present disclosure provides pharmaceutical compositions and methods for treating a fatty liver disease or condition in an individual in need thereof, the method comprising: selecting an individual having or suspected of having a fatty liver disease or condition, wherein The individual has a serum HbA1c content of 6.4% or less or an individual having a fasting serum glucose content of 125 mg/dl or less; and administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound selected from the group consisting of: twenty carbon Ethyl oleate (EPA-E), eicosapentaenoic acid (EPA) and its pharmaceutically acceptable indoleamines, salts, esters and phospholipids; and the administration in step b causes serum EPA in individuals The AA ratio is improved by 0.1 or more, 0.15, 0.2, 0.25, 0.3, 0.35 or 0.4 compared to the baseline EPA/AA ratio. In some cases, the EPA-E or EPA present may comprise a total of at least 40% by weight of the fatty acid and its derivatives.

The present disclosure also provides pharmaceutical compositions and methods for treating fatty liver diseases or conditions in an individual in need thereof, the method comprising: selecting a person suffering from or suspected of having fatty liver disease Or an individual of a condition wherein the individual exhibits normal or substantially normal biliary function or serum gamma glutamine thiotransferase (GGT) content equal to or less than 24, 25, 26, 27, 28, 29, 30, 31, 32 , 33, 34, 35, 40, 45, 50, 55, 60 or 78 IU/L, or a male GGT content equal to or less than 30 or 85 IU/L and a female GGT content equal to or less than 24 or 55 IU/L, and And a therapeutically effective amount of a pharmaceutical composition comprising at least one compound selected from the group consisting of ethyl eicosapentaenoate (EPA-E), eicosapentaenoic acid (EPA), and pharmaceutically acceptable The amines, salts, esters and phospholipids. In some cases, the EPA-E or EPA present may comprise a total of at least 40% by weight of the fatty acid and its derivatives.

In some embodiments, the present disclosure provides pharmaceutical compositions and methods for treating a fatty liver disease or condition in an individual in need thereof, the method comprising: selecting an individual having or suspected of having a fatty liver disease or condition, wherein The individual has a serum HbA1c content of 6.4% or less or an individual having a fasting serum glucose content of 125 mg/dl or less; wherein the individual is not treated with an antidiabetic agent or has been previously treated with an antidiabetic agent; and the therapeutically effective amount comprises at least one A pharmaceutical composition selected from the group consisting of ethyl eicosapentaenoate (EPA-E), eicosapentaenoic acid (EPA), and pharmaceutically acceptable indoleamines, salts, and esters thereof Phospholipids In some cases, the EPA-E or EPA present may comprise a total of at least 40% by weight of the fatty acid and its derivatives.

In some embodiments, the present disclosure provides pharmaceutical compositions and methods for treating a fatty liver disease or condition in an individual in need thereof, the method comprising: selecting an individual having or suspected of having a fatty liver disease or condition, wherein The individual exhibits normal or substantially normal biliary function or serum gamma glutamine thiotransferase (GGT) content equal to or less than 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 40, 45, 50, 55, 60 or 78 IU/L or male GGT content equal to or less than 30 or 85 IU/L and female GGT content equal to or less than 24 or 55 IU/L, (a) effective dose to the individual a pharmaceutical composition comprising at least one compound selected from the group consisting of ethyl eicosapentaenoate (EPA-E), eicosapentaenoic acid (EPA), and pharmaceutically acceptable guanamine thereof, Salts, esters and phospholipids; (b) Improving the steatosis and lobular inflammatory condition of the individual and the fibrosis stage score does not deteriorate; and (c) the individual exhibits at least one of the following changes in the marker compared to the pre-treatment baseline content: ALT, AST, TG, TG /HDL ratio, free fatty acid, AA, MUFA, palmitoleic acid, oleic acid, oleic acid/stearic acid ratio, palmitoleic acid/palmitic acid ratio, stearic acid/palmitic acid ratio, gamma-linolenic acid/linseed oil Acid ratio, adrenal/AA ratio, ferritin, thioredoxin, TNFα, sTNF-R1, sTNF-R2, Hs-CRP, CTGF, sCD40, leptin, complement factor D, CK18 fragment, serum HMGB1, Fas , hyaluronic acid, type IV collagen (7s domain), procollagen III peptide or PAI-1 reduced by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95%; EPA or EPA/AA ratio increased by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 , 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 200, 250, 300, 350 , 400, 450, 500, 600, 700, 800, 900, 1000, 1500, 2000, 3000, 4000, 5000%; DPA, AA/high-γ-linolenic acid ratio or serum adiponectin increased by at least 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 , 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 200, 250, 300 , 350, 400, 450, 500%; ALP, bilirubin, GGT, albumin, HDL-C, LDL-C, TC, non-HDL-C, HOMA-IR, HbA1c, glucose, fasting plasma glucose, postprandial Plasma glucose, OGTT, platelet count, sFas, M30, NASH risk score or BMI will not worsen.

In some embodiments, the present disclosure provides pharmaceutical compositions and methods for treating fatty liver disease or condition in an individual in need thereof, the method comprising: selecting suffering or suspecting An individual having a fatty liver disease or condition, wherein the individual has a serum HbA1c content of 6.4% or less or an individual having a fasting serum glucose content of 125 mg/dl or less; administering a therapeutically effective amount comprising at least one selected from the group consisting of Pharmaceutical composition of the compound and one or more anti-diabetic agents: ethyl eicosapentaenoate (EPA-E), eicosapentaenoic acid (EPA) and its pharmaceutically acceptable indoleamine, salt, ester And phospholipids.

In some embodiments, the present disclosure provides pharmaceutical compositions and methods for treating fatty liver disease or disorder in an individual in need thereof, the method comprising: selecting at least one individual selected from the group consisting of: a group indicative of fatty liver disease : NAS score, steatosis score, lobular inflammatory score, air swell score, and fibrosis stage; and wherein the individual shows serum γ-glutaminyl transferase (GGT) content equal to or less than 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60 or 78 IU/L or male GGT content equal to or less than 30 or 85 IU/L and female GGT content equal to or less than 24 or 55 IU/L; and administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound selected from the group consisting of ethyl docosapentaenoate (EPA-E), eicosapentaenoic acid (EPA) And pharmaceutically acceptable indoleamines, salts, esters and phospholipids thereof. In some cases, the EPA-E or EPA present may comprise a total of at least 40% by weight of the fatty acid and its derivatives.

In some embodiments, the disclosure provides pharmaceutical compositions and methods for treating a fatty liver disease or disorder in an individual in need thereof, the method comprising selecting an individual having a NAS score greater than or equal to 3; or a steatosis score equal to Or greater than 1; or a lobular inflammatory score equal to or greater than 1; or a swell score equal to or greater than 1; or a fibrosis score equal to or greater than 1; administering to the individual a therapeutically effective amount comprising at least one compound selected from the group consisting of Pharmaceutical composition: ethyl eicosapentaenoate (EPA-E), eicosapentaenoic acid (EPA) and its pharmaceutically acceptable indoleamines, salts, esters and phospholipids; and the individual serum HbA1c The content of the fasting serum glucose of the individual is equal to or less than 6.4% or ii) is equal to or less than 125 mg/dl.

In some embodiments, the disclosure provides a lipid for treating an individual in need thereof A pharmaceutical composition and method for a fatty liver disease or condition, the method comprising: selecting an individual having a NAS score greater than or equal to 3; or a steatosis score equal to or greater than 1; or a lobular inflammatory score equal to or greater than 1; or an inflation score equal to Or greater than 1; or a fibrosis score equal to or greater than 1; determine the individual's sFas or M30 serum content or NASH risk score; and if i) the individual presents with no hepatocyte apoptosis or early hepatocyte apoptosis or sFas content equal to or less than 10.0 9.9, 9.8, 9.7, 9.6, 9.5, 9.4, 9.3, 9.2, 9.1, 9.0, 8.9, 8.8, 8.7, 8.6, 8.5, 8.4, 8.3, 8.2, 8.1 or 8.0 ng/mL (preferably equal to or less than 9.5) The ng/mL) and/or M30 content is equal to or less than 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600, 500 U/L (preferably equal to or less than 900 U/L, more preferably equal to or less than 500 U/L) or NASH risk score equal to or less than 3.0, 2.9, 2.859, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1 or 2.0 (preferably equal to or less than 3.0), then the treatment is effective for the individual A pharmaceutical composition comprising at least one compound selected from the group consisting of: twenty carbon five Ethyl enoate (EPA-E), eicosapentaenoic acid (EPA) and its pharmaceutically acceptable indoleamines, salts, esters and phospholipids. In some embodiments, the fatty liver disease or condition is selected from the group consisting of non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

In some embodiments, the invention provides an individual characterized by at least one criterion selected from the group consisting of: no hepatocyte apoptosis or early hepatocyte apoptosis; sFas content equal to or less than 10.0, 9.9, 9.8, 9.7, 9.6 9.5, 9.4, 9.3, 9.2, 9.1, 9.0, 8.9, 8.8, 8.7, 8.6, 8.5, 8.4, 8.3, 8.2, 8.1 or 8.0 ng/mL (preferably equal to or less than 9.5 ng/mL); M30 content is equal to Or less than 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600 or 500 U/L (preferably equal to or less than 900 U/L, more preferably equal to or less than 500 U/L); the NASH risk score is equal to or Less than 3.0, 2.9, 2.859, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1 or 2.0 (preferably equal to or less than 3.0); baseline steatosis grade is about 2 to 3; and baseline lobular inflammatory grade is about 2 to 3.

In some embodiments, the invention provides an individual who is free of diabetes, pre-diabetes or mild diabetes. In some aspects of the disclosure, the individual does not receive a diabetes treatment or an anti-diabetic agent. In some aspects of the disclosure, the individual receives at least one diabetes treatment or at least one anti-diabetic agent. In some aspects of the disclosure, the individual receives at least one diabetes treatment or at least one anti-diabetic agent administered concurrently with the pharmaceutical composition.

In some embodiments, the invention provides an anti-diabetic agent selected from the group consisting of a PPAR gamma agonist, a biguanide, a protein tyrosine phosphatase-1B (PTP-1B) inhibitor, meglitinide, alpha Glucosidase inhibitors, insulin secretagogues, A2 antagonists, insulin and related compounds, PPAR dual agonists, sodium gluconate cotransporter (SGLT) 2 inhibitors, GSK 3β/GSK 3 inhibitors, dipeptidyl peptides Enzyme IV (DP-IV) inhibitors, peptides, sulfonylureas and non-sulfonylurea secretagogues.

In some embodiments, the invention provides an individual consuming a diabetic diet or a Western diet.

In some embodiments, the disclosure provides pharmaceutical compositions and methods for treating a fatty liver disease or disorder in an individual in need thereof, the method comprising: selecting an individual having a NAS score greater than or equal to 3; or a steatosis score equal to Or greater than 1; or lobular inflammatory score equal to or greater than 1; or swell score equal to or greater than 1; or fibrosis score equal to or greater than 1; determination of individual gamma glutamine thiol transferase (GGT) serum content; i) showing that the serum γ-glutaminyl transferase (GGT) content is equal to or less than 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60 or 78 IU/L or a male GGT content equal to or less than 30 or 85 IU/L and a female GGT content equal to or less than 24 or 55 IU/L, the subject is administered a therapeutically effective amount comprising at least one selected from the group consisting of Pharmaceutical compositions of the compounds: ethyl eicosapentaenoate (EPA-E), eicosapentaenoic acid (EPA), and pharmaceutically acceptable indoleamines, salts, esters, and phospholipids thereof.

In some embodiments, the fatty liver disease or condition is selected from the group consisting of: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

In some embodiments, selecting an individual having or suspected of having a fatty liver disease or condition comprises selecting an individual having a score selected from the group consisting of: a NAS score greater than or equal to 3, a steatosis score equal to or greater than 1, leaflet The inflammatory score is equal to or greater than 1, the swell score is equal to or greater than 1 and the fibrosis score is equal to or greater than 1.

In some embodiments, the disclosure provides for selecting an individual having or suspected of having a fatty liver disease or condition, further comprising selecting an overweight individual.

In some embodiments, the disclosure provides for selecting an individual having or suspected of having a fatty liver disease or condition, further comprising selecting a body mass index (BMI) greater than or equal to 25, 25.5, 26, 26.5, 27, 27.5, 28. Individuals of 28.5, 29, 29.5, 29.9, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 kg/m ² .

In some embodiments, the disclosure provides for selecting an individual having or suspected of having a fatty liver disease or condition, further comprising selecting an individual having a family history of fatty liver disease.

In some embodiments, the disclosure provides for selecting an individual having or suspected of having a fatty liver disease or condition, further comprising selecting an individual having a NAS score greater than or equal to 4.

In some embodiments, the disclosure provides an individual selected to have or suspected of having a fatty liver disease or condition comprising selecting an individual having a normal serum direct bilirubin content equal to or less than 0.4, 0.3, 0.2, 0.17, or 0.1.

In some embodiments, the individual is characterized by at least one criterion selected from the group consisting of: a baseline ALT value of from about 10 to about 300 IU/L; a baseline AST value of from about 10 to about 250 IU/L; a baseline steatosis grade of About 2 to 3; and the baseline lobular inflammatory rating is about 2 to 3.

In some embodiments, the invention provides a fatty liver disease characterized by a pre-treatment baseline level of at least one individual selected from the group consisting of: ALT at 10 IU/L In the range of 300 IU/L, AST is in the range of 10 IU/L to 250 IU/L, HDL/C is in the range of 25 mg/dl to 55 mg/dl, and LDL-C is in the range of 100 mg/dl to 200 mg/dl, triglyceride. In the range of 100 mg/dl to 1000 mg/dl, TC is in the range of 170 mg/dl to 300 mg/dl, high TG and low HDL-C, TG/HDL-C ratio is in the range of 3.75 to 10, and non-HDL-C is in 100 mg. In the range of /dl to 250mg/dl, free fatty acids range from 400μ Eq/L to 1000μ Eq/L, HOMA-IR ranges from 1.5 to 5, HbA1c ranges from 5.7% to 10%, and fasting plasma glucose is 100mg/ Glucose intolerance and metabolic syndrome in the range of dl to 200 mg/dl.

In some embodiments, the invention provides a fatty liver disease characterized by at least one pre-treatment baseline level of an individual selected from the group consisting of: low levels compared to each of the individuals having fatty liver disease EPA, docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), EPA/arachidonic acid (AA), DHA/AA, DHA/DPA, AA/high-γ-linseed oil Acid, and high content of AA, monounsaturated fatty acid (MUFA), palmitoleic acid, oleic acid, oleic acid/stearic acid, palmitoleic acid/palmitic acid, gamma-linolenic acid/linolenic acid, adrenal acid/AA .

In some embodiments, the invention provides for administration of EPA-E and/or EPA and/or pharmaceutically acceptable indoleamine, salt, ester or phospholipid for about 1 year, and the individual exhibits at least one selected from the group consisting of Group improvement: a reduced ALT value compared to the baseline ALT value; a reduced AST value compared to the baseline AST value; a reduced grade of steatosis compared to the baseline steatosis grade; and a level of inflammation associated with the baseline lobule Decreased lobular inflammation level.

In some embodiments, the invention provides a therapeutically effective amount of EPA-E and/or EPA administered to an individual and/or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof at about 1800 mg/day and about Amount between 2700 mg / day.

In some embodiments, the invention provides a therapeutically effective amount of EPA-E and/or EPA administered to an individual and/or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof of at least 1800 mg/day.

In some embodiments, the invention provides a therapeutically effective amount of EPA-E and/or EPA administered to an individual and/or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof of at least 2700 mg/day.

In some embodiments, the invention provides that the individual is further characterized by having at least one condition selected from the group consisting of high triglycerides and low HDL-C, glucose intolerance, and metabolic syndrome.

In some embodiments, the invention provides a reduced ALT value that is at least 1%, 2%, 3%, 4%, or 5% lower than the baseline ALT value and/or the reduced AST value is at least lower than the baseline AST value. 1%, 2%, 3%, 4% or 5%.

In some embodiments, the invention provides for determining a baseline serum content of at least one member selected from the group consisting of: ALT in the range of 10 IU/L to 300 IU/L, and AST in the range of 10 IU/L to 250 IU/L. In the range, HDL-C is in the range of 25 mg/dl to 55 mg/dl, LDL-C is in the range of 100 mg/dl to 200 mg/dl, triglyceride is in the range of 100 mg/dl to 1000 mg/dl, and TC is 170 mg/dl. To the range of 300 mg/dl, high TG and low HDL-C, TG/HDL-C ratio in the range of 3.75 to 10, non-HDL-C in the range of 100 mg/dl to 250 mg/dl, free fatty acid in 400 μEq/L To the range of 1000 μ Eq/L, HOMA-IR is in the range of 1.5 to 5, HbA1c is in the range of 5.7% to 10%, and fasting plasma glucose is in the range of 100 mg/dl to 200 mg/dl.

In some embodiments, the invention provides for administration of ethyl eicosapentaenoate for at least 3 months, the individual exhibiting at least one of the following changes in labeling compared to baseline: ALT, AST, TG, TG/ HDL ratio, free fatty acid, AA, MUFA, palmitoleic acid, oleic acid, oleic acid/stearic acid ratio, palmitoleic acid/palmitic acid ratio, adrenal acid/AA ratio, ferritin, thioredoxin, TNFα, sTNF-R1, sTNF-R2, Hs-CRP, CRGF, sCD40, leptin, complement factor D, CK18 fragment, serum HMGB1, Fas, hyaluronic acid, type IV collagen (7s domain), procollagen III peptide or PAI -1 reduces at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95%; EPA or EPA/AA ratio increased by at least 5%; DPA, AA/high-γ-linoleic acid ratio or serum adiponectin increased by at least 1%; ALP, bilirubin, GGT, albumin , HDL-C, LDL-C, TC, non-HDL-C, HOMA-IR, HbA1c, glucose, fasting plasma glucose, postprandial plasma glucose, OGTT, platelet count, sFas, M30, NASH risk score or BMI will not worsen .

In some embodiments, the present invention provides improved adipose degeneration and lobular inflammatory conditions in the subject and the fibrosis stage score does not deteriorate.

In some embodiments, the invention provides to improve the synthetic score of the individual's NAS scores (i) to ≦3 and the fibrosis stage score does not deteriorate, or (ii) at least two of the NAS components are improved ≧2 and The fibrosis stage score does not deteriorate.

In some embodiments, the present invention provides an improvement in serum EPA/AA ratio compared to baseline EPA/AA ratio.

In some embodiments, the present invention improves serum EPA/AA ratio by a factor of equal to or greater than 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, or 0.4 compared to a baseline EPA/AA ratio.

In some embodiments, the invention provides for administering to a subject 1 to 4 pharmaceutical compositions per day.

In some embodiments, the invention provides compositions in one or more capsules.

In some embodiments, the present invention provides a composition comprising a self-emulsifying composition comprising 50% to 95% by weight of an omega-3 polyunsaturated fatty acid or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, the present invention provides a composition comprising a self-emulsifying composition comprising 50% to 95% by weight of EPA-E or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, the present invention provides a composition comprising a self-emulsifying composition, The self-emulsifying composition comprises at least 60% by weight of EPA-E or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, the present invention provides a composition comprising a self-emulsifying composition comprising at least 70% by weight of EPA-E or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, the present invention provides a composition comprising a self-emulsifying composition comprising at least 80% by weight of EPA-E or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, the present invention provides a composition comprising a self-emulsifying composition comprising at least 90% by weight of EPA-E or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, the present invention provides a composition comprising a self-emulsifying composition comprising at least 95% by weight of EPA-E or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, the present invention provides a composition comprising a self-emulsifying composition comprising at least 96% by weight of EPA-E or a pharmaceutically acceptable salt or ester thereof.

In some embodiments, the invention provides a composition comprising from 5% to 50% by weight of an emulsifier having a hydrophilic lipophilic balance of at least 10.

In some embodiments, the present invention provides a composition comprising 10% to 50% by weight of an emulsifier having a hydrophilic lipophilic balance of at least 10.

In some embodiments, the invention provides a composition comprising from 20% to 50% by weight of an emulsifier having a hydrophilic lipophilic balance of at least 10.

In some embodiments, the present invention provides a composition comprising 30% to 50% by weight of an emulsifier having a hydrophilic lipophilic balance of at least 10.

In some embodiments, the invention provides from 40% to 50% by weight of having A composition of less than 10 hydrophilic and lipophilic balanced emulsifiers.

In some embodiments, the invention provides compositions comprising a total content of the compound and emulsifier comprising an ethanol content of up to 4% by weight.

In some embodiments, the invention provides compositions that are free of ethanol.

In some embodiments, the present invention provides at least one emulsifier selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol Fatty acid esters, polyoxyethylene polyoxypropylene diols, sucrose fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, and lecithin.

In some embodiments, the invention provides an emulsifier as at least one member selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, sucrose fatty acid Esters, sorbitan fatty acid esters and glycerol fatty acid esters.

In some embodiments, the present invention provides polyoxyethylene hydrogenated castor oil as at least one member selected from the group consisting of polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxygen Ethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil and polyoxyethylene (100) hydrogenated castor oil.

In some embodiments, the present invention provides a polyoxyethylene sorbitan fatty acid ester as at least one member selected from the group consisting of polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan tri-hard Fatty acid esters, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate and polyoxyethylene sorbitan monolaurate.

In some embodiments, the present invention provides a polyoxyethylene castor oil as at least one member selected from the group consisting of: a compound prepared by addition polymerization of ethylene oxide and castor oil, wherein the average ethylene oxide The number of moles is 3, 10, 20, 30, 40, 50 or more.

In some embodiments, the invention provides a sucrose fatty acid ester as at least one member selected from the group consisting of sucrose laurate, sucrose myristate, sucrose brown Palmitic acid ester, sucrose stearate and sucrose oleate.

In some embodiments, the present invention provides a polyoxyethylene polyoxypropylene diol as at least one member selected from the group consisting of polyoxyethylene (3) polyoxypropylene (17) diol, polyoxyethylene (20) Polyoxypropylene (20) diol, polyoxyethylene (42) polyoxypropylene (67) diol, polyoxyethylene (54) polyoxypropylene (39) diol, polyoxyethylene (105) polyoxypropylene ( 5) diol, polyoxyethylene (120) polyoxypropylene (40) diol, polyoxyethylene (160) polyoxypropylene (30) diol, polyoxyethylene (196) polyoxypropylene (67) diol and Polyoxyethylene (200) polyoxypropylene (70) diol.

In some embodiments, the invention provides a sorbitan fatty acid ester as at least one member selected from the group consisting of: sorbitan monolaurate, sorbitan monostearate, sorbitan monol Acid esters, sorbitan monopalmitate, sorbitan trioleate and sorbitan sesquioleate.

In some embodiments, the invention provides a glycerin fatty acid ester as at least one member selected from the group consisting of glycerol monooleate, glyceryl monostearate, decaglyceryl monooleate, decaglycerin, single laurel Acid esters of glycerol trioleate and tetraglycerol monooleate.

In some embodiments, the invention provides a composition comprising lecithin, wherein the lecithin is at least one member selected from the group consisting of: soy lecithin, enzymatically degraded soy lecithin, hydrogenated soy lecithin, and egg yolk lecithin .

In some embodiments, the present invention provides a composition comprising a polyol, wherein it may further comprise propylene glycol or glycerin.

In some embodiments, the present invention provides a composition comprising at least one member selected from the group consisting of eicosapentaenoic acid, docosahexaenoic acid, and pharmaceutically acceptable indoleamines, salts thereof, Esters and phospholipids.

In some embodiments, the present invention provides compositions containing less than 5% eicosapentaenoic acid and pharmaceutically acceptable indoleamines, salts, esters, and phospholipids thereof.

In some embodiments, the present invention provides compositions containing less than 5% docosahexaenoic acid and pharmaceutically acceptable indoleamines, salts, esters, and phospholipids thereof.

In some embodiments, the present invention provides compositions comprising ethyl eicosapentaenoate and/or ethyl docosahexaenoate.

In some embodiments, the present invention provides a composition having a total content of emulsifiers of at least 10 HLB with respect to at least one 100 parts by weight of a compound selected from the group consisting of 10 to 100 parts by weight: omega-3 Polyunsaturated fatty acids and their pharmaceutically acceptable indoleamines, salts, esters and phospholipids.

In some embodiments, the present invention provides a composition having a total content of emulsifiers of at least 10 HLB with respect to at least one 100 parts by weight of a compound selected from the group consisting of 10 to 50 parts by weight: EPA-E And/or EPA and/or its pharmaceutically acceptable indoleamines, salts, esters and phospholipids.

In some embodiments, the invention provides a serum HbA1c content of an individual equal to 6.4%, less than 6.4%, between 5.7% and 6.4%, equal to 5.6%, or less than 5.6%.

In some embodiments, the invention provides an individual having a fasting serum glucose content equal to 125 mg/dL, less than 125 mg/dL, between 100 mg/dL and 125 mg/dL, equal to 100 mg/dL or less than 100 mg/dL.

In some embodiments, the invention provides for the measurement of serum HbA1c content in an individual using a technique selected from the group consisting of: high performance liquid chromatography (HPLC); immunoassay; enzymatic analysis; colorimetric analysis; capillary electrophoresis and boric acid affinity chromatography. .

In some embodiments, the individual exhibits a serum gamma glutamine thiotransferase (GGT) content of 24 IU/L or less.

In some embodiments, the individual has no condition selected from the group consisting of alcoholic liver damage, drug-induced liver damage, chronic active hepatitis, cirrhosis, liver cancer, hepatic steatosis, and biliary tract disease.

In some embodiments, the invention provides for measuring the glucose content of an individual using a method selected from the group consisting of: FPG, RPG, and OGTT.

In some embodiments, the individual shows no obstruction or normal excretion of bile, not suffering from Liver damage, showing no liver dysfunction, showing normal levels of direct bilirubin, no biliary tract disease or individuals with early biliary tract disease.

In some embodiments, the individual has no condition selected from the group consisting of alcoholic liver injury, drug-induced liver damage, chronic active hepatitis, cirrhosis, liver cancer, hepatic steatosis, and hepatocyte apoptosis.

In some embodiments, the individual does not have liver damage, does not exhibit liver dysfunction, exhibits a sFas, M30 content or a NASH risk score corresponding to no hepatocyte apoptosis or early hepatocyte apoptosis, or does not have Hepatocyte apoptosis or early hepatocyte apoptosis.

In some embodiments, the individual consumes a diabetic diet or a Western diet.

In some embodiments, EPA-E or EPA comprises at least 40% by weight of the total fatty acids and derivatives thereof in the composition.

In some embodiments, the pharmaceutical compositions of the present invention may contain any of the EPA or EPA-E composition, comprising commercial sources, e.g. Epadel® (Mochida Pharmaceutical Co., ^{Ltd., Tokyo Japan), Lovaza TM (} Glaxo SmithKline, FL ^{USA), Omacor TM (Pronova Biopharma} ASA, Oslo Norway), Lotriga TM (Takeda Pharmaceutical Co., Osaka Japan) or Vascepa ^TM (Amarin Pharma company, NJ USA).

Incorporated by reference

All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference herein in the extent of The way to incorporate.

The novel features of the device of the present disclosure are set forth in detail in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by the following detailed description of the embodiments of the invention.

Figure 1 represents the group of patients without diabetes (including pre-diabetes) and mild diabetes. A table of the proportion of EPA-E treatment responders (NAS score ≦ 3 or at least two of the NAS components improved ≧ 2).

Figure 2 is a table representing further characterization of the patient in Figure 1. The table reflects the proportion of EPA-E treatment responders (NAS score ≦ 3 or at least two of the NAS components improved ≧ 2) in a subgroup of patients with no diabetes (including pre-diabetes) with HbA1c content = < 6.4.

Figure 3 is a table representing further characterization of the patient of Figure 1. The table reflects the fasting glucose content = <125 mg / dL without diabetes (including pre-diabetes) and the subgroup of diabetic patients responded to EPA-E (at least two of the NAS score ≦ 3 or NAS component improved ≧ 2 )proportion.

Figure 4 is a table representing further characterization of the patient of Figure 1. The chart reflects fasting glucose levels = <125 mg/dL and HbA1c content = < 6.4 in non-diabetic (including pre-diabetes) and subgroups of diabetic patients responding to EPA-E (at least NAS scores 3 or NAS components) The two have improved the ratio of ≧ 2).

Figure 5 (5-1 to 5-5) is a table of possible criteria for the evaluation of NASH for baseline scores before or after treatment.

Figure 6 is a schematic representation of experimental screening of administration at the end of a clinical trial as described herein.

Figure 7 shows the discovery of γ-glutamine thiotransferase (GGT) content. The proportion of patients in the 33 IU/L group who responded to EPA-E treatment (the NAS score ≦3 or at least two of the NAS components improved ≧2).

Fig. 8 (8-1 to 8-2) is a table showing the γ-glutaminyl transferase (GGT) content of the patient shown in Fig. 7 at the completion of the study.

Figure 9 is a table representing a further characterization of the patient shown in Figure 7. This table reflects the content of γ-glutamine thiotransferase (GGT) The NAS score of patients with 33 IU/L was improved.

Figure 10 is a table representing a further characterization of the patient shown in Figure 7. This table reflects the content of γ-glutamine thiotransferase (GGT) on day 365. The serum EPA/AA ratio was improved in 33 IU/L patients.

Figure 11 (11-1 to 11-2) corresponds to the content of γ-glutamine thiotransferase (GGT) 33 IU/L patients and γ-glutamine thiotransferase (GGT) content A table of reference values for parameters of liver function in patients of 33 IU/L.

Figure 12 is a graph representing the serum EPA/AA ratio of EPA-E administered at different doses over time.

Figure 13 represents the content of γ-glutamine thiotransferase (GGT) A chart of serum ALP for patients at 33 IU/L.

Figure 14 is a representation of a EPA-E treatment responder (NAS score ≦ 3 or NAS component) in a patient group found to have a serum content of sFas equal to or less than 9.5 ng/mL associated with NASH (1800 mg EPA-E, TID). At least the two have improved the proportion of ≧ 2).

Figure 15 (15-1 to 15-2) is a table showing the sFas content of the patient shown in Figure 1 at the completion of the study.

Figure 16 is a table representing a further characterization of the patient shown in Figure 1. This table reflects the improvement in NAS scores for patients with sFas equal to or less than 9.5 ng/mL associated with NASH (1800 mg EPA-E, TID).

Figure 17 is a graph showing the EPA-E treatment response (NAS score) in a patient group found to have a serum content of M30 (cytokeratin-18 fragment) equal to or less than 1500 U/L associated with NASH (1800 mg EPA-E, TID). At least two of the ≦3 or NAS components improve the ratio of ≧2).

Figure 18 (18-1 to 18-2) represents serum sFas associated with NASH (1800 mg EPA-E, TID and 2700 mg EPA-E, TID) equal to or less than 10.0 ng/mL and M30 equal to or less than 1500 U/L. The proportion of patients with serum levels to responders.

Figure 19 represents the proportion of patients to responders who were determined to have a NASH risk score equal to or less than 3.0 associated with NASH (1800 mg EPA-E, TID).

Figure 20 shows the parameters of hepatocyte apoptosis in patients with sFas ≦ 9.5 ng/mL. Values and tables of reference values as determined by Tamimi TI. et al., J. Hepatol., 54, 1224-1229, 2011.

Figure 21 is a graph representing the serum EPA/AA ratio of EPA-E administered at different doses over time.

Figure 22 is a table of corresponding EPA/AA ratios for patients including patients whose serum sFas content is equal to or less than 9.5 ng/mL.

I. Terminology

The terminology of the present invention is intended to be illustrative only, and is not intended to limit the compositions, methods, and devices of the present disclosure.

The term "therapeutic method" means to ameliorate, prevent or ameliorate the symptoms and/or effects associated with a condition associated with NAFLD, including steatosis (simple fatty liver), NASH, and advanced liver scar (hardening). As used herein, reference to a "treatment" of a patient is intended to include prevention.

As used herein, a "therapeutically effective amount" of a pharmaceutical or pharmaceutical composition or formulation or medicament as used herein will have the desired therapeutic effect (eg, alleviating, ameliorating, alleviating or eliminating an individual when administered to an individual having a disease or condition). The amount of a drug or agent that manifests one or more of the disease or condition. The complete therapeutic effect does not have to occur by administration of a single dose and can occur only after administration of a series of doses. Thus, one or more administrations can be administered to administer a therapeutically effective amount.

An "individual" or "patient" is a mammal (preferably a human), but may also be an animal that requires veterinary treatment, such as a companion animal (eg, a dog, a cat, and the like), a farm animal (eg, a cow, a sheep, a pig, Horses and the like) and laboratory animals (eg, rats, mice, guinea pigs, and the like).

The term "pre-diabetes" is a condition in which an individual is pre-diagnosed as having type 2 diabetes. Pre-diabetes extends the definition of glucose intolerance to include fasting blood glucose High normal range of 100 mg/dL (JB Meigs, et al. Diabetes 2003; 52: 1475-1484) and fasting hyperinsulinemia (increased plasma insulin concentration), fasting serum glucose levels between 100 mg/dL and 125 mg/dL Individuals with an HbA1c content between 5.7% and 6.4%. Position Statement entitled "The Prevention or Delay of Type 2 Diabetes" issued by the American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Diseases (Diabetes Care 2002; 25:742-749) The development of identifying pre-diabetes as the scientific and medical basis for serious health threats. Pre-diabetes may be included in the absence of diabetes as provided by the present disclosure.

The term "mild diabetes" is a condition in which an individual develops early in the development of type 2 diabetes. Diabetes extends the definition of glucose intolerance to individuals with fasting blood glucose in the high normal range of ≧126 mg/dL and/or HbA1c content ≧6.5%. Mild diabetes is not treated with diabetes, anti-diabetic agents, or diabetes that only receives one anti-diabetic agent.

The term "no diabetes" is a condition in which an individual does not exhibit glucose intolerance and includes an individual whose fasting blood glucose is within a normal range of less than 100 mg/dL or whose HbA1c content is equal to or less than 5.6%.

The term "medical nutrition therapy" is a method of treating a medical condition and its associated symptoms by using a specially conditioned diet designed and monitored by a registered dietitian. The diet is based on the patient's medical and psychological history, physical examination, functional tests, and dietary history (eg, diabetes diet, low-salt diet, low-fat diet, low-carbohydrate diet, Western diet, Oriental diet, Japanese diet, or Mediterranean diet).

The term "physical exercise" is any physical activity that enhances or maintains physical fitness and overall health and integrity. It is implemented for a variety of reasons, including intensive and cardiovascular systems, tempering exercise capacity, weight loss or maintenance, and for enjoyment purposes.

The term "HbA1c" refers to the product of non-enzymatic saccharification of the heme B chain. HbA1c value system It is determined by HbA1c (NGSP: National Glycohemoglobin Standardization Program, USA) or A1C (USA). HbA1c also includes HbA1c (JDS: Japan Diabetes Society, Japan), HbA1c (IFCC: International Federation of Clinical Chemistry, International), and Mono-S (Sweden). The conversion factor of HbA1c (NGSP) or A1C compared to each of HbA1c is shown below; HbA1c(JDS)=(0.980×(HbA1c(NGSP))−0.245, HbA1c(IFCC)=(10.93×HbA1c(NGSP) )) -23.50 and Mono-S = (1.081 × HbA1c (NGSP)) - 1.440.

Those skilled in the art are familiar with their assays. The HbA1c value is of particular importance in the monitoring of diabetes. Since its production basically depends on the blood sugar level and the life of the red blood cells, HbA1c reflects the average blood sugar level of the aforementioned 4-6 weeks in the sense of "blood sugar memory".

The term "biliary function" is any anatomical, physiological or biochemical function provided by the biliary tract in the body. The common anatomical term for the biliary system to transport bile from the liver to the small intestine (duodenum). As provided by the present disclosure, biliary function can also include secretion of bile. In addition, biliary function may also include excretion of bilirubin, a by-product of red blood cells recirculated by the liver.

The term "normal" or "substantially normal" as used for biliary function means that the bile is non-occlusive or otherwise transported. Abnormal biliary or biliary tract disorders used interchangeably herein may include, but are not limited to, biliary tract disease, biliary obstruction, reduced bile or bilirubin secretion, inability to secrete bile or bilirubin, abnormal pressure in the bile duct, Gallstones or markers associated with cirrhosis due to their abnormalities or elevations.

The term "GGT" refers to γ-glutamine thiotransferase or γ-glutamine thiotransferase (also γ-glutamine thiotransferase, GGT, GGTP, γ-GT). This enzyme catalyzes the transfer of the γ-glutamine thiol functional group of glutathione, and the glutathione is a strong antioxidant. It has been found to be the most prominent of many tissues in many tissues and is of importance as a diagnostic marker in medicine. Other evidence indicates that GGT can also act as a pro-oxidant, the digested product of glutathione "Cys- Gly" combines with metal ions to produce reactive oxygen species. Therefore, the oxidative stress can be increased while the GGT content is kept high.

The term "GGT test" refers to a common liver function test used to test the degree of activity of GGT. GGT blood test results show that the normal value is 8-78IU/L (Merck Manual Appendix II, 2001, Merck Sharp & Dohme, NJ USA), for males 2-30IU/L (Duh SH., Laboratory Reference Range Values) , 2005, Stedmans Online, Lippincott Williams & Wilkins, PA USA) or 15-85 IU/L ( General Laboratory Manual. Department of Pathology, Hackensack University Medical Centre. 2010. p. 117), and for women 1-24 IU/L (Laboratory Reference Range Values) or 5-55 IU/L ( General Laboratory Manual. Department of Pathology, Hackensack University Medical Centre. 2010. p. 117).

The terms "liver injury" or "liver disease" or "liver dysfunction" are used interchangeably and refer to any liver injury including, but not limited to, cirrhosis, liver scarring, decreased or abnormal biliary function, abnormal liver enzyme activity, liver Hardening, such as abnormal physiology, hepatic necrosis, and the like as determined by common diagnostic methods including, but not limited to, ultrasound or biopsy/tissue pathology.

The term "EPA" means any pharmaceutically acceptable indoleamine, salt, ester and phospholipid of eicosapentaenoic acid (EPA) and/or EPA or any of the EPA metabolism or the incorporation of EPA into body fluids, tissues or organs. Other forms include, but are not limited to, inorganic salts (such as sodium and potassium salts), organic salts (such as benzylamine salts and diethylamine salts), salts with basic amino acids (such as arginine and Amino acid salts, and exemplary esters include alkyl esters (eg, ethyl esters) and esters such as mono-, di-, and TG, and exemplary phospholipids (eg, phospholipid choline, phospholipid thioglycolamine, phospholipid oxime) Baseline acid, phospholipid glycerol and phospholipid creatinine). Preferred examples include ethyl ester and TG ester, and more preferably ethyl ester. More specifically, preferred examples include EPA-E, TG ester of EPA, and the like. The term "DHA" means any pharmaceutically acceptable indoleamine, salt, ester and phospholipid of docosahexaenoic acid (DHA) and/or DHA or DHA metabolizes or incorporates DHA into any other form in a body fluid, tissue or organ, including but not limited to inorganic salts (eg, sodium and potassium salts), organic salts (eg, benzylamine salts and diethylamine salts), having Salts of basic amino acids (eg, arginine and persalt), and exemplary esters include alkyl esters (eg, ethyl esters) and esters such as mono-, di-, and TG, and exemplary phospholipids ( For example, phospholipid choline, phospholipid thioglycolamine, phospholipid thioglycine, phospholipid glycerol, and phospholipid creatinine). Preferred examples include ethyl ester and TG ester, and more preferably ethyl ester. More specifically, preferred examples include ethyl docosahexaenoic acid (DHA-E), TG ester of DHA, and the like.

The term "hepatocyte apoptosis" refers to any pattern of cell death of hepatocytes. The term can be used to encompass cell death characterized by apoptosis, necrosis, programmed necrosis, autophagy, or keratinization. Hepatocyte apoptosis can be from any form of liver injury or disease (including but not limited to cancer and fatty liver disease or condition, which can further include nonalcoholic steatohepatitis (NASH), non-alcohol-related fatty liver disease, secondary Sexual NAFLD, steatosis, progressive fibrosis, liver failure, and sclerosis). As used herein, secondary NAFLD may refer to NAFLD or similar symptoms resulting from the use of one or more of the following medicines: amiodarone, antiviral drugs (eg, nucleoside analogs, aspirin or NSAID), corticosteroids, amines Methotrexate, nifedipine, perhexiline, tamozifen, tetracycline and valproic acid. Hepatocyte apoptosis is a clear pathological feature of human NASH and the amount of apoptosis present is associated with the degree of liver damage and the stage of fibrosis.

For example, "non-" or "early" for hepatocyte apoptosis refers to a benign stage in which the liver does not have cell death or cell death in the liver. Non- and early hepatocyte apoptosis can be detected and measured by any suitable means (including appropriate immunoassays, biochemical analysis, abnormal or elevated levels of markers associated with hepatocyte apoptosis (eg sFas or M30), tissue Academic studies, microscopic studies, or NASH risk scores calculated to be 3.0 or less). In some cases, no hepatocyte apoptosis or early hepatocyte apoptosis refers to a patient equal to or less than 10.0 Serum content of ng/mL sFas. In some cases, hepatocyte-free apoptosis or early hepatocyte apoptosis refers to a serum content of M30 equal to or less than 1500 U/L in a patient. In some cases, hepatocyte-free apoptosis or early hepatocyte apoptosis refers to a NASH risk score equal to or less than 3.0.

The term "sFas" refers to soluble Fas. Fas is a death receptor for the tumor necrosis factor (TNF) family and is involved in the protein of the caspase activation pathway associated with cell death. Fas can also be called Apo-1 or CD95. sFas is produced by alternate mRNA splicing or proteolysis of membrane Fas. sFas may refer to any Fas or variant thereof that is capable of binding to a Fas ligand. sFas refers to any relevant sFas that can be used for biochemical labeling as measured in serum to indicate the presence or absence of hepatocyte apoptosis in an individual.

The term "cytokeratin M30" or "M30" refers to the cytokeratin-18 fragment M30 (M30). Cytokeratin-18 is a type I cytokeratin or intermediate filament protein. M30 refers to a soluble fragment of the cleavable cytokeratin-18 protein. M30 can be produced by, for example, hepatocytes during apoptosis or cell death by any caspase. In some cases, M30 can be produced via cleavage of cytokeratin-18 by caspase-3. "M30", "M30 Fragments" or CK-18 fragments can be used interchangeably as provided herein. M30 may also be referred to as ccK18, K19-Asp396, cytokeratin 18, ccCK18 or CK18-Asp396. M30 may further refer to any relevant soluble fragment of cytokeratin-18, which may be used in biochemical labeling as measured in serum, to indicate the presence or absence of hepatocyte apoptosis in an individual.

In some cases, NASH patients may be characterized by a median plasma sFas as determined by the method of Tamimi TI. et al., J. Hepatol., 54, 1224-1229, 2011, incorporated herein by reference. 25. The 75th percentile value was 11.8 (7.8, 12.5) ng/mL and the M30 median (25th, 75th percentile) value was 598 (280, 846) U/L. Patients without NASH may be characterized by a median sFas plasma (25th, 75th percentile) value of 5.9 (4.8, 8.3) ng/mL and a median M25 (25th, 75th percentile) value of 176 (131, 224). U/L.

The term "NASH risk score" or "risk score" is calculated by the following equation Synthesis score: risk score = -6.4894 + 0.0078 × M30 (U / L) + 0.4668 × sFas (ng / mL), as quoted by Tamimi TI. et al, J. Hepatol., 54, 1224-1229, 2011 . Serum or plasma values sFas and M30 are measured in the individual and are used to calculate a risk score based on the regression equation as provided herein.

The terms "liver injury" or "liver disease" or "liver dysfunction" are used interchangeably and refer to any liver injury including, but not limited to, cirrhosis, liver scarring, decreased or abnormal biliary function, abnormal liver enzyme activity, liver Apoptosis, hardening of the liver, abnormal physiology, hepatic necrosis, and the like as determined by common diagnostic methods including, but not limited to, ultrasound or biopsy/tissue pathology.

As used herein, the singular forms "a", """," In addition, when the terms "including" ("including", "includes"), "having" ("having", "has", "with") or variations thereof are used in the detailed description and/or the scope of the application, Terms such as are intended to mean a range of inclusions in a manner similar to the term "comprising". The term "unit (U)" as used herein is intended to include not only "U" but also "International Unit (IU)".

Ranges herein may be expressed as "about" a particular value and/or to "about" another particular value. In expressing this range, another embodiment includes from that one particular value and/or to another particular value. Similarly, when values are expressed as approximations using the antecedent "about", it is understood that a particular value forms another embodiment. It is further understood that the endpoint of each range is valid in the context of the other endpoint and the other endpoint. The term "about" as used herein refers to a range of plus or minus 15% from the stated value in the context of a particular use. For example, about 10 may include a range of 8.5 to 11.5. The term "about" also contemplates typical errors or inaccuracies in the measurement of values.

The term "combination use" as used in the present invention means an embodiment in which another drug is administered when there is an effect and/or effect of one drug in a patient. In some embodiments, two The drug is also present in the patient, such as the blood of the patient. In some embodiments, another drug is administered within 24 hours after administration of the first drug. The combination of the present invention is generally conceived and is not particularly limited as long as the active ingredient is used in combination. Illustrative examples of pharmaceutical administration include, for example, (1) administration of a single preparation having two active ingredients incorporated therein; (2) by preparing separate preparations each containing different active ingredients and in producing or not Producing the two active ingredients by administering the separate preparations from the same administration route under the same combination of the two preparations; (3) by preparing separate preparations each containing different active ingredients and producing or not producing In the combination of the two formulations, the two active ingredients are administered from the same administration route at the different timings of the delay; (4) by preparing separate preparations each containing different active ingredients and The combination of the two preparations with or without the combination of the two preparations is administered simultaneously from the different administration routes (same patients in different locations) to the two active ingredients; and (5) by preparation Separate preparations of the active ingredient and the separate administration routes (same patients at different locations) from the different administration routes (with the same patient at different locations) at the different timings of the delay to administer the two separate formulations Of ingredients.

When the active ingredient is administered at different timings of the delay, the first and second components may be administered in this order or in the reverse order. When the active ingredients are administered simultaneously, if the administration route is the same, the ingredients can be mixed immediately before administration, and the active ingredients can be administered separately. The active ingredient can be used deliberately at various times for various purposes. In an exemplary embodiment, one component can be administered, and thereafter, another component can be administered while the effect of the first component is imminent or the effect of the first component is still completely present.

In another embodiment, a drug, and in particular a second component, can be administered once or twice a day by using an extended release formulation, and the other component, and in particular the first component, can be formulated by using an extended release. The object is administered two or more times, such as two or three times a day or another option, once or twice a day. When the two drugs are administered once or twice a day, and more preferably, the two drugs are administered once or twice a day or by incorporating the compounding When administered, the burden on the patient can be reduced to improve drug compliance and thereby improve prevention/improvement or therapeutic effects and reduce side effects. It is also possible to administer two drugs and abstain from one drug, while the effects of the ingredients are imminent or the effects of the ingredients are still completely present.

II. Therapeutic indications

The methods and compositions of the present invention are useful for treating individuals suffering from fatty liver-related disorders by administering an effective amount of EPA and are known or suspected to have no diabetes, pre-diabetes or mild diabetes. The methods and compositions of the present invention can also be used to treat individuals with fatty liver-related disorders by administering an effective amount of EPA and are known to have or suspected of having normal or substantially normal biliary function.

A. fatty liver disease or disease

The present disclosure provides compositions and methods for treating fatty liver diseases or conditions, which may include, but are not limited to, non-alcoholic steatohepatitis (NASH), non-alcohol-related fatty liver disease, secondary NAFLD, steatosis, progressive fibrosis, liver failure and sclerosis. As used herein, secondary NAFLD may refer to NAFLD or similar symptoms resulting from the use of one or more of the following medicines: amiodarone, antiviral drugs (eg, nucleoside analogs, aspirin or NSAID), corticosteroids, methotrexate , nifedipine, perhexiline, tamoxifen, tetracycline and valproic acid. The term fatty liver disease or disorder, as used herein, NASH may be referred to herein as NASH and is used interchangeably.

B. Diabetes

The present disclosure also provides compositions and methods for treating NASH individuals who may also have or are suspected of having no diabetes, pre-diabetes or mild diabetes. Diabetes mellitus (commonly referred to as diabetes) refers to a disease process that is derived from a variety of etiological factors and is characterized by elevated plasma glucose levels (referred to as hyperglycemia). There are two main forms of diabetes: type 1 diabetes (also known as insulin-dependent diabetes or IDDM) and type 2 diabetes (also known as non-insulin dependent diabetes or NIDDM). Type 1 diabetes is the result of an absolute deficiency of insulin (a hormone that regulates glucose utilization). Type 1 diabetes The disease has two forms: immune-mediated diabetes, which is produced by cell-mediated autoimmune destruction of beta cells of the pancreas; and idiopathic diabetes, which refers to a form of disease without known pathogens. Type 2 diabetes is characterized by a disease in which insulin resistance is accompanied by relative rather than absolute insulin deficiency. Premature atherosclerosis and increased cardiovascular and peripheral vascular disease rates are characteristic features of patients with diabetes.

Individuals referred to herein as "diabetes" may have diabetes or related conditions. Diabetes may include, but is not limited to, type 1 diabetes, type 2 diabetes, gestational diabetes (GDM), youthful diabetes (MODY), pancreatitis, polycystic ovarian disease, glucose intolerance, insulin resistance Hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, X syndrome, metabolic syndrome and related diseases, diabetic complications (including retinopathy, neuropathy, nephropathy) and sexual dysfunction . The conditions, diseases and conditions collectively referred to as "X syndrome" or metabolic syndrome (as detailed in Johanson, J. Clin. Endocrinol. Metab., 1997, 82, 727-734 and other publications) include hyperglycemia and / or pre-diabetes insulin resistance syndrome, and characterized by an initial insulin resistance state that produces hyperinsulinemia, abnormal dyslipidemia, and glucose intolerance, which may progress to characterized by hyperglycemia and may progress to diabetic complications or Type II diabetes in NAFLD.

C. biliary function

The present disclosure also provides compositions and methods for treating NASH individuals having or suspected of having normal or substantially normal biliary function. As described herein, biliary function generally refers to any function of the biliary tract in the body, including anatomical, physiological, and biochemical functions. The main function of the biliary tract is to deliver bile secreted by the liver to the small intestine. As provided by the present disclosure, biliary function can also include secretion of bile.

Bile (bile or gall) is a dark green or light yellow fluid that aids in the digestion of lipids in the small intestine. Bile is stored in the gallbladder and is expelled into the duodenum after eating. Bile contains water, bile salts, mucus and pigments, fats and inorganic salts.

Bile is used as a surfactant to help emulsify fat in food. Bile salts are amphiphilic in which the salt contains hydrophilic and hydrophobic elements. Bile can form micelles around hydrophobic molecules such as fats and fatty acids with the hydrophobic side oriented toward the hydrophobic molecule and the hydrophilic side facing outward. Bile is also used to excrete bilirubin, a by-product of red blood cells that are recirculated by the liver. It is well known that bile enhances the absorption of fatty acids in micelles and small intestines.

D. Hepatocyte apoptosis

The present disclosure also provides compositions and methods for treating NASH individuals known to have or suspected of having no hepatocyte apoptosis or early hepatocyte apoptosis. As described herein, hepatocyte apoptosis generally refers to any pattern of cell death of hepatocytes. Cell death includes mechanisms or biochemical pathways characterized by apoptosis, necrosis, programmed necrosis, autophagy or keratinization. Hepatocyte apoptosis can be from any form of liver injury or disease (including but not limited to cancer and fatty liver disease or condition, which can further include nonalcoholic steatohepatitis (NASH), non-alcohol-related fatty liver disease, secondary Sexual NAFLD, steatosis, progressive fibrosis, liver failure, and sclerosis).

i.Caspase-dependent apoptosis

In some cases, hepatocyte apoptosis can be induced by a caspase-dependent or caspase-independent pathway. Biochemically, apoptosis is usually initiated and performed by activation of intracellular caspase (a cysteine-dependent aspartate-specific protease). Like other intracellular proteases, caspase synthesis is a zymogen that must undergo proteolytic cleavage to exert proteolytic activity. Caspase has a predominantly specificity for protein acceptors containing four or five amino acid sequences containing aspartate residues in the P1 position (NH _{2 with} easy splitting bonds ₎ - Amino acids on the terminal side), which are unique features of such proteases. The caspase itself should be cleaved at the aspartate residue for activation, and thus the caspase enzyme is activated by other caspases. Such proteases can be classified as the starter caspase (which contains a long prodomain for forming a scaffold with other proteins) and an activator (effector) caspase that contains a short prodomain. The starter caspase includes caspase 2, 8, 9 and 10. The initiators caspase 8 and 10 are involved in death receptor-mediated apoptosis, whereas caspase 9 initiates apoptosis after mitochondrial dysfunction. "Executor caspase" (eg, caspase 3, 7 and 6) is activated by caspase cleavage by the aspartate residue and by cell Death receptor for apoptosis or activation of the mitochondrial pathway. These caspases can activate caspase-activated DNase (CAD) by cleavage of ICAD, an inhibitor of this enzyme. CAD activation causes DNA cleavage at the junction region of the nucleosomes of DNA, resulting in a ladder pattern of DNA cleavage that can have apoptotic features (multiplied by a 180-bp nucleosome region).

Ii. sFas in hepatocyte apoptosis

Death receptors (eg, Fas) are a subset of the TNF/neural growth factor (NGF) receptor superfamily that can act to induce apoptosis in hepatocytes. These cytokine receptors have three different regions of the type I transmembrane protein (a single transmembrane protein with extracellular NH ₂ terminus): the extracellular NH ₂ -terminal ligand interaction domain is characterized by continuous cysteamine-rich The acid repeat domain, the transmembrane region, and the intracellular COOH-terminal domain (characterized by about 60 to 80 of the "death domain" required to initiate a cytotoxic signal upon engagement by a cognate ligand) Alkyl acid segment). Some death receptors (ie, Fas (CD95/APO1), TNF-R1 (p55/CD120a), TRAIL-R1 (death receptor 4-DR4), and TRAIL-R2 (death receptor 5-DR5/APO-2/) KILLER)) is generally expressed in the liver. These receptors bind to specific ligands, most of which belong to the type II transmembrane protein of the TNF family (a single transmembrane protein with extracellular COOH terminus). The so-called non-inherent pathway that triggers apoptosis by the engagement of its corresponding ligand (such as Fas ligand (FasL) or soluble Fas ligand (sFasL)), which causes the effector caspase activation and Signaling cascade of cell death. The liver contains a high degree of death receptor expression and makes it more susceptible to excessive apoptosis in this pathway. Death receptors manifested in the liver involve various liver damages in different pathological settings.

Fas receptors are constitutively characterized by each cell type in the liver. Its ligand FasL can be expressed as a transmembrane protein on the cell surface that activates cytotoxic T lymphocytes (CTL), but it can also Soluble non-membrane binding form (sFasL) was found. Both forms of FasL (including sFasL) play a role in hepatocyte apoptosis. In some pathological conditions, sFasL can also be expressed by hepatocytes and induce sFasL to express the cell death of the cells of the hepatocytes, thereby expanding tissue damage. Kupffer cells also respond to the ingestion of apoptotic bodies (ie, pathological conditions that exacerbate hepatocyte apoptosis and liver damage and, for example, promote liver inflammation and fibrosis in fatty liver-related diseases such as NASH or NAFLD). ) Performance FasL. sFas can be expressed as alternative splice variants in response to pathological conditions (eg, NASH).

FasL binds to the pre-oligo Fas receptor on the plasma membrane to initiate a signaling cascade. FasL binds to the inducible conformational change of the receptor's intracellular domain, which, after relocalization of the receptor to lipid rafts, causes the adaptor protein FADD (Fas-associated protein with a death domain) and caspase 8 and/or 10 collection. Multiple receptors can then be recruited to lipid rafts to form larger aggregates, which are then internalized via clathrin-mediated endocytosis and delivered to the early endosomal compartment, ie, effective complex formation and death signal amplification. The steps required. This complex (containing Fas, FasL, FADD, and caspase 8) is called the Death Induction Signaling Complex (DISC), which triggers cell death.

The dysregulation of apoptosis in Fas and sFas cells is associated with several liver diseases. It is known that toxic bile acids accumulated in hepatocytes in biliary obstructive diseases induce hepatocyte apoptosis in a manner mediated by sFas. The intracellular concentration of elevated bile acids induces the translocation of Fas from the cytosol and the Golgi complex to the plasma membrane, with increased surface density favoring the initiation of oligo and apoptotic signals.

Compared with normal liver, Fas expression and hepatocyte apoptosis are elevated in the liver of NASH patients, and the sensitivity to sFasL is increased in steatosis liver, indicating that Fas-mediated cell death may be NASH and fatty liver disease. Important features. sFas has been shown to be a suitable biomarker for the evaluation of NASH disease.

Iii. Cytokeratin-M30 and sFas in hepatocyte apoptosis

Cytokeratin-18 fragment M30 (M30) is a type I cleavable during hepatocyte apoptosis Cytokeratin or intermediate filament protein. M30 refers to a soluble fragment or product of this enzymatic cleavage. M30 can be produced by the enzyme (including caspase cleavage, eg, using caspase-3) during activation of the caspase cascade pathway described herein. As mentioned in US7883904, M30 can be a suitable biomarker for hepatocyte apoptosis.

E. Evaluation criteria for individuals with NASH

Generally, any suitable method or combination of methods can be used to assess an individual's NASH. In terms of physical symptoms, NASH is usually asymptomatic until severe liver damage occurs. Patients can usually feel good early and only begin to have symptoms (eg, fatigue, weight loss, and weakness) once the disease develops or hardens. The progress of NASH can take years or even decades. This process can be stopped and in some cases reversed itself without specific therapy. In some cases, NASH can slowly deteriorate, causing scarring or "fibrosis" to occur and accumulate in the liver. When fibrosis deteriorates, hardening occurs; the liver becomes severely scarred, hardens, and does not function properly. Not everyone with NASH has a hardening, but in the presence of severe scarring or hardening, very little treatment can stop progress. People with sclerosis experience fluid retention, muscle wasting, intestinal bleeding, and liver failure. These physical symptoms in the advanced stages of the condition can be used to determine the presence or absence of NASH in an individual.

i. Health check

Due to the asymptomatic nature of the condition, particularly in the early stages of the disease, one or more techniques and methods can be used to assess the presence or absence of NASH in the individual. In some cases, a biopsy is performed on the liver where the needle skin is inserted through the skin to remove the small piece of liver. NASH was diagnosed when microscopic examination of tissues revealed obesity as well as inflammation and damage to liver cells. Simple fatty liver or NAFLD is diagnosed if the tissue shows obesity without inflammation and damage. In some cases, the biopsy may also indicate the presence or absence of scar tissue that occurs in the liver. Currently, no blood tests or scans can reliably provide this information.

Ii. Blood testing and biomarkers

Although there is no single laboratory test for NASH, various abnormal levels of liver enzymes/biological Markers and other biological blood components can be used to aid in the diagnosis of a condition. For example, in some cases, elevated serum aminotransferases can be indicative of NASH. In some cases, the amount of a plurality of suitable biomarkers can be measured using a sample derived from the individual. In some cases, adipocytokines, apoptotic markers, and/or cell death markers can be analyzed and compared to a reference level to aid in the diagnosis of NASH.

In some cases, individuals who are treated for NASH in accordance with the present invention may also be evaluated for baseline scores for the following criteria prior to treatment, and may be assessed for possible changes in their criteria after treatment. The evaluated criteria may include one or more of the following criteria described in FIG.

Iii.NAS score

In some cases, a patient or individual treating NASH in accordance with the present invention may also be assessed using a combination of standardized histological scores as known in the art. Due to the apparent differences between observers in the clinical diagnosis of NASH and the severity of the condition at a given time, a synthetic score using the histological features of the standardized NASH scoring system has been performed and can be used to provide a measure of NASH in an individual. This combined measure is called the Nonalcoholic Fatty Liver Disease Activity Score (NAS).

In some cases, the individual's NAS score can be determined prior to initiation of treatment to provide a baseline value or score for the criteria and assessed after the dosing regimen to assess any criteria improvement. In other cases, the NAS score of the individual undergoing treatment is determined. In some cases, NASH disease progression can be assessed using a comparison of NAS scores over time and NAS scores.

Nonalcoholic fatty liver disease activity score (NAS) is defined as the value of steatosis (between 0 and 3), the value of lobular inflammation (between 0 and 3) and the value of bloating (between 0 and 2) The unweighted sum of the range, thereby providing a NAS score range of o to 8. (See Kleinen et al., Design and Validation of a Histological Scoring System for Nonalcoholic Fatty Liver Disease, Hepatology, Vol. 41, No. 6, 2005, pp. 1313-1321). Patients treated with NASH in accordance with the present invention may show a pre-treatment NAS score of ≧4, with a minimum score of 1 for steatosis and lobular inflammation plus bloating, or at least 1 for sinus fibrosis and finding or suggesting steatohepatitis. In the administration / treatment After one year of treatment (for example), the patient can show a complex NAS score of ≦3, ≦2 or ≦1, and fibrosis does not deteriorate. Alternatively, the patient may display a value of at least two of the NAS components that improve the ≧2 and that the fibrosis does not deteriorate. Alternatively, the patient may display a NAS score improvement of 、3, 4, 5, 6, 7, or 8.

Iv. Fatty degeneration

Steatosis is broadly understood to address the process involved in the abnormal accumulation of lipids in the liver, which inhibits normal liver function. Liver biopsy allows analysis and scoring of steatosis in patients with scores ranging from 0 to 3. A patient having a NASH treatment according to the present invention may have a steatosis score of 1, 2 or 3, such as between about 2 and about 3. After treatment, it is expected that the patient will show that the steatosis does not deteriorate, or that the steatosis score is reduced by at least 1 or the steatosis score is reduced by 2 or 3. Steatosis is traditionally graded as follows: a score of 1 indicates the presence of fat droplets in less than 33% of hepatocytes, a score of 2 indicates that fat droplets are observed in 33-66% of hepatocytes, and a score of 3 indicates greater than 66% of liver Fat droplets were observed in the cells. (See Kleinen et al., Design and Validation of a Histological Scoring System for Nonalcoholic Fatty Liver Disease, Hepatology, Vol. 41, No. 6, 2005, pp. 1313-1321).

V. lobular inflammation

The lobular inflammation was also assessed after liver biopsy and scored with a value of 0-3. (See Kleinen et al., Design and Validation of a Histological Scoring System for Nonalcoholic Fatty Liver Disease, Hepatology, Vol. 41, No. 6, 2005, pp. 1313-1321, Table 1). The lobular inflammatory score of a patient who is to be treated for NASH can be 1, 2 or 3, or between 1 and 2 or between 2 and 3. After treatment, the patient's lobular inflammatory score may be reduced by at least 1, or the lobular inflammatory score may be reduced by 2 or 3, and the lobular inflammatory score will at least not deteriorate.

Inflation

Hepatocyte bloating is usually scored using a value of 0-2 (see Kleinen et al., Design and Validation of a Histological Scoring System for Nonalcoholic Fatty Liver Disease, Hepatology, Vol. 41, No. 6, 2005, pp. 1313-1321, Table 1), and the flatness score of a patient treated with NASH according to the present invention may be 0. -2, including a specific value of 1 or 2, or a score in the range of 1 to 2. After treatment, the patient may show that the bloating score does not deteriorate at least, or that the bloating score is reduced by at least one value, or that the bloating score is decreased by two.

Vii. Fibrosis stage

Fibrosis was also assessed after liver biopsy and scored using a value of 0-4. The score was defined as: 0 for no fibrosis, 1 for sinus or peripheral fibrosis, 1a for mild zone 3 sinus fibrosis, and 1b for Moderate zone 3 sinus periplasmic fibrosis; 1c represents anal/peripheral fibrosis; 2 represents sinus perianth and anal/peripheral fibrosis; 3 represents bridging fibrosis; and 4 represents sclerosis. (See Kleinen et al., Design and Validation of a Histological Scoring System for Nonalcoholic Fatty Liver Disease, Hepatology, Vol. 41, No. 6, 2005, pp. 1313-1321). The fibrotic stage score of a patient treated according to the present invention may be 0-3, including 0, 1, 1a, 1b, 1c, 2 or 3, and the fibrosis stage score may be at least 1a. After treatment, the patient's fibrosis stage score may be at least not worse than the baseline score, or the fibrosis stage score may be reduced by at least 1 value, or at least 2 or 3 values.

F. NASH Individual Diabetes Assessment Criteria

As described herein, the methods and compositions of the present invention can be used to treat a condition associated with fatty liver and a known or suspected diabetes-free, pre-diabetic or mildly diabetic individual by administering an effective amount of EPA. The presence or absence of diabetes, pre-diabetes or mild diabetes in an individual can be determined using any suitable method known in the art. In general, a better test for diabetes in NASH patients can be characterized by two groups: a test based on serum glucose and glycated proteins. Tests based on serum glucose can include, but are not limited to, tests such as fasting plasma glucose (FPG), random plasma glucose (RPG), and oral glucose tolerance test (OGTT). Testing for glycated proteins can include, but is not limited to, measuring proteins Test (eg HbA1c). In some cases, one or more tests can be used to determine the presence or absence of diabetes, pre-diabetes, or mild diabetes. In some cases, a combination of tests can be used to assess diabetes in a NASH individual.

i. Fasting plasma glucose (FPG)

The FPG test is a simple plasma glucose measurement obtained after a fasting of at least 8 hours (usually overnight fasting). This test can be used to screen and diagnose diabetes in NASH individuals due to convenience, cost, and risk factors. The ADA test was selected for the diagnosis of both FPG pre-diabetes and diabetes. In the direct comparison, FPG had better intra-individual reproducibility of plasma glucose 2 hours after loading, with an intra-individual coefficient of 6.41.41% for FPG of 14.3-16.7% for 2 hours of plasma glucose.

FPG can be a reliable predictor of diabetic complications for the current threshold of diagnosis, and has emphasized many current knowledge of the pathology of diabetes in the FPG study. However, as is known in the art, the threshold of pre-diabetes and its relationship to complications can vary between individuals or groups of individuals. This article describes the general range of FPGs used to evaluate non-diabetic, pre-diabetes or mild diabetes.

Ii. Random plasma glucose (RPG)

RPG (or "random" plasma glucose) measurements can be readily obtained from NASH individuals without the need for fasting and are typically included in the basal metabolomes arranged for other purposes. The RPG test measures diabetes, and the generally accepted RPG threshold is 200 mg/dl, as well as symptoms of polyuria, polydipsia, and unexplained weight loss to indicate a second test for confirming the diagnosis. RPG at 140-199 mg/dl indicates pre-diabetes. Based on the diagnosis by OGTT, RPG 200 mg/dl is not sensitive, but has a specificity close to 100%.

The overall utility of RPG as a test tool is that there is no direct comparison of its ratio to diabetes-specific complications. For this reason, the RPG test can be used to test symptomatic NASH individuals with high specificity at any time, quickly.

Iii. Oral glucose tolerance test (OGTT)

The glucose replacement test can also include an oral glucose tolerance test. In some cases, it is a better test for the diagnosis of diabetes. Regarding the diagnosis of diabetes, OGTT identified about 2% more individuals than FPG, and OGTT has poor reproducibility compared to other glucose-based tests such as HbA1c (NGSP) or A1C.

The HbA1c test is known in the industry as a standardized measurement of diabetes diagnosis, which is now widely used for research and clinical purposes and can be used to determine the presence or absence of diabetes, pre-diabetes or mild diabetes in NASH individuals. The main practical advantage is that it can be obtained in both fasting and non-fasting states, and it represents the average glucose control over a period of months rather than a single point value. The ADA recommends this test as a one-line test for screening and diagnosis. At about the same time, the International Expert Committee released a diagnostic HbA1c content for diabetes. 6.5% of the form is recommended.

The HbA1c content can be measured using any suitable biochemical technique. Such techniques can include, but are not limited to, high performance liquid chromatography (HPLC); immunoassays; enzyme assays; colorimetric assays; capillary electrophoresis and boric acid affinity chromatography.

Regarding the glucose-based test, there is no finite threshold for HbA1c with normal termination and beginning of diabetes. The International Committee of Experts has chosen to recommend a specific cut-off point for the diagnosis of diabetes. Note that this will "balance the individual's erroneous identification of the stigma and cost of diabetes and the minimum clinical outcome of delayed diagnosis of HbA1c levels <6.5%."

Iv. Assessing the general threshold of diabetes

The recommended tests for screening are the same as those used for the diagnosis. The result is a positive screening equivalent to the diagnosis of mild diabetes, pre-diabetes or diabetes. The term "pre-diabetes" is assigned to those who are considered to be at higher risk of developing diabetes. In some cases, pre-diabetes is diagnosed by having one or both of the following: 1 ) FPG of 100-125 mg/dl, also known as fasting glucose deficiency (IFG), 2 ) 2 hours of 75-g OGTT, The 2-hour plasma glucose content was 140-199 mg/dl, which is also described as IGT. To get a diagnosis of diabetes, patients should meet one of the following criteria: 1 ) Symptoms of diabetes (polyuria, polydipsia, and unexplained weight loss) and RPG 200mg/dl, 2 ) FPG 126 mg/dl, or 3 ) 2 hours plasma glucose level during 75-g OGTT 200mg/dl. HbA1c results An additional 6.5% of the diagnostic criteria may also indicate pre-diabetes or mild diabetes. Individuals with mild diabetes may have values that are or are similar to the thresholds as described herein.

As already stated herein, the term "pre-diabetes" in the present invention extends the definition of glucose intolerance to include a fasting blood glucose level within a high normal range of ≧100 mg/dL (JB Meigs et al. Diabetes 2003; 52: 1475-1484). And individuals with fasting hyperinsulinemia (increased plasma insulin concentration) or HbA1c levels between 5.7% and 6.4%.

The term "mild diabetes" extends the definition of glucose intolerance to include fasting blood glucose in the high normal range of ≧126 mg/dL and/or HbA1c content ≧6.5% and no treatment for diabetes, antidiabetic agents or only one antibiotic. Individuals of diabetes agents.

The term "no diabetes" is a condition in which an individual does not exhibit glucose intolerance and includes an individual whose fasting blood glucose is within a normal range of less than 100 mg/dL or whose HbA1c content is equal to or less than 5.6%.

In some cases, where the NASH individual can be pre-diabetic or mildly diabetic, the NASH individual can undergo treatment or receive an anti-diabetic agent. In some cases, NASH individuals may have a Western diet that may include foods that are heavy carbohydrates and fats. In other instances, a NASH individual may take a diabetic diet, which may include a lower carbohydrate diet. In some instances, a NASH individual can receive only one or an anti-diabetic agent or a combination with a pharmaceutical composition of the present disclosure. In some cases, anti-diabetes can be administered concurrently with the pharmaceutical composition. In some cases, the pharmaceutical composition is administered after the NASH individual receives one or more anti-diabetic agents.

Anti-diabetic agent

In some cases, as NASH, an individual may receive one or more anti-diabetic agents, which may include: a PPAR gamma agonist, such as glitazone (eg, WAY-120, 744, AD 5075, paglitazone ( Balaglitazone), ciglitazone, darglitazone (CP-86325, Pfizer), englitazone (CP-68722, Pfizer), isaculate (isaglitazone) (MIT) / J & J), MCC- 555 (Mitsibishi, disclosed in U.S. Pat. No. 5,594,016), pioglitazone (of pioglitazone) (e.g., Actos ^(TM) pioglitazone; Takeda), rosiglitazone ^{(rosiglitazone) (Avandia TM; Smith} Kline Beecham), Rosiglitazone maleate, troglitazone (Rezulin®, disclosed in U.S. Patent No. 4,572,912), rivoglitazone (CS-011, Sankyo), GL-262570 (Glaxo Welcome) ), BRL49653 (disclosed in WO98/05331), CLX-0921, 5-BTZD, GW-0207, LG-100641, JJT-501 (JPNT/P&U), L-895645 (Merck), R 119702 (Sankyo/Pfizer ), NN-2344 (Dr. Reddy/NN), YM-440 (Yamanouchi), LY-300512, LY-519818, R483 (Roche), T131 (Tularik), and the like. In some embodiments, the possessive based rosiglitazone pioglitazone, rosiglitazone or troglitazone.

In some cases, anti-diabetic agents may include biguanides, such as metformin hydrochloride (metformin hydrochloride) (N, N- dimethyl-biguanide hydrochloride, e.g. ^{Glucophage TM, Bristol-Myers Squibb)} ; metformin hydrochloride with glyburide ( glyburide), e.g. ^{Glucovance TM, Bristol-Myers Squibb)} ; buformin (buformin) (N- butyl - biguanide); by Tuo Fuming (etoformine) (1- butyl-2-ethyl-biguanide, Schering AG); Other metformin salt forms (including those wherein the salt is selected from the group consisting of acetate, benzoate, citrate, fumarate, pamoate, chlorophenoxyacetate, glycolate, Palmitate, aspartate, methanesulfonate, maleate, p-chlorophenoxyisobutyrate, formate, lactate, succinate, sulfate, tartrate, cyclohexane Formate, hexanoate, octanoate, citrate, palmate, octadecanoate, benzenesulfonate, trimethoxybenzoate, p-toluenesulfonate, adamantanecarboxylic acid Salt, glyoxylate, glutamate, pyrrolidone formate, naphthalene sulfonate, 1-gluconate phosphate, lemon Acid salts, sulfites, dithionates and phosphates) and phenformin; bile acid sequestrants including, but not limited to, cholestyramine (ie, QUESTRAN®, QUESTRAN LIGHT®, CHOLYBAR® , CA registration number 11041-12-6), colesevelam (ie, WELCHOL®, CA registration numbers 182815-43-6 and 182815-44-7), colestipol (ie, COLESTID) ®, CA registration numbers 50925-79-6 and 37296-80-3), sevelamer, cross-linked polydextrose dialkylaminoalkyl derivatives, LOCHOLEST®, DEAE-Sephadex (SECHOLEX® , POLIDEXIDEL®), water-soluble derivatives (eg 3,3-ioene, N-(cycloalkyl)alkylamines and poliglusam), insoluble quaternary ammonium Polystyrenes, saponins, and mixtures thereof, and their bile acid sequestrants (including pharmaceutically acceptable salts or mixtures thereof) as disclosed in WO 97/11345, WO 98/57652, U.S. Patent No. 3,692,895, and U.S. Patent No. 5,703,188. ). Suitable inorganic cholesterol chelating agents include barium strontium sulphate plus smectite clay, aluminum hydroxide and calcium carbonate sulphuric acid. In some embodiments, the biguanide is metformin hydrochloride, metformin hydrochloride, and glibenclamide, butyl guanidine or etomifin. In some embodiments, the bile acid sequestrant used is a dialkylaminoalkyl derivative of cholestyramine, colestipol or cross-linked polydextrose, and DEAE-Sephadex.

In some cases, the anti-diabetic agent may comprise a protein tyrosine phosphatase-1B (PTP-1B) inhibitor, such as A-401, 674, KR 61639, OC-060062, OC-83839, OC-297962, MC52445, MC52453, ISIS 113715 and their disclosures in WO 99/585521, WO 99/58518, WO 99/58522, WO 99/61435, WO 03/032916, WO 03/032982, WO 03/041729, WO 03/055883, WO 02/26707, WO 02/26743, JP 2002114768 and Pharmaceutically acceptable salts and esters; sulfonylureas, such as acetohexamide (eg, Dymelor, Eli Lilly), carbutamide, chlorpropamide ( For example, Diabinese®, Pfizer), gliamilide (Pfizer), gliclazide (eg, Diamcron, Servier Canada), glimepiride (eg, disclosed in US patents) No. 4,379,785, for example Amaryl ^TM, Aventis), Glenn pentyl urea (glipentide), glipizide (glipizide) (e.g., Glucotrol or Glucotrol XL Extended Release, Pfizer), gliquidone (gliquidone), Glenn Glisolamide, glibenclamide (eg, Mic) Ronase or Glynase Prestab, Pharmacia & Upjohn and Diabeta, Aventis), tolazamide (e.g., Tolinase), and tolbutamide (e.g., Orinase) and pharmaceutically acceptable salts and esters thereof.

In some cases, the anti-diabetic agent may comprise meglitinide, such as repaglinide (eg, Pranidin®, Novo Nordisk), KAD1229 (PF/Kissei), mitiglinide (eg Glufast®, Kissei) And nateglinide (eg, Starlix®, Novartis) and pharmaceutically acceptable salts and esters thereof; in some cases, the anti-diabetic agent may comprise an alpha glucoside hydrolase inhibitor (or a glucoside inhibitor), e.g. acarbose (acarbose) (e.g., Precose ^TM, Bayer, disclosed in the U.S. Patent No. 4,904,769), miglitol (miglitol,) (e.g. Glyset ^TM, Pharmacia & Upjohn, disclosed in U.S. Patent No. 4,639,436 of ), caliglibose (methyl 6-deoxy-6-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)hexahydropyridine ]]-α-D-glucopyranoside, Marion Merrell Dow), voglibose (Takeda), lipolytic, emiglitate, pradimicin- Q), salbostatin, CKD-711, MDL-25, 637, MDL-73, 945 and MOR 14 and the like. For example, the alpha glucoside hydrolase inhibitor is acarbose, voglibose or miglitol.

In some cases, the anti-diabetic agent may comprise an insulin secretagogue such as linogliride, A-4166, forskilin, dibutyl decyl cAMP, isobutylmethylxanthine (IBMX), and pharmaceuticals thereof. Acceptable salts and esters, fatty acid oxidation Formulations (e.g., clomoxir and etomoxir, and pharmaceutically acceptable salts and esters thereof).

In some cases, the anti-diabetic agent may comprise an A2 antagonist, such as midaglizole, isaglidole, deriglidole, idazoxan, orroxan. And fluparoxan and its pharmaceutically acceptable salts and esters.

In some cases, the anti-diabetic agent may comprise insulin and related compounds (eg, insulin mimetics), such as biota, LP-100, novarapid, insulin detemir, deuterium. Insulin (lisulin lispro), insulin glargine, insulin zinc suspension (slow and ultra slow), Lys-Pro insulin, GLP-1 (1-36) guanamine, GLP-1 (73-7) ( Insulinotropic hormones, disclosed in U.S. Patent No. 5,614,492), LY-315902 (Lilly), GLP-1 (7-36)-NH2), AL-401 (autoimmune), as disclosed in U.S. Patent No. 4,579,730 U.S. Patent No. 4,849, 405, U.S. Patent No. 4,963,526, U.S. Patent No. 5,642,868, U.S. Patent No. 5,763,396, U.S. Patent No. 5,824,638, U.S. Patent No. 5,843,866, U.S. Patent No. 6,153,632, U.S. Patent No. 6,191,105, and WO Certain compositions of 85/05029, and primates, rodent or rabbit insulin (including biologically active variants thereof, including allelic variants), human insulin obtainable in recombinant form (source of human insulin) Including medicine And sterile by the formulation, such as their self Eli Lilly (Indianapolis, Ind.46285) to Humulin ^TM (insulin human rDNA origin) who also see the Physician's Desk Reference, 55th edition Supplement (2001) Medical Economics, Thomson Healthcare (discovering other suitable human insulin).

In some cases, the anti-diabetic agent may comprise a PPAR dual agonist and pharmaceutically acceptable salts and esters thereof; a PPAR alpha/gamma dual agonist, such as AR-HO39242 (Astrazeneca), GW- 409544 (Glaxo-Wellcome), BVT-142 (Biovitrum), CLX-0940, GW-1536 (Glaxo-Wellcome), GW-1929 (Glaxo-Wellcome), GW-2433 (Glaxo-Wellcome), KRP-297 (Kyorin) Merck; 5-[(2,4-dioxaoxythiazolidinyl)methyl]methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide), L -796449, LR-90, LY-578 (lilly), LY-4655608 (lilly), LSN-862, LY-510929 (lilly), LY-929 (lilly), DRF4158 (Dr Reddys), MK-0767 (Merck /Kyorin/Banyu), SB 219994 (SmithKline Beecham), muralgliatazar (BMS), tesaglitzar (Astrazeneca), reglitazar (JT-501, JTT) -501), farglitazar (GW-2570/GI-262579), aleglitazar (Roche), saroglitazar (Zydus) and the like; PPARα/δ double Agonists such as GFT505 (Genfit), TIPP401 (Okayama University), and the like.

In some cases, the anti-diabetic agent may comprise an SGLT2 inhibitor, such as canagliflozin (Mitsubishi Tanabe, TA-7284), dapagliflozin (Astrazeneca), and Luseogliflozin ( Taisho, TS-071), tofogliflozin (Kowa, CSG452), empagliflozin (Boehringer-Ingelheim, Lilly, BI-10773), ipragliflozin (Astellas, ASP1941) ), BI44847 (Boehringer-Ingelheim, Ajinomoto), LX-4211 (Lexicon), DSP-3235/GSK1614235 (Glaxo SmithKline, Dainippon Sumitomo, Kissei), ISIS 388626 (Isis), sergliflozin (Glaxo SmithKline), Remogliflozin (Glaxo SmithKline) and the like.

In some cases, the anti-diabetic agent may comprise a GSK 3β/GSK 3 inhibitor, such as 4-[2-(2-bromophenyl)-4-(4-fluorophenyl-1H-imidazo-1-5-yl) Pyridine and the like.

In some cases, the anti-diabetic agent may comprise a dipeptidyl peptidase IV (DPP-IV) inhibitor (eg, sitagliptin, vildagliptin, alogliptin) (alogliptin), linagliptin and saxagliptin, sucrose-like peptide 1 derivative reagents (eg exenatide, lixisenatide and lira) Liraglutide or peptide (including amlintide and Symlin® (pramlintide acetate).

Evaluation criteria for gallbladder function in G.NASH individuals

As described herein, the methods and compositions of the present invention can be used to treat a condition associated with fatty liver and an individual known or suspected of having no diabetes, having pre-diabetes or mild diabetes by administering an effective amount of EPA. The presence or absence of normal or substantially normal biliary function in an individual can be determined using any suitable method known in the art. In general, better tests for biliary function in NASH patients can be characterized by two groups: physiological based tests and biochemical based tests. Physiological-based tests may include, but are not limited to, abdominal ultrasound, abdominal CT scan, retrograde endoscopic cholangiopancreatography (ECRP), percutaneous transhepatic cholangiography (PTCA), or magnetic resonance cholangiopancreatography ( MRCP). Biochemical-based tests can include, but are not limited to, GGT testing, liver function testing, bilirubin testing, alkaline phosphatase (ALP) testing, liver enzyme testing, amylase blood testing, lipase blood testing, prothrombin Time and urine bilirubin measurements. In some cases, one or more tests can be used to characterize bile function. In some cases, a combination of tests can be used to evaluate the bile function of a NASH individual.

i. Physiological testing

Typically, physiological tests (examples of which are provided herein) provide visualization of the bile duct, which can aid in the diagnosis of obstruction. For example, if gallstones are present, they can cause obstruction or partial obstruction of the bile duct and visualize the presence of gallstones. In some cases, visualization is achieved using X-rays (PTCA or Abdominal CT), Magnetic Resonance (MRCRP), or Ultrasound. In some cases, direct blocking may not be visualized. In some cases, such methods may indicate secondary effects of bile duct stenosis or obstruction. These tests can also assist in assessing the bile function of NASH individuals.

Ii. GGT test

The GGT test is a common liver function enzyme test that measures the activity of the enzyme GGT. GGT blood test results show that the normal value is 8-78IU/L (Merck Manual Appendix II), for males 2-30IU/L (Laboratory Reference Range Values) or 15-85IU/L ( General Laboratory Manual. Department of Pathology , Hackensack University Medical Centre. 2010. p. 117), and for women 1-24 IU/L (Laboratory Reference Range Values) or 5-55 IU/L ( General Laboratory Manual. Department of Pathology, Hackensack University Medical Centre. 2010 Page 117).

In some cases, elevated serum GGT activity may be indicative of diseases of the liver, biliary system, and pancreas. In this regard, it is similar to the alkaline phosphatase (ALP) test, as described herein in the detection of biliary tract diseases. Both ALP and GGT can be used as biochemical indicators of potential liver disease, but GGT testing often provides increased sensitivity. A slightly elevated serum GGT may also be associated with cardiovascular disease in NASH individuals. GGT can accumulate in atherosclerotic plaques and can circulate in the blood in the form of different protein aggregates, some of which can indicate specific conditions, such as metabolic syndrome, alcohol addiction, and chronic liver disease. A high body mass index (BMI) can be associated with type 2 diabetic individuals with high serum GGT. GGT content testing can be used alone or in combination with other tests to assess biliary function in NASH individuals.

Iii. ALP test

The ALP test is a common liver function enzyme test that measures the activity of the enzyme ALP. The normal range is 36-92 IU/L (Merck Manual Appendix II) or 20-140 IU/L ( General Laboratory Manual. Department of Pathology, Hackensack University Medical Centre. 2010. p. 117). High ALP levels can indicate biliary obstruction. The content is significantly higher in children and pregnant women.

Iv. Other biochemical based tests

In general, any suitable biochemical test can be used to evaluate the biliary function of NASH individuals. can. In some cases, testing can be used to assess bile function as part of a standard liver function group. In some cases, the bilirubin test can be used to evaluate bile function. One or more tests can be used to evaluate bile function in a combination test as provided herein.

Iv. General threshold for assessing bile function

The tests recommended for screening are the same as those used for the diagnosis. The result is a positive screening equivalent to the diagnosis of normal or substantially normal bile function. In this case, normal or substantially normal can also include individuals at risk of biliary disease. In some cases, the biliary tract disease is diagnosed by having one or both of the following: 1 ) GGT is equal to or exceeds 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35 40, 45, 50, 55, 60 or 78 IU/L or male GGT content equal to or less than 30 or 85 IU/L and female GGT content equal to or less than 24 or 55 IU/L, 2 ) ALP test equals or exceeds 92 or 140 IU/L. In order to obtain a diagnosis of abnormal biliary function, the patient should meet one of the following criteria: 1 ) Symptoms of biliary tract disease (ie biliary stricture or obstruction, weight loss, abdominal pain) and abnormal levels of GGT or ALP. Additional diagnostic criteria for one or more of these indicators may also indicate abnormal biliary function. In some cases, biliary tract disease is diagnosed by having serum direct bilirubin equal to or greater than 0.3 or 0.4. Individuals with early biliary tract disease may have values that are or are similar to the thresholds as described herein.

D. Evaluation criteria for hepatocyte apoptosis in NASH individuals

As described herein, the methods and compositions of the present invention can be used to treat conditions associated with fatty liver and known or suspected to be non-hepatocytes by administering an effective amount of ethyl eicosapentaenoic acid (EPA-E). Apoptosis or an individual known or suspected of having apoptosis in early hepatocytes. The presence or absence of hepatocyte-free apoptosis or early hepatocyte apoptosis in an individual can be determined using any suitable method known in the art. In general, better tests for hepatocyte apoptosis or early hepatocyte apoptosis in NASH patients can be characterized by two groups: physiological based tests and biochemical based tests. Physiological-based tests may include, but are not limited to, abdominal ultrasound, abdominal CT scan, retrograde endoscopic cholangiopancreatography (ECRP), and percutaneous transhepatic cholangiography (PTCA) or magnetic resonance cholangiopancreatography (MRCP). Biochemical based tests may include, but are not limited to, serum content measurements of sFas and M30, liver function tests, liver enzyme tests or as provided by Tamimi TI. et al., J. Hepatol., 54, 1224-1229, 2011. Complex NASH risk score. In some cases, one or more tests can be used to characterize hepatocyte apoptosis. In some cases, a combination of tests can be used to assess hepatocyte apoptosis in NASH individuals.

i. Physiological testing

In general, physiological tests (examples provided herein) provide visualization of the liver, which can aid in the diagnosis of hepatocyte apoptosis. For example, if apoptosis is present, a histological sample can be taken to visualize the tissue. In some cases, visualization is achieved using differential staining (eg, using hematoxylin and eosin stains). Other stains specific for death or positive dead cells can also be used to visualize hepatocyte apoptosis. In some cases, fluorescent microscopy can also be used to visualize apoptotic cells. In some cases, visualization of other histological or cellular indicators (eg, elevated lysosomes) may also be used to assess hepatocyte apoptosis.

Ii.sFas measurement

In some cases, sFas can be used as a biochemical marker to assess hepatocyte apoptosis. In some cases, sFas is measured as a protein in serum or plasma of an individual with or suspected of having NASH. The blood test results of sFas indicate that the content of the individual having no hepatocyte apoptosis or having early hepatocyte apoptosis is equal to or less than 10.0 ng/mL, and the preferred content is equal to or less than 9.5 ng/mL.

In some cases, elevated serum or plasma sFas levels may be indicative of liver disease and hepatocyte apoptosis. Increased sFas may also be associated with cardiovascular disease in NASH individuals. sFas can be circulated and can indicate specific conditions such as metabolic syndrome, alcohol addiction, and chronic liver disease. A high body mass index (BMI) can be associated with individuals with type 2 diabetes who have high sFas. The sFas content test can be used alone or in combination with other tests to assess hepatocyte apoptosis in NASH individuals.

Generally, any suitable means for assessing the sFas content can be used. In some cases, sFas can be determined using any suitable biochemical assay including, but not limited to, immunoassays, ELISA, Western blotting, PCR, activity assays, binding assays, chromatography, spectroscopy, mass spectrometry, and the like.

For example, sFas can be measured by any non-commercial or commercial kit. Commercial kits may include, but are not limited to, Quantikine Human soluble Fas kit (R&D Systems, Minneapolis, MN), sFas ELISA kit (Orient Yeast, Osaka, Japan), Human Soluble Fas Ligand ELISA kit (Kamiya Biomedical, Seattle, WA) or FAS Ligand (Soluble) Human ELISA kit (Invitrogen, Camarillo, CA). The concentration of sFas in the sample can usually be expressed in ng/ml (ng/mL) or picogram/ml (pg/mL).

By comparing the value of hepatocyte apoptosis with a predetermined value, the analytical content of sFas can be correlated with liver damage and/or progression of liver disease. In one aspect of the invention, the predetermined value can be based on sFas in a comparative sample obtained from a selected population of a general population or a human individual. For example, a selection population can include individuals who are clearly healthy. In other words, if examined by a medical professional, the individuals may be characterized by healthy and liver-free symptoms.

Iii. Measurement of M30

In some cases, M30 can be used as a biochemical marker to assess hepatocyte apoptosis. In some instances, the M30 is measured as a protein in serum or plasma of an individual having or suspected of having NASH. The blood test result of M30 indicates that the content of the individual having no hepatocyte apoptosis or having early hepatocyte apoptosis is equal to or less than 1500 U/L, preferably the content is equal to or less than 900 U/L, and more preferably the content is equal to or less than 500 U/ L.

In some cases, elevated serum or plasma M30 levels may be indicative of liver disease and hepatocyte apoptosis. It can also be seen that elevated M30 fragments are associated with cardiovascular disease in NASH individuals. M30 is recyclable and can indicate specific conditions (eg, metabolic syndrome, alcohol addiction, and chronic liver disease). High body mass index (BMI) can be associated with type 2 diabetes with high serum M30 content Body related. The M30 content test can be used alone or in combination with other tests to assess hepatocyte apoptosis in NASH individuals.

Generally, any suitable means for assessing the M30 content can be used. In some cases, M30 can be determined using any suitable biochemical assay including, but not limited to, immunoassays, ELISA, Western blotting, PCR, activity assays, binding assays, chromatography, spectroscopy, mass spectrometry, and the like.

For example, the M30 can be measured by any non-commercial or commercial kit. Commercial kits can include, but are not limited to, M30-Apoptosense ELISA (Peviva, Bromma, Sweden) or human cytokeratin 18-M30, CK 18-M30 ELISA kit (Cusabio, Newark, DE).

In some cases, M30 can be detected and/or quantified using an immunoassay, such as an enzyme-linked immunosorbent assay (ELISA). In an ELISA, an antibody specific for a particular antigen is used to detect the presence of a particular molecule or to measure the amount of a particular molecule. For example, an M30-APOPTOSENSE (PEVIVA, Grünwald, Germany) ELISA can be used to detect the presence or amount of a CK-18 fragment produced by caspase 3 or to measure its amount or amount. The APOPTOSENSE assay uses the M30 antibody, which recognizes the antibody binding site in the C-terminal domain of CK-18, the C-terminal domain of CK-18 in the CK-18 cysteine after the aspartate residue 396 The winter enzyme (eg, caspase 3) is exposed after cleavage. A mouse monoclonal antibody against the M30 anti-system IgG2b subtype used in the APOPTOSENSE assay.

An ELISA typically comprises the steps of contacting a sample taken from an individual with one or more antibodies and subsequently analyzing the formation of a complex between the antibody and the protein or peptide in the sample. For ease of detection, the antibody can be attached to a substrate (eg, a column, a plastic disk, a substrate, or a membrane (eg, nitrocellulose)). The sample may be untreated, subjected to precipitation, fractionation, separation or purification, and then combined with the antibody. APOPTOSENSE analysis is, for example, a solid phase two-site immunoabsorption assay. In some cases, body samples (such as blood serum) can be combined with mouse monoclonal antibody M5 (for CK-18 and fixed to polystyrene pores) and horseradish peroxidase. M30 monoclonal antibody reaction. After formation of the solid phase/antigen/labeled antibody core, excess unbound conjugate can be removed by a washing step. It should be noted that the APOPTOSENSE assay can also be used in combination with the M65 ELISA (PEVIVA, Grünwald, Germany) measuring total CK-18. Combining the two analyses allowed calculation of the relative fraction of CK-18 for caspase cleavage.

In an ELISA, the interaction between one or more antibodies and a protein or peptide fragment in a sample is detected by radiometric, colorimetric or fluorescent means, size separation or precipitation. In one example, the antibody-protein or peptide complex is detected by the addition of a secondary antibody that is coupled to a detectable tag (eg, an enzyme, fluorophore, or chromophore). In the present invention, a tetramethyl-benzidine substrate can be added to the analysis and the color development is directly proportional to the bound analyte. Color development can then be stopped and the color intensity measured at 450 nm in a microplate reader. The amount of CK-18 fragment that produces caspase 3 in a body sample can be calculated by plotting a standard curve of the measured absorbance from a known concentration. The concentration of the M30 fragment in the sample can be expressed in units per liter (U/L).

Additional analysis can be used to detect and/or quantify the M30 fragment in the body sample. Such additional assays may include other immunoassays, such as immunoassays using antibodies disclosed in U.S. Patent Nos. 6,296,850, 6,716,968, 6,706,488, and 7,883,904, all of which are incorporated herein by reference. Into this article. Other immunoassays that detect antibodies using CK-18 can be used to detect CK-18 fragments. Such assays may include radioimmunoassays (both solid and liquid), fluorescence-linked assays, and competitive immunoassays, as well as other assays (eg, mass spectrometry (MS) based methods (eg, liquid chromatography MS) And electrospray ionization MS)). The MS based method can be used to detect and/or quantify the amount of the M30 fragment as, for example, the parent molecule, i.e., the undissociated M30 fragment molecule will have a different quality than the M30 fragment. In addition, methods such as HPLC can also be used to detect the presence of the M30 fragment due to different mother-daughter ion transitions following cleavage of CK-18 by caspase 3. Thus, the difference in charge and polarity between the cleaved and uncleaved CK-18 proteins has a high probability of showing different residence times on HPLC.

By comparing the value of hepatocyte apoptosis with a predetermined value, the analytical content of M30 can be associated with liver damage. And/or related to liver disease progression. In one aspect of the invention, the predetermined value can be based on the amount of Ck-18 fragment (eg, IU/L) in the comparative sample obtained from a selected population of the general population or human individual. For example, a selection population can include individuals who are clearly healthy. In other words, if examined by a medical professional, the individuals may be characterized by healthy and liver-free symptoms.

Iv. Additional biochemical based testing

Generally, any suitable biochemical test for assessing hepatocyte apoptosis in a NASH individual can be used. In some cases, the test can be used to assess hepatocyte apoptosis as part of a standard liver function group. In some cases, lysosomal enzymes (β-galactosidase, β-glucuronidase, cell autolysin C, and cellular autolysin) present in a sample (eg, liver tissue) can be assayed. The ratio of B) evaluates the state of lysosomes. Can also measure caspase 3 activity (DEVDase) or measure sulfite cytochrome c reductase (an enzyme located in the mitochondrial membrane space and released in hepatocytes on the apoptotic pathway) ) Monitoring apoptosis. In general, any protein, gene or biomarker known to be involved in cell death or apoptosis related pathways of hepatocytes can be used to assess hepatocyte apoptosis.

Iv. General threshold for assessing hepatocyte apoptosis

The recommended tests for screening are the same as those used for the diagnosis. The result is a positive screening equivalent to the diagnosis of no hepatocyte apoptosis or early hepatocyte apoptosis. In this case, hepatocyte-free apoptosis or early hepatocyte apoptosis may also include individuals at risk of no hepatocyte apoptosis or early hepatocyte apoptosis. In some cases, hepatocyte-free apoptosis or early hepatocyte apoptosis is diagnosed by having one or both of the following: 1 ) sFas content is equal to or less than at least 10.0, 9.9, 9.8, 9.7, 9.6, 9.5, 9.4 , 9.3, 9.2, 9.1, 9.0, 8.9, 8.8, 8.7, 8.6, 8.5, 8.4, 8.3, 8.2, 8.1 or 8.0 ng/mL or sFas content equal to or less than at most 10.0, 9.9, 9.8, 9.7, 9.6, 9.5, 9.4, 9.3, 9.2, 9.1, 9.0, 8.9, 8.8, 8.7, 8.6, 8.5, 8.4, 8.3, 8.2, 8.1, or 8.0 ng/mL; 2 ) M30 content is equal to or less than at least 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600 or 500 U/L or M30 content equal to or less than at most 1500, 1400, 1300, 1200, 1100, 1000, 900, 800, 700, 600 or 500 U/L; NASH risk score equals Or less than at least 3.0, 2.9, 2.859, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1 or 2.0 or a NASH risk score equal to or less than at most 3.0, 2.9, 2.859, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1 or 2.0. In some cases, in order to obtain a diagnosis of hepatocyte-free apoptosis or early hepatocyte apoptosis, patients may also meet one of the following criteria: 1 ) symptoms of hepatocyte apoptosis (ie histological visualization, cirrhosis or Other clinical symptoms associated with liver damage) and sFas or M30 content correspond to no hepatocyte apoptosis or early hepatocyte apoptosis. Additional diagnostic criteria for one or more of these indicators may also indicate abnormal biliary hepatocyte apoptosis. Individuals with early hepatocyte apoptosis may have values that are or are similar to the thresholds as described herein.

III. Pharmaceutical Composition A. Composition containing EPA

Eicosapentaenoic acid (EPA) is known as an omega-3 polyunsaturated long chain fatty acid. A component of an omega-3 fatty acid oil such as fish oil. A variety of commercially available products are advocated for containing omega-3 fatty acids or salts, esters, phospholipids, derivatives, combinations thereof, and the like. Eicosapentaenoic acid (EPA) is also known in the form of its ethyl ester (i.e., ethyl eicosapentaenoate (EPA-E)). According to the present invention, EPA (including but not limited to EPA or EPA-E) can be administered in the composition. The EPA content in the total fatty acid of the composition of the present invention is not particularly limited as long as the composition contains EPA as its effective component and the desired effect of the present invention is obtained, and high purity EPA is preferably used.

The present invention may be self-contained comprising a total of 50% by weight to 95% by weight of EPA, preferably a total of 60% by weight or more, more preferably 90% by weight or more, and still more preferably 96.5% by weight or more of fatty acids and derivatives thereof. Emulsion composition. In some cases, the pharmaceutical composition can comprise a total of at least about 40%, 46%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% of the fatty acid and its derivatives. %, 95%, 96%, 96.5% or 98% EPA. In some cases, the pharmaceutical composition may comprise up to about a total of fatty acids and derivatives thereof. 40%, 46%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 96.5% or 98% EPA. EPA can be administered to patients in highly purified form, including products called Epadel® (Mochida Pharmaceutical Ltd., Tokyo Japan) and their pharmaceutically acceptable indoleamines, salts, esters and phospholipids.

The EPA used in the present invention may be synthetic, semi-synthetic, natural EPA or a natural oil containing the EPA. Examples of natural EPA include extracts of natural oils containing EPA produced by methods known in the art, crude purified natural oils containing EPA, and highly purified natural oils containing EPA. Exemplary semi-synthetic EPAs include EPA produced by microorganisms or the like and EPA or natural EPA subjected to chemical treatment (eg, esterification or transesterification).

B. Formulations

In some embodiments, the omega-3 fatty acid is formulated as a self-emulsifying composition. The self-emulsifying composition of the present invention preferably has at least one of the following effects: excellent self-emulsifying properties for the patient, excellent dispersibility in the composition, excellent emulsion stability, excellent storage stability, excellent absorption properties (and specific For example, excellent absorption properties and rate under fasting) and excellent convenience or compliance, so that the composition can exhibit the pharmacological effects of EPA. In some cases, the EPA may have an emulsifier having an HLB of at least 10 from 5 wt% to 50 wt%.

In some cases, the pharmaceutical compositions can comprise at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50% emulsifiers. In some cases, the pharmaceutical compositions can comprise up to about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50% emulsifiers. The self-emulsifying composition contains no ethanol or a low ethanol content. The invention also provides a medicament for the self-emulsifying composition, a method for producing the same, and a method of using the same.

Examples of pharmaceutically acceptable salts of EPA include inorganic salts (such as sodium and potassium salts), organic salts (such as benzylamine salts and diethylamine salts), salts with basic amino acids (such as arginine). Salts and persalts), and exemplary esters include alkyl esters (e.g., ethyl esters) and esters such as mono-, di-, and TG. Preferred examples include ethyl ester and TG ester, and more preferably ethyl ester. More specifically, preferred examples include EPA-E, TG ester of EPA, and the like.

The EPA used as the starting material of the self-emulsifying composition of the present invention is not particularly limited in its purity. The purity generally makes the total EPA content of the fatty acid and its derivative in the composition of the present invention preferably at least 40% by weight, 45% by weight, 46.5% by weight, 50% by weight, 51% by weight, 52% by weight, and 53% by weight. 54% by weight, 55% by weight, 56% by weight, 57% by weight, 58% by weight, 59% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, more preferably at least 80% by weight, still more Preferably at least 85% by weight, still more preferably at least 90% by weight, and most preferably at least 96.5% by weight. EPA containing high purity EPA and DHA (for example, (EPA + DHA) relative to EPA is a total of at least 50%, 555%, 60%, 65%, 70% by weight of the fatty acid and its derivatives 75% by weight, 80% by weight, 85% by weight), and more preferably in a total amount of at least 90% by weight of the fatty acid and its derivative, still more preferably at least 96.5% by weight of the fatty acid and its derivative, And preferably a total of at least 98% by weight of the fatty acid and its derivatives. In other words, the composition of the invention preferably has a high purity EPA in the total fatty acids.

For example, when using EPA-E and DHA-E, the composition ratio of EPA-E/DHA-E and the content of (EPA-E+DHA-E) relative to the total fatty acid are not specifically limited as long as the combination of the present invention The purity of EPA in the product may be within the range as described above. However, the composition ratio of EPA-E/DHA-E is preferably at least 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.5, more preferably at least 2.0, and most preferably at least 2.5.

The composition of the present invention may also contain omega-3 polyunsaturated fatty acids other than EPA and DHA, such as DPA, hexadecatrienoic acid (HTA), alpha-linolenic acid (ALA), eicosatrienoic acid (ETE). ), stearidonic acid (SDA), arachidonic acid (ETA), docosapentaenoic acid (HPA), docosapentaenoic acid (TPA) or docosahexaenoene Acid (THA) or a pharmaceutically acceptable indoleamine, salt or ester thereof. However, the content of the omega-3 polyunsaturated fatty acid other than EPA and DHA is preferably lower, more preferably less than 60% by weight, 55% by weight, 50% by weight, 45% by weight, 40% by weight, 35% by weight, 30%. % by weight, 25% by weight, 20% by weight, 15% by weight, 10% by weight, 5% by weight, 4% by weight, 3% by weight, 2% by weight, still more preferably less than 1% by weight weight%. The compositions of the present invention may also contain omega-6 polyunsaturated fatty acids other than EPA, such as linoleic acid, gamma linolenic acid, or dihomo-gamma-linolenic acid or a pharmaceutically acceptable indoleamine, salt or ester thereof. However, the content of the omega-6 polyunsaturated fatty acid is preferably lower, more preferably less than 5% by weight, 4% by weight, 3% by weight, 2% by weight, 1% by weight and 0.5% by weight, still more preferably less than 0.2% by weight. . Specifically, the content of arachidonic acid or a pharmaceutically acceptable salt or ester is preferably lower than the total fatty acid and its derivative, more preferably less than 2% by weight, 1% by weight, 0.5% by weight, 0.2% by weight, 0.1% by weight, still more preferably less than 0.05% by weight, and optimally, the composition is substantially free of arachidonic acid or a pharmaceutically acceptable salt or ester.

In some embodiments, the compositions of the present invention comprise EPA and DPA, or EPA, DPA, and HPA, or EPA, DPA, and TPA, or EPA, DPA, HPA, and TPA. Preferred EPA: DPA ratio is between 99:1 and 1:99, between 90:1 and 1:90, between 60:1 and 1:60, between 40:1 and 1: Between 40, between 30:1 and 1:30, between 20:1 and 1:20, between 10:1 and 1:10, between 5:1 and 1:5 Between and between 2:1 and 1:2.

In some embodiments, the compositions of the present invention comprise EPA, DHA, and DPA, or EPA, DHA, DPA, and HPA, or EPA, DHA, DPA, and TPA, or EPA, DHA, DPA, HPA, and TPA. Preferably DHA: DPA ratio does not exceed 1:100, does not exceed 1:95, does not exceed 1/90, does not exceed 1:80, does not exceed 1/70, does not exceed 1:60, does not exceed 1:50, does not exceed 1:40, no more than 1:30, no more than 1:20, no more than 1:10, no more than 1:5, no more than 1:2, no more than 1:1, no more than 2:1, no more than 5: 1. No more than 10:1, no more than 20:1, no more than 50:1 and no more than 100:1.

The EPA-E used in the compositions or therapeutic agents of the present invention contains impurities, such as saturated fatty acids and arachidonic acid, which are detrimental to cardiovascular events at lower levels compared to fish oil or fish oil concentrates, and this enables Achieve the desired effect without causing problems with excessive nutrients or vitamin A intake. When EPA-E is used in the form of an ester, a sufficiently stable composition can be obtained by adding a conventional antioxidant, since the ester forms a fish which is mainly in the form of TG. The oil has a high oxidative stability.

Purified fish oil can also be used in EPA, and the use of EPA monoglycerides, diglycerides and TG derivatives, and combinations thereof, are also preferred embodiments. EPA variety of commercially available products contain, for ^{example, Incromega TM DHA27, Incromega TM DHA46} , Incromega TM DHA700E, Incromega TM DHA700TG, Incromega TM DHA500TG, Incromega TM E400200, Incromega TM E4030, Incromega TM E4520, Incromega TM E460180, Incromega TM E5020 ^{, Incromega TM E530200, Incromega TM E6814} , Incromega TM E1050, Incromega TM E1070, Incromega TM E3322, Incromega TM E3525, Incromega TM E3826, Incromega TM E7010, Incromega TM EPA500EE, Incromega TM EPA500TG, Incromega TM EPA700E, Incromega TM TGO525, Incromega ^{TM TG1040, Incromega TM TG1050, Incromega} TM TG3322, Incromega TM TG3322SR, Incromega TM TG4030, Incromega TM TG6015, Incromega TM TG7010, Incromega TM TrioEE and ^{Incromega TM Trio EE (Croda International PLC} , Yorkshire, England) and EPAX6500EE, EPAX6015TG, EPAX6015EE EPAX6000TG, EPAX6000EE, EPAX6000TGN, EPAX6000FA, EPAX5500EE, EPAX5000TG, EPAX4510TG, EPAX4020TG, EPAX4020EE, EPAX2050TG, EPAX7010EE, EPAX1050TG, EPAX1050TGN, K85TG, K85EE and K80EE (FMC, Philadelphia, USA). Such products are commercially available and used in the compositions of the present invention.

In the present invention, "polyoxyethylene hydrogenated castor oil" is preferably a compound obtained by addition polymerization of ethylene oxide and hydrogenated castor oil, which is a castor oil to which hydrogen is added. Various compounds having different average degrees of polymerization of ethylene oxide are commercially available, and examples include polyoxyethylene (20) hydrogenated castor oil (NIKKOL HCO-20, Nikko Chemicals Co., Ltd.), polyoxyethylene (40) hydrogenated castor oil. (NIKKOL HCO-40, Nikko Chemicals Co., Ltd., polyoxyethylene (50) hydrogenated castor oil (NIKKOL HCO-50, Nikko Chemicals Co., Ltd.), polyoxyethylene (60) hydrogenated castor oil (NIKKOL HCO-60, Nikko Chemicals Co., Ltd.) and polyoxyethylene (100) Hydrogenated castor oil (NIKKOL HCO-100, Nikko Chemicals Co., Ltd.), and preferably polyoxyethylene (60) hydrogenated castor oil. These polyoxyethylene hydrogenated castor oils may be used singly or in combination of two or more kinds thereof. In the present invention, "polyoxyethylene hydrogenated castor oil" includes all such compounds unless otherwise stated.

In the present invention, "polyoxyethylene sorbitan fatty acid ester" is a polyoxyethylene ether of a fatty acid ester in which a part of a hydroxyl group of anhydrous sorbitol is esterified with a fatty acid. Various compounds having different esterified fatty acids are commercially available, and examples include polyoxyethylene (20) sorbitan monolaurate (NIKKOL TL-10, Nikko Chemicals Co., Ltd.), polyoxyethylene (20) sorbitol single. Palmitate (NIKKOL TP-10V, Nikko Chemicals Co., Ltd.), polyoxyethylene (20) sorbitan monostearate (NIKKOL TS-10V, Nikko Chemicals Co., Ltd.), polyoxyethylene (20) sorbitan Tristearate (NIKKOL TS-30V, Nikko Chemicals Co., Ltd.), polyoxyethylene (20) sorbitan monoisostearate (NIKKOL TI-10V, Nikko Chemicals Co., Ltd.), polyoxyethylene (20) Sorbitan monooleate (NIKKOL TO-10V, Nikko Chemicals Co., Ltd.) and polyoxyethylene (20) sorbitan trioleate (NIKKOL TO-30V, Nikko Chemicals Co., Ltd.), and preferably condensed Oxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate and polyoxyethylene (20) sorbitol An anhydride monooleate, and more preferably a polyoxyethylene (20) sorbitan monooleate. These polyoxyethylene sorbitan fatty acid esters may be used singly or in combination of two or more thereof. In the present invention, "polyoxyethylene sorbitan fatty acid ester" includes all unless otherwise specified. These compounds.

In the present invention, "polyoxyethylene castor oil" is a compound obtained by addition polymerization of ethylene oxide and castor oil. Various compounds with different average ethylene oxide moles Commercially available, and examples include Kolliphor EL (BASF), Kolliphor EL-P (BASF), NIKKOL CO-3 with an average ethylene oxide molar number of 3 (Nikko Chemicals Co., Ltd.), and average ethylene oxide mole Number 10 of NIKKOL CO-10 (Nikko Chemicals Co., Ltd.), EMALEX C-20 (Nippon Emulsion Co., Ltd.) with an average number of ethylene oxide moieties of 20, and EMALEX C with an average number of ethylene oxide moieties of 30 -30 (Nippon Emulsion Co., Ltd.), EMALEX C-40 (Nippon Emulsion Co., Ltd.) with an average ethylene oxide molar number of 40, and EMALEX C-50 with an average ethylene oxide molar number of 50 (Nippon Emulsion Limited) the company). These materials may be used singly or in combination of two or more kinds thereof. In the present invention, "polyoxyethylene castor oil" includes all such compounds unless otherwise stated.

In the present invention, the "polyethylene glycol fatty acid ester" is a fatty acid ester of polyethylene glycol which is a fatty acid polymerized with ethylene oxide. Various compounds having different esterified fatty acids are commercially available, and examples include polyethylene glycol monolaurate (NIKKOL MYL-10, Nikko Chemicals Co., Ltd.), polyethylene glycol monostearate (NIKKOL MYS-10V, MYS-25V, MYS-40V, NYS-45V and MYS-55V, Nikko Chemicals Co., Ltd.), polyethylene glycol monooleate (NIKKOL MYO-6 and MYO-10, Nikko Chemicals Co., Ltd.), polyethylene glycol Distearate (NIKKOL CDS-6000P, Nikko Chemicals Co., Ltd.) and polyethylene glycol diisostearate (NIKKOL CDIS-400, Nikko Chemicals Co., Ltd.). These materials may be used singly or in combination of two or more kinds thereof. In the present invention, "polyethylene glycol fatty acid ester" includes all such compounds unless otherwise stated.

In the present invention, the "polyoxyethylene polyoxypropylene diol" is a compound obtained by addition polymerization of ethylene oxide and polypropylene glycol, and polypropylene glycol-based polymerization propylene oxide. Various compounds having different average degrees of polymerization of propylene oxide and ethylene oxide are commercially available, and examples include polyoxyethylene (3) polyoxypropylene (17) diol (Adeka Pluronic L-31, ADEKA), polyoxygen Ethylene (20) polyoxypropylene (20) diol (Adeka Pluronic L-44, ADEKA), polyoxyethylene B Alkene (42) polyoxypropylene (67) diol (Adeka Pluronic P-123, ADEKA), polyoxyethylene (54) polyoxypropylene (39) diol (Newdet PE-85, Sanyo Chemical Industries Co., Ltd.), poly Oxyethylene (105) polyoxypropylene (5) diol (PEP101, Sanyo Chemical Industries Co., Ltd.), polyoxyethylene (120) polyoxypropylene (40) diol (Adeka Pluronic F-87, ADEKA), polyoxyethylene (160) Polyoxypropylene (30) diol (Adeka Pluronic F-68, ADEKA), polyoxyethylene (196) polyoxypropylene (67) diol (Lutrol F127, BASF Japan) and polyoxyethylene (200) Oxypropylene (70) diol, and more preferably polyoxyethylene (105) polyoxypropylene (5) diol. These materials may be used singly or in combination of two or more kinds thereof. In the present invention, "polyoxyethylene polyoxypropylene diol" includes all such compounds unless otherwise stated.

In the present invention, "sucrose fatty acid ester" is an ester of a sugar and a fatty acid. Various compounds having different types of esterified fatty acids and degrees of esterification are commercially available, and examples include Surfhope SE PHARMA J-1216 (Mitsubishi-Kagaku Foods) containing 95% lauric acid in fatty acids and 95% myristic acid in fatty acids. Surfhope SE PHARMA J-1416 (Mitsubishi-Kagaku Foods), Surfhope SE PHARMA J-1615 and J-1616 (Mitsubishi-Kagaku Foods) with 80% palmitic acid in fatty acids, 70% stearic acid in fatty acids J-1811, J-1815 and J-1816 (Mitsubishi-Kagaku roods) and Surfhope SE PHARMA J-1715 containing 70% oleic acid in fatty acids, which may be used singly or in combination of two or more. "Sucrose fatty acid ester" as used in the present invention includes all such compounds.

The emulsifier added to the self-emulsifying composition of the present invention may have an HLB of at least 10, preferably at least 11 and more preferably at least 12.

The total content of the emulsifier having at least 10 HLB in the self-emulsifying composition of the present invention is not particularly limited as long as it is at least 10 parts by weight based on 100 parts by weight of the EPA. The content is usually 10 to 100 parts by weight, preferably 10 to 80 parts by weight, and more preferably 10 to 50 parts by weight, per 100 parts by weight of EPA.

In the present invention, "sorbitan fatty acid ester" is an ester of anhydrous sorbitol and a fatty acid. Various compounds having different types of esterified fatty acids and degrees of esterification are commercially available, and examples include sorbitan monolaurate (NIKKOL SL-10, Nikko Chemicals Co., Ltd.), sorbitan monostearate (NIKKOL). SS-10MV, Nikko Chemicals Co., Ltd.), sorbitan monooleate (NIKKOL SO-10V, Nikko Chemicals Co., Ltd.), sorbitan monopalmitate (NIKKOL SP-10V, Nikko Chemicals Co., Ltd.), sorbitol Anhydride trioleate (NIKKOL SO-30, Nikko Chemicals Co., Ltd.) and sorbitan sesquioleate (NIKKOL SO-15MV, Nikko Chemicals Co., Ltd.).

In the present invention, the "glycerin fatty acid ester" is an ester of monoglycerin or polyglycerin and a fatty acid. Various compounds having different types of esterified fatty acids and degrees of esterification are commercially available, and examples include glycerol monooleate (PECEOL), glyceryl monostearate (NIKKOL MGS-F50SEV, Nikko Chemicals Co., Ltd.), decaglycerin Monooleate (NIKKOL Decaglyn 1-OV, Nikko Chemicals Co., Ltd.), decaglyceryl monolaurate (NIKKOL Decaglyn 1-L, Nikko Chemicals Co., Ltd.), decyl trioleate (NIKKOL Decaglyn 3-OV, Nikko) Chemicals Co., Ltd.) and tetraglycerol monooleate (NIKKOL Tetraglyn 1-OV, Nikko Chemicals Co., Ltd.).

In the present invention, "lecithin" is a class of glycerophospholipids, and examples include soy lecithin, enzymatically decomposed soy lecithin, hydrogenated soy lecithin, egg yolk lecithin, hydrogenated phospholipids, phospholipids derived from milk, lysolecithin, phospholipids Mercaptocholine and phospholipid thioglycolic acid. Preferred are soybean lecithin, enzymatically decomposed soy lecithin, hydrogenated soy lecithin and egg yolk lecithin, and more preferably soy lecithin. These materials may be used singly or in combination of two or more kinds thereof. In the present invention, "lecithin" includes all such compounds unless otherwise stated.

Commercially available products include purified soy lecithin (Nisshin Oilio), purified egg yolk lecithin (Asahi Kasei Pharma), and egg yolk lecithin PL-100M (Kewpie), and This product can be used.

In the present invention, the "polyol" is a polyol compound having a structure of a linear or cyclic aliphatic hydrocarbon in which two or more carbon atoms are each substituted with one hydroxyl group. Such exemplary polyols include divalent alcohols such as ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butanediol, tetramethylene glycol, 1,3-butanediol, 2,3 - butanediol and pentamethylene glycol; trivalent alcohols (such as glycerol, trimethylolpropane and 1,2,6-hexanetriol) and polyol polymers (such as diethylene glycol, dipropylene glycol) , triethylene glycol, polyethylene glycol, polypropylene glycol and polyglycerol), and preferably propylene glycol or glycerin. In the present invention, "polyol" includes all such compounds unless otherwise stated.

The total amount of lecithin and/or polyol added to the self-emulsifiable composition of the present invention is not specifically limited. However, the total amount of lecithin and/or polyol is usually from 0 to 50 parts by weight, preferably from 3 to 40 parts by weight, and more preferably from 5 to 30 parts by weight, relative to 100 parts by weight of EPA-E.

The amount of ethanol used in the self-emulsifying composition of the present invention preferably does not cause a change in quality during the process of encapsulation, distribution or storage, and the amount does not cause a change in the content of the capsule, and the amount does not exceed the upper limit of the daily dose as the drug. . The ethanol content is usually up to 10% by weight, preferably up to 4% by weight, more preferably up to 1% by weight, still more preferably up to 0.5% by weight, still more preferably up to 0.2% by weight, still more preferably up to 0.1% by weight and most preferably 0% by weight ( No ethanol was added).

The preferred ethanol concentration can be adequately determined by considering the EPA-E concentration and daily dose in the self-emulsifying composition. When the self-emulsifying composition of the present invention is orally administered in a daily dose of 1800 mg in terms of EPA-E and, for example, the preparation contains 75% by weight of EPA-E, when the ethanol content does not exceed 0.135 wt%, it will not exceed " The maximum daily dose of 3.26 mg as described in Dictionary of Drug Additives (Japanese).

A preferred embodiment of the self-emulsifying composition of the present invention containing such EPA and emulsifier is a combination of EPA and/or DHA with at least one emulsifier selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene Sorbitan fatty acid ester, polyoxyethylene castor oil, sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, and lecithin. In this hair When the self-emulsifiable composition is used as a food (for example, a special purpose food, a functional health food, and a health food), it is preferably a combination of EPA and/or DHA and sucrose fatty acid ester and/or lecithin, which has a food as a food. Good results for additives. When sucrose fatty acid esters are used, preferred amounts are from 1% by weight to 20% by weight, more preferably from 4% by weight to 20% by weight and most preferably from 4% by weight to 10% by weight of the self-emulsified composition. The preferred embodiment is a combination of EPA with polyoxyethylene (50) hydrogenated castor oil or polyoxyethylene (60) hydrogenated castor oil; a combination of EPA and polyoxyethylene (20) sorbitan monooleate; EPA and poly a combination of oxyethylene castor oil; and a combination of EPA and sucrose fatty acid ester J-1216 or J-1816.

Also preferred are further combinations with lecithin (e.g., soy lecithin) and/or polyol (e.g., propylene glycol).

When the emulsifier is at least one member selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene castor oil, the polyol is preferably a diol, and propylene glycol is used. good. When the emulsifier is a sucrose fatty acid ester, the polyol is preferably a triol, and glycerin is more preferably used.

Preferably, the compositions and therapeutic agents of the invention are substantially free of water. "Substantially free of water" means that the water content is at most 10% by weight. When the total amount of the self-emulsifiable composition is 100% by weight, the amount of water used is preferably from 0.5% by weight to 6% by weight, more preferably from 0.5% by weight to 4% by weight, still more preferably from 0.5% by weight to 3% by weight, and Optimum 1% to 3% by weight.

The self-emulsifying composition of the present invention may also contain additives such as emulsifying aids, stabilizers, bactericides, surfactants, and antioxidants. Exemplary emulsification aids include fatty acids having from 12 to 22 carbon atoms such as stearic acid, oleic acid, linoleic acid, palmitic acid, linolenic acid, and myristic acid and salts thereof. Exemplary stabilizers include phosphatidic acid, ascorbic acid, glycerin, and cetyl alcohol, and exemplary bactericides include ethyl p-oxybenzoate and propyl p-oxybenzoate. Exemplary surfactants include sucrose fatty acid esters having less than 10 HLB, sorbitan fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl groups. Ether, polyoxyethylene fatty acid ester, polyoxyethylene alkylphenyl Ether and polyoxyethylene polyoxypropylene alkyl ether. Exemplary antioxidants include oil soluble antioxidants such as butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, propyl gallate, pharmaceutically acceptable guanidine, astaxanthin and alpha - Tocopherol.

In addition, sufficient carriers or mediators, colorants, flavoring agents, and optionally vegetable oils or additives (such as non-toxic organic solvents or non-toxic solubilizing agents (such as glycerin)), emulsifiers, suspending agents (such as Tween), which are commonly used in the industry, can be sufficiently combined. 80 and gum arabic solution), isotonic agents, pH adjusting agents, stabilizers, flavoring agents, flavoring agents, preservatives, antioxidants or absorption enhancers to prepare suitable pharmaceutical preparations.

More specifically, since EPA is highly unsaturated, it is preferred to incorporate an effective amount of an oil-soluble antioxidant into the composition (for example, at least one selected from the group consisting of butylated hydroxytoluene, butylated hydroxyanisole, gallic acid C) Ester, propyl gallate, pharmaceutically acceptable guanidine, astaxanthin and members of alpha-tocopherol). The storage temperature is preferably room temperature, and storage storage is preferably avoided, since freezing may result in self-emulsifying properties, dispersibility in the composition, or loss of emulsion stability.

The self-emulsifying composition of the present invention can be obtained by mixing EPA, emulsifier having at least 10 HLB, sorbitan fatty acid ester or glycerin fatty acid ester under optional heating, and optionally adding components (for example, lecithin, polyol) , water and antioxidants) are produced in dissolved components.

In some cases, the pharmaceutical composition may comprise additional elements, which may include, but are not limited to, antihypertensive agents, such as angiotensin II receptor blockers, such as irbesartan, olmesartan medoxomil (olmesartan medoxomil), candesartan cilexetil, telmisartan, valsartan, and losartan potassium; vasoconstrictor-converting enzyme inhibitors such as Arap Alicepril, imidapril hydrochloride, enalapril maleate, captopril, quinapril hydrochloride, cilazapril (quinapril hydrochloride) Ciladapril) hydrate, temocapril hydrochloride, depalril hydrochloride, group Trandolapril, benazepril hydrochloride, perindopril and lisinopril hydrate; calcium antagonists such as azelnidipine, benzenesulfonic acid Amlodipine, aranidipine, efenidipine hydrochloride, cilnidipine, nicardipine hydrochloride, nifedipine, nimodipine, nitrendipine, nilvadipine , barnidipine hydrochloride, felodipine, benidipine and manidipine; alpha receptor blockers such as tolazoline and phentol Phentolamine; beta blockers, such as atenolol, metoprolol, acebutolol, propranolol, guanolol ( Pindolol), carvedilol and labetalol hydrochloride; receptor stimulants such as clonidine and methyldopa; and diuretics such as eple Epleenone, hydrochlorothi Azide) and furosemide.

In some cases, a pharmaceutical composition can include additional elements, which can include, but are not limited to, an anti-diabetic agent as described herein.

In some cases, the pharmaceutical composition may contain additional elements, which may include, but are not limited to, vitamins such as ascorbic acid (vitamin C), tocopherol (vitamin E), and tocopherol nicotinate and N-ethylcysteine cysteamine. Acid, probucol.

In some cases, the pharmaceutical composition may contain additional elements, which may include, but are not limited to, blood flow improvers such as aspirin, cilostazol, ticlopidine hydrochloride, alprostadil (alprostadil), limaprost, beraprost sodium, sarpogrelate hydrochloride, argatroban, naftidrofuryl, isoxsuprine hydrochloride, baqu Enzyme (batroxobin), hydrogen methalin mesylate, tolazoline hydrochloride, hepronicate and shimotsu-to extract.

In some cases, the pharmaceutical composition may include additional elements, which may include (but are not limited to a bile acid derivative, optionally as a farnesoid X receptor (FXR) ligand, such as ursodeoxycholic acid, chenodeoxycholic acid, obeticholic acid, GW4064 , bile powder, deoxycholic acid, bile acid, bile extract, bear bile, bezoar and dehydrocholic acid. Preferred examples also include biotin (vitamin B7), cyanocobalamin (vitamin B12), pantothenic acid (vitamin B5), folic acid (vitamin B9), thiamine (vitamin B1), vitamin A, vitamin D, vitamins. K, tyrosine, pyridoxine (vitamin B6), branched chain amino acids (such as leucine, isoleucine and valine), calcium, iron, zinc, copper and magnesium. Other examples include designated health foods and functional nutraceuticals (eg, soy protein, chitosan, low molecular weight sodium alginate, dietary fiber from psyllium husk, bound phospholipids, phytosterol esters, plant stanol esters, A component used in dimercaptoglycerol, globin degradation product, and soybean olein of tea catechin.

C. Administration and dosage

It can be used in the present disclosure to include the composition comprises EPA EPA composition of commercially available (e.g. above ^{Epadel®, Lovaza TM, Omacor TM,} Lotriga TM or Vascepa ^TM) or the developing composition (e.g. Epanova ^TM (Omthera, Astrazeneca), or MAT9001 (Matinas Biopharma)). The composition comprising EPA can be administered in the form of a lozenge, capsule, powder or any other solid oral dosage form, in liquid form, in the form of a soft gel capsule or other capsule, or other dosage form suitable and convenient for administration to a patient in need thereof. The compositions may also include pharmaceutically acceptable excipients known to those skilled in the art, including surfactants, oils, cosolvents or combinations of such excipients, and Stabilizers, emulsifiers, preservatives, solubilizers and/or other inactive pharmaceutical ingredients known to those skilled in the art.

The dosage and duration of EPA used in the self-emulsifying composition of the present invention are sufficient to achieve the desired dosage and period of time, which may depend on the route of administration, the frequency of daily administration, the severity of the symptoms, the weight, age, and other factors. Adjustment.

The compositions of the invention may be administered to a patient orally, rectally or vaginally. However, suffering from The oral administration can be preferably carried out by oral administration, and in the case where the patient undergoes dialysis or the patient suffers from ingestion, the composition can gel by gelatinizing the composition by gelatin or the like. Formulation form is administered.

The above mentioned effects (ie, therapeutic or prophylactic treatment), the nature of the disease to be treated or prevented, the condition of the patient, body weight, age, sex and the like are suitably determined as the active ingredients mentioned above. The dose of the composition. The methods and sequences of administration that are desirable in practice depend on the purpose of the administration (ie, therapeutic or prophylactic treatment), the nature of the condition to be treated or prevented, the condition of the patient, weight, age, sex, and the like. The preferred methods and sequences for the administration of the compounds set forth herein in the context of the present invention are suitably selected by those skilled in the art using the present specification and the common techniques and information contained in the field of the invention.

In the case of oral administration, in the case of EPA, the composition may be from 0.05 g/day to 10 g/day, from 0.1 g/day to 5 g/day, from 0.2 g/day to 4 g/day, from 0.3 g/day to 3 g/ Day, 0.4g/day to 2g/day, 0.5g/day to 1g/day, preferably 0.2g/day to 4g/day, 0.3g/day to 3.6g/day, 0.6g/day to 2.7g/day , 0.9 g / day to 1.8 g / day, more preferably 0.3 g / day to 3.0 g / day, 0.5 g / day to 2.5 g / day, 1.0 g / day to 2.0 g / day and the best 0.6 g / day to A dose of 2.7 g/day, 0.9 g/day to 1.8 g/day is administered in 1 to 3 divided doses. In the case of oral administration, in the case of EPA, the composition may be 0.1 g/day, 0.3 g/day, 0.5 gg/day, 0.6 g/day, 0.9 g/day, 1.0 g/day, 1.2 g/day. , 1.5 g / day, 1.8 g / day, 2.0 g / day, 2.1 g / day, 2.4 g / day, 2.5 g / day, 2.7 g / day, 3.0 g / day, 3.3 g / day, 3.5 g / day 3.6 g/day, 3.9 g/day, 4.0 g/day, 4.2 g/day, 4.5 g/day, 4.8 g/day, 5.0 g/day, 5.1 g/day, 5.4 g/day, 5.5 g/day , 5.7 g / day, 6.0 g / day, 6.3 g / day, 6.5 g / day, 6.6 g / day, 6.9 g / day, 7.0 g / day, 7.2 g / day, 7.5 g / day, 7.8 g / day 8.0 g/day, 8.1 g/day, 8.4 g/day, 8.5 g/day, 8.7 g/day, 9.0 g/day, 9.3 g/day, 9.5 g/day, 9.6 g/day, 9.9 g/day And a dose of 10.0 g/day is administered in 1 to 3 divided doses. However, the entire dose can be administered in one dose or in divided doses. Despite the meal Responding to the absorption of EPA, and the EPA is preferably administered during or after the meal and more preferably immediately after the meal (within 30 minutes after the meal), but the self-emulsifying composition of the present invention also has excellent absorption under fasting. And therefore, even when administered during the meal, after the meal, or immediately after the meal (for example, before or immediately before the meal or before going to bed), it also exhibits the expected effect; for patients with reduced intestinal absorption capacity (eg, elderly, enteric patients, post-intestinal patients, terminal cancer patients, or patients taking lipase inhibitors); or used at reduced doses.

The composition of EPA is administered to an individual or patient in accordance with the present disclosure to provide the patient with about 0.3-10 g EPA per day, or 0.5-8 g per day, or 0.6-6 g per day, or 1-4 g per day, or 0.9-3.6 g per day or Specifically, about 1800 mg per day or about 2700 mg EPA per day.

The composition to be administered may contain other fatty acids, especially any omega-3 unsaturated fatty acids, especially DHA. The ratio of EPA/DHA in the composition, the content of EPA and DHA in total fatty acids, and the amount of EPA and DHA are not limited, but the ratio is preferably 0.8 or more, more preferably 1.0 or more, still more Good 1.2 or bigger. The composition is preferably highly purified; for example, the ratio of EPA + DHA in the fatty acid and its derivative is preferably 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight. %, 75% by weight, 80% by weight, 85% by weight or more, more preferably 90% by weight or more, and still more preferably 96.5% by weight or more. For EPA+DHA, the daily amount is usually from 0.3 g/day to 10.0 g/day, preferably from 0.5 g/day to 6.0 g/day and still more preferably from 1.0 g/day to 4.0 g/day, or 0.9- 3.6 g/day or specifically about 1800 mg/day or about 2700 mg/day of EPA+DHA. The low content of other long-chain saturated fatty acids is preferred, and among the long-chain unsaturated fatty acids, the content of omega-6 fatty acids in the total fatty acids and derivatives thereof, and specifically the content of arachidonic acid, is preferably as low as less than 2 weights. %, 1% by weight, 0.5% by weight, 0.2% by weight, 0.1% by weight and more preferably less than 0.05% by weight. For example, it contains about 46 wt% EPA-E and about 38% by weight soft capsules (Lovaza ^TM, Omacor ^TM and Lotriga ^TM) DHA-E in the U.S. and other countries as a therapeutic agent of hypertriglyceridemia has City Soft capsules (VascepaTM ⁾ sold and containing at least 96% by weight of EPA-E are commercially available as therapeutic agents for hypertriglyceridemia in the United States and contain about 50-60% by weight of EPA and about 15-25% by weight of DHA. soft capsules (Epanova ^TM) and comprising MTA9001 DHA and EPA in the United States as a therapeutic agent is the development of hypertriglyceridemia.

The EPA can be administered to a patient treating NASH for 3, 6 or 9 months or up to 1 year, 2 years, 3 years, 4 years, 5 years or more according to the present disclosure, and can be as suitable for patient therapy. One, two or three doses per day or other multiple doses per day (including 1 to about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2 dosage units/day) are administered. The term "dose unit" and "dosage unit" as used herein refers to a portion of a pharmaceutical composition that contains EPA for the amount administered to a single individual.

When administered orally at this dose, the administration period can be sufficiently determined depending on the degree of the target disease and symptoms. For example, when administered to NASH, there are no specific restrictions on the duration of the administration, as long as the improvement of biochemical markers associated with NASH, improvement of pathological conditions or therapeutic effects, and metabolic syndrome, cardiovascular or cerebrovascular events or limbs are achieved. The inhibition of the ulcers and gangrene at the end and the periphery can be suppressed. However, the administration period was determined to achieve plasma lipid labeling (total cholesterol (hereinafter abbreviated as Cho), TG, postprandial TG, low density lipoprotein Cho, high density lipoprotein Cho, very low density lipoprotein Cho, non-high density Lipoprotein Cho, intermediate density lipoprotein Cho, very high density lipoprotein Cho, free fatty acid, phospholipid, chylomicron, ApoB, lipoprotein (a), residual lipoprotein Cho, small dense low density lipoprotein Cho, etc. Improved concentration, increased skin temperature at the extremities and peripherals (which can be measured by temperature or the like), increased walking distance, increased serum CPK or other test values, and various symptoms (eg, numbness, cold, pain, rest) , itching, cyanosis, flushing, frostbite, neck stiffness, anemia, facial color, itching and peristalsis) improved. The improvement or therapeutic effect can be monitored by other biochemical, pathological or symptomatic parameters associated with NASH. It is preferred to continue the administration as long as an abnormality is observed in the biochemical index (e.g., serum lipid concentration or pathology). Alternatively, the composition can be administered every other day or 2 or 3 days of the week, or as appropriate. The withdrawal period may be included from about 1 day to 3 months and more preferably from about 1 week to 1 month.

If indicated by the physician, oral administration on the first day may begin at a lower dose than the recommended daily EPA dose, and then the dose may be gradually increased to the maximum daily dose as a maintenance dose. The dosage can be reduced depending on the condition of the patient. In view of reducing side effects, lower daily doses are preferred, and one or two administrations per day are preferred in view of drug compliance.

The pharmaceutical compositions and methods of the present invention can be administered a therapeutically effective amount of a pharmaceutical composition comprising a combination of EPA and a second effective component. The second effective component can be fully determined depending on the severity of the target disease and symptoms. However, the second effective component is preferably a component which does not adversely affect the effect of EPA, and examples include a therapeutic agent for hyperlipidemia, an antihypertensive drug, an antidiabetic agent, an antioxidant, a blood flow improver, a farnesol X receptor (FXR) ligand and a bile acid derivative. More preferably, the second effective component is for a hyperlipidemia agent, an antihypertensive drug, an antidiabetic agent, and a farnesoid X receptor (FXR) ligand.

In a preferred embodiment of the second effective component, exemplary therapeutic agents for hyperlipidemia include polyene phospholipid choline, unsaponifiable soybean oil (soy sterol), gamma-oryzanol, butyrate nucleus Flavin, polydextrose sodium sulphate 18, pantethine, niceritorol and elastase; statins, such as lovastatin, pravastatin, pravastatin, Simvastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin, and cerivastatin; fibrate ), for example, simfibrate, clofibrate, clinofibrate, bezafibrate, and fenofibrate; lipolytic enzyme inhibitors such as Orly Orlistat and cetirita; resins such as colestyramine and colestimide; and ezetimibe. Preferred agents for hyperlipidemia are statins such as lovastatin, pravastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin and cerivastatin; Fibrates such as bisbate, clofibrate, clebyl and benzalbe Pre-protein convertase subtilisin/kexin type 9 (PCSK9) antibodies, such as Evolocumab (Amgen, AMG145), SAR236553/Regn727 (sanofi and Regeneron), RN316 (Pfizer) and LGT209 (Novartis); and ezetimidate shell. More preferred agents for hyperlipidemia are statins such as pravastatin, simvastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin and cerivastatin.

Exemplary antihypertensive agents include angiotensin II receptor blockers such as irbesartan, olmesartan medoxomil, candesartan cilexetil, telmisartan, valsartan, and losartan potassium; blood vessels Contraction peptide invertase inhibitors, such as alapril, midazolam hydrochloride, enalapril maleate, captopril, quinapril hydrochloride, cilazapril hydrate, temocapril hydrochloride, Dalapril hydrochloride, trandolapril, benazepril hydrochloride, perindopril and lisinopril hydrate; calcium antagonists, such as adipine, amlodipine besylate, adipine, hydrochloric acid Eflipidipine, cilnidipine, nicardipine hydrochloride, nifedipine, nimodipine, nitrendipine, nilvadipine, banidipine hydrochloride, felodipine, benidipine and manidipine; Body blockers, such as tolazoline and phentolamine; [beta] receptor blockers, such as atenolol, metoprolol, acebutolol, propranolol, guanolol , carvedilol and labetalol hydrochloride; receptor stimulants, such as clonidine and methyldopa; and diuretics, such as eplerenone, hydrochlorothiazide And furosemide. Preferred antihypertensive agents are angiotensin II receptor blockers (eg, irbesartan, olmesartan medoxomil, candesartan cilexetil, telmisartan, valsartan, and losartan potassium), Angiotensin-converting enzyme inhibitors (eg, alapril, midazolam hydrochloride, enalapril maleate, captopril, quinapril hydrochloride, cilazapril hydrate, temocapril hydrochloride) , lapilapril hydrochloride, trandolapril, benazepril hydrochloride, perindopril and lisinopril hydrate) and calcium antagonists (eg adipine, amlodipine besylate, cilnidipine) , nicardipine hydrochloride, nifedipine and manidipine). Better antihypertensive drugs are vasopressin II receptor blockers (eg, irbesartan, olmesartan medoxomil, candesartan cilexetil, telmisartan, valsartan, and losartan potassium), Angiotensin-converting enzyme inhibitors (eg, imidapril hydrochloride, enalapril maleate, captopril, and lisinopril hydration) And calcium antagonists (eg, adesodipine, amlodipine besylate, and cilnidipine).

Exemplary anti-diabetic agents include [α]-glucosidase inhibitors, such as acarbose, voglibose, and miglitol; sulfonylurea hypoglycemic agents, such as gliclazide, glibenclamide , glimepiride and tolbutamide; fast-acting insulin secretagogues such as nateglinide and mitiglinide; biguanide hypoglycemic agents such as metformin hydrochloride and diacetyl guanidine; dipeptidyl phosphatase 4 inhibitor For example, sitagliptin, vildagliptin, alogliptin, linagliptin and saxagliptin; thiazolidine reagents such as pioglitazone hydrochloride and rosiglitazone maleate; glycoside-like peptide 1 derived Reagents such as exenatide, lixisenatide and liraglutide; PPARα/γ dual agonists such as AR-HO39242, GW-409544, BVT-142, CLX-0940, GW-1536, GW-1929 , GW-2433, KRP-297, L-796449, LR-90, LY-578, LY-4655608, LSN-862, LY-510929, LY-929, DRF4158, MK-0767, SB 219994, Moglita , segaglita, regitaza and fagritata; PPAR alpha/delta dual agonists, such as GFT505 and TIPP401; and SGLT2 inhibitors, such as cardiglazine, Dag Net, net Ruger row, column Torg net, net Yipa column, Ignatius column net, BI44847, LX-4211, DSP-3235 / GSK1614235 and ISIS388626. Preferred anti-diabetic agents are [α]-glucosidase inhibitors (such as acarbose and voglibose), sulfonylurea hypoglycemic agents (such as glibenclamide, glimepiride and toluene) Urea), a fast-acting insulin secretagogue (such as nateglinide and mitiglinide), a biguanide hypoglycemic agent (such as metformin hydrochloride and butyl hydrazine hydrochloride), a dipeptidyl phosphatase 4 inhibitor (such as sitagliptin) , vildagliptin, alogliptin, linagliptin and saxagliptin), thiazolidine reagents (such as pioglitazone hydrochloride and rosiglitazone maleate), glycoside-like peptide 1 derivative reagents (eg Exenatide, lixisenatide and liraglutide), PPARα/γ dual agonists (eg moglitastat, ticagrelor, regitaza and fagritazin), PPARα/ δ dual agonists (eg GFT505) and SGLT2 inhibitors (eg, cardiglipin, dapagliflozin, rugliflozin, togliflozin, epagliflozin, and iglitavir). More excellent anti-diabetic agents are sulfonylurea hypoglycemic agents (such as glibenclamide, glimepiride and tolbutamide), and biguanide hypoglycemic agents (eg Such as metformin hydrochloride and butyl hydrazine hydrochloride, dipeptidyl phosphatase 4 inhibitors (such as sitagliptin, vildagliptin, alogliptin, linagliptin and saxagliptin), thiazolidine reagent ( For example, pioglitazone hydrochloride and rosiglitazone maleate), glycosidin-like peptide 1 derivative reagents (such as exenatide, lixisenatide and liraglutide), PPARα/γ dual agonists (eg Moog Lista, tesseglita, regitaza and fagritazide) and SGLT2 inhibitors (eg, cagliflozin, dagliflozin, rugliflozin, togliflozin, epapi Net and Iglesia). The best anti-diabetic agents are dipeptidyl phosphatase 4 inhibitors (eg, sitagliptin, vildagliptin, alogliptin, linagliptin, and saxagliptin) and thiazolidine reagents (eg, pioglitazone hydrochloride and Rosiglitazone maleate).

The dose of the second effective component is not specifically limited, as the dose depends on the condition of the individual patient and the type of the body. However, the exemplary daily dose of the second effective component is equal to or less than the recommended daily dose of the monotherapy. In the case of lovastatin, a recommended daily dose of less than 10 mg/day, preferably at least 0.2 mg and at most 8 mg, more preferably at least 0.4 mg and at most 6 mg and still more preferably at least 1 mg and at most 4 mg; in pravastatin sodium salt In the case of less than 40 mg/day, preferably at least 1 mg and at most 30 mg, more preferably at least 2 mg and at most 25 mg and still more preferably at least 4 mg and at most 20 mg of the recommended daily dose; in the case of simvastatin, less than 1 day 5 mg a recommended daily dose of preferably at least 0.1 mg and at most 4 mg, more preferably at least 0.2 mg and at most 2 mg and still more preferably at least 0.4 mg and at most 1 mg; in the case of atorvastatin calcium hydrate, less than 20 mg/day, Preferably a recommended daily dose of at least 0.4 mg and at most 16 mg, more preferably at least 0.8 mg and at most 12 mg and still more preferably at least 2 mg and at most 10 mg; in the case of fluvastatin sodium salt, less than 20 mg/day, preferably at least 0.4 a recommended daily dose of mg and up to 16 mg, more preferably at least 0.8 mg and up to 12 mg and still more preferably at least 1.5 mg and up to 8 mg; in the case of pitavastatin calcium salt, less than 1 day 1 mg, preferably at least 0.02 mg and most 0.8 mg, more preferably at least 0.04 mg and at most 0.6 mg and still more preferably at least 0.1 mg and at most 0.4 mg Recommended daily dose; in the case of rosuvastatin calcium salt, less than 2.5 mg, preferably at least 0.05 mg and up to 2 mg, more preferably at least 0.1 mg and A recommended daily dose of at most 1.5 mg and still more preferably at least 0.2 mg and at most 1 mg and in the case of bezafibrate, less than 800 mg, preferably at least 50 mg and at most 600 mg, more preferably at least 100 mg and at most 500 mg and still better at least A recommended daily dose of 200 mg and up to 400 mg.

In the case of irbesartan, a recommended daily dose of less than 50 mg/day, preferably at least 1 mg and at most 40 mg, more preferably at least 2 mg and at most 30 mg and still more preferably at least 5 mg and at most 20 mg; in the case of olmesartan medoxomil a recommended daily dose of less than 10 mg/day, preferably at least 0.2 mg and at most 8 mg, more preferably at least 0.5 mg and at most 6 mg and still more preferably at least 1 mg and at most 4 mg; in the case of candesartan cilexetil, less than a recommended daily dose of 4 mg/day, preferably at least 0.1 mg and at most 3 mg, more preferably at least 0.2 mg and at most 2 mg and still more preferably at least 0.4 mg and at most 1 mg; in the case of telmisartan, less than 20 mg/day, Preferably a recommended daily dose of at least 0.5 mg and at most 15 mg, more preferably at least 1 mg and at most 10 mg and still more preferably at least 2 mg and at most 5 mg; in the case of valsartan, less than 40 mg/day, preferably at least 1 mg and at most 30 mg More preferably, at least 2 mg and still more than 20 mg and still more preferably at least 4 mg and up to 10 mg of the recommended daily dose; and in the case of losartan potassium salt, less than 50 mg/day, preferably at least 1 mg and up to 40 mg, more preferably at least 2 mg And a recommended daily dose of up to 30 mg and still more preferably at least 4 mg and up to 20 mg.

In the case of pioglitazone hydrochloride, a recommended daily dose of a daily dose equal to or less than 60 mg/day, preferably at least 5 mg and at most 50 mg, more preferably at least 10 mg and at most 40 mg and still more preferably at least 20 mg and at most 30 mg; in maleic acid In the case of glitazone, the recommended daily dose of a daily dose equal to or less than 16 mg/day, preferably at least 1 mg and at most 12 mg, more preferably at least 2 mg and at most 10 mg and still more preferably at least 4 mg and at most 8 mg; in nateglinide In the case of less than 500 mg/day, preferably at least 10 mg and at most 400 mg, more preferably at least 20 mg and at most 350 mg and still more preferably at least 50 mg and at most 300 mg of the recommended daily dose; in the case of metformin hydrochloride, the daily dose is equal to or less than 2000 mg/day, preferably at least 40 mg and at most 1500 mg, more preferably at least 80 mg and at most 1200 mg and still better at least Suggested daily dose of 200 mg and up to 1000 mg; in the case of bupreson hydrochloride, a recommended date of less than 400 mg/day, preferably at least 10 mg and at most 300 mg, more preferably at least 20 mg and at most 250 mg and still more preferably at least 50 mg and at most 200 mg Dosage; in the case of iriaglip, a daily dose of 100 mg/day, preferably at least 5 mg and at most 90 mg, more preferably at least 10 mg and at most 75 mg and still more preferably at least 25 mg and at most 50 mg of the recommended daily dose and In the case of ruglipide, the recommended daily dose is a daily dose equal to or less than 5 mg/day, preferably at least 0.5 mg and at most 4 mg, more preferably at least 1 mg and at most 3 mg and still more preferably at least 1.5 mg and at most 2.5 mg.

Exemplary antioxidants include vitamins such as ascorbic acid (vitamin C), tocopherol (vitamin E) and tocopherol nicotinate and N-acetylcysteine, probucol.

Exemplary blood flow improvers include aspirin, cilostazol, ticlopidine hydrochloride, alprostadil, limoprost, beraprost sodium, sarpogrelate hydrochloride, argatroban, naproxil, hydrochloric acid Ikesulin, batroxobin, hydrogen ergotine mesylate, tolazoline hydrochloride, chlorfenapyr and shimotsu-to extract.

Exemplary bile acid derivatives include ursodeoxycholic acid, chenodeoxycholic acid, bile powder, deoxycholic acid, bile acid, bile extract, bear bile, bezoar, and dehydrocholic acid. Preferred examples also include biotin (vitamin B7), cyanocobalamin (vitamin B12), pantothenic acid (vitamin B5), folic acid (vitamin B9), thiamine (vitamin B1), vitamin A, vitamin D, vitamin K, cheese. Amine acid, pyridoxine (vitamin B6), branched chain amino acids (such as leucine, isoleucine and valine), calcium, iron, zinc, copper and magnesium. Other examples include designated health foods and functional nutraceuticals (eg, soy protein, chitosan, low molecular weight sodium alginate, dietary fiber from psyllium husk, bound phospholipids, phytosterol esters, plant stanol esters, A component used in dimercaptoglycerol, globin degradation product, and soybean olein of tea catechin. Exemplary antioxidants include vitamins such as ascorbic acid (vitamin C), tocopherol (vitamin E) and tocopherol nicotinate and N-acetylcysteine, probucol. A preferred antioxidant is tocopherol (vitamin E).

Exemplary blood flow improvers include aspirin, cilostazol, ticlopidine hydrochloride, clopidogrel, prasugrel, edoxaban tosilate hydrate, Rivaroxaban, dabigatran etexilateal prostadil, limatoprost, beraprost sodium, sarpogrelate hydrochloride, argatroban, naproxil, isoxacillin hydrochloride , batroxobin, hydrogen ergotine mesylate, tolazoline hydrochloride, trimethoprim and shimotsu-to extract. Preferred blood flow improvers are aspirin, clopidogrel, prasugrel, edoxafloxacin p-toluenesulfonate hydrate, rivaroxaban and dabigatran etexilate.

Exemplary bile acid derivatives (which are optionally FXR ligands) include ursodeoxycholic acid, chenodeoxycholic acid, oleic acid, GW4064, bile powder, deoxycholic acid, bile acid, bile extract, Bear bile, bezoar and dehydrocholic acid. Preferred bile acid derivatives are ursodeoxycholic acid, chenodeoxycholic acid, oleic acid, GW4064, bile powder, deoxycholic acid and cholic acid. More preferred bile acid derivatives are FXR ligands such as chenodeoxycholic acid, oleic acid and GW4064. Preferred examples also include biotin (vitamin B7), cyanocobalamin (vitamin B12), pantothenic acid (vitamin B5), folic acid (vitamin B9), thiamine (vitamin B1), vitamin A, vitamin D, vitamin K, cheese. Amine acid, pyridoxine (vitamin B6), branched chain amino acids (such as leucine, isoleucine and valine), calcium, iron, zinc, copper and magnesium. Other examples include designated health foods and functional nutraceuticals (eg, soy protein, chitosan, low molecular weight sodium alginate, dietary fiber from psyllium husk, bound phospholipids, phytosterol esters, plant stanol esters, A component used in dimercaptoglycerol, globin degradation product, and soybean olein of tea catechin. In the case of tocopherol (vitamin E), the daily dose is equal to or less than 1600 IU/day, preferably at least 100 IU and at most 1200 IU, more preferably at least 200 IU and at most 1000 IU and still more preferably at least 400 IU and at most 800 IU, or the daily dose is equal to or Less than 600 mg/day, preferably at least 50 mg and at most 500 mg, more preferably at least 100 mg and at most 400 mg and still more preferably at least 200 mg and at most 300 mg, and in the case of ascorbic acid (vitamin C) or vitamin B, the daily dose is equal to or less than 2000 mg /day, preferably at least 40mg and most 1500 mg, more preferably at least 80 mg and at most 1200 mg and still more preferably at least 200 mg and at most 1000 mg. In the case of ursodeoxycholic acid, the daily dose is equal to or less than 30 mg/day, preferably at least 1 mg and at most 25 mg, more preferably at least 2 mg and at most 20 mg and still more preferably at least 5 mg and at most 15 mg, and in the form of oleic acid In this case, the daily dose is equal to or less than 50 mg/day, preferably at least 1 mg and at most 40 mg, more preferably at least 2 mg and at most 30 mg and still more preferably at least 5 mg and at most 25 mg.

Preferred combinations include at least EPA and lovastatin, EPA and pravastatin, EPA and simvastatin, EPA and atorvastatin, EPA and fluvastatin, EPA and pitavastatin, EPA and rosuvastatin, EPA and cerivastatin, EPA and bisbate, EPA and clofibrate, EPA and celebrate, EPA and bezafibrate, EPA and ezetimibe, EPA and AMG145, EPA and SAR236553/Regn727 , EPA and RN316, EPA and LGT209, EPA and irbesartan, EPA and olmesartan medoxomil, EPA and candesartan cilexetil, EPA and telmisartan, EPA and valsartan, EPA and losartan Potassium, EPA and alapril, EPA and midazolam hydrochloride, EPA and enalapril maleate, EPA and captopril, EPA and quinapril hydrochloride, EPA and cilazapril hydrate, EPA and temoprol hydrochloride, EPA and tralipid hydrochloride, EPA and trandolapril, EPA and benazepril hydrochloride, EPA and perindopril, EPA and lisinopril hydrate, EPA and A Adipine, EPA and amlodipine besylate, EPA and cilnidipine, EPA and nicardipine hydrochloride, EPA and nifedipine, EPA and manidipine, EPA and acarbose, EPA and voglibine Sugar, EPA and glibenclamide, EPA and glimepiride, EPA and tolbutamide, EPA and nateglinide, EPA and mitiglinide, EPA and metformin hydrochloride, EPA and diacetyl HCl, EPA and West Gliptin, EPA and vildagliptin, EPA and alogliptin, EPA and linagliptin, EPA and saxagliptin, EPA and pioglitazone hydrochloride, EPA and rosiglitazone maleate, EPA and AI Serena, EPA and lixisenatide, and EPA and liraglutide, EPA and moglita, EPA and ticagrelor, EPA and regitaza, EPA and fagitaza, EPA and GFT505, EPA and Cagliflozin, EPA and Daglip, EPA And ruglippine, EPA and togliflozin, EPA and epapaprime, EPA and Iglibine, EPA and tocopherol (vitamin E), EPA and aspirin, EPA and clopidogrel, EPA and prasugrel , EPA and edoxaban p-toluenesulfonic acid salt hydrate, EPA and rivaroxaban, EPA and dabigatran etexilate, EPA and ursodeoxycholic acid, EPA and chenodeoxycholic acid, EPA and aobei Cholic acid, EPA and GW4064, EPA and bile powder, EPA and deoxycholic acid, and EPA and cholic acid. A better combination consists of at least EPA and pravastatin, EPA and simvastatin, EPA and atorvastatin, EPA and fluvastatin, EPA and pitavastatin, EPA and rosuvastatin, EPA and ezetimibe. Shellfish, EPA and irbesartan, EPA and olmesartan medoxomil, EPA and candesartan cilexerate, EPA and telmisartan, EPA and valsartan, EPA and losartan potassium, EPA and sigma Ting, EPA and vildagliptin, EPA and alogliptin, EPA and linagliptin, EPA and saxagliptin, EPA and pioglitazone hydrochloride, EPA and rosiglitazone maleate, EPA and Essex Peptides, EPA and lixisenatide, and EPA and liraglutide, EPA and cagliflozin, EPA and dapagliflozin, EPA and rugliflozin, EPA and togliflozin, EPA and epapa Net, EPA and Iglide, EPA and tocopherol (vitamin E), EPA and chenodeoxycholic acid, EPA and oleic acid, EPA and GW4064. The best combination consists of at least EPA and atorvastatin, EPA and fluvastatin, EPA and pitavastatin, EPA and rosuvastatin, EPA and irbesartan, EPA and olmesartan medoxomil, EPA and Candi Satancepsis, EPA and telmisartan, EPA and valsartan, EPA and losartan potassium, EPA and sitagliptin, EPA and vildagliptin, EPA and alogliptin, EPA and lira Litin, EPA and saxagliptin, EPA and pioglitazone hydrochloride, EPA and rosiglitazone maleate, EPA and tocopherol (vitamin E), EPA and chenodeoxycholic acid, EPA and oleic acid. A preferred combination is EPA, at least one member selected from the group consisting of the above-mentioned agents for hyperlipidemia, and at least one member selected from the group consisting of the above-mentioned antihypertensive drugs. A preferred combination is EPA, at least one member selected from the group consisting of the above-mentioned agents for hyperlipidemia, and at least one member selected from the group consisting of the above-mentioned anti-diabetic agents. A preferred combination is EPA, at least one selected from the above-mentioned drugs for hyperlipidemia A member of the group of agents and tocopherols (vitamin E). A preferred combination is EPA, at least one member selected from the group consisting of the above-mentioned agents for hyperlipidemia, and at least one member selected from the group consisting of blood flow improvers. Preferably, the combination is EPA, at least one member selected from the group consisting of the above-mentioned agents for hyperlipidemia, and at least one member selected from the group consisting of bile acid derivatives (including FXR ligands) mentioned above. Member of the group.

A preferred combination is EPA, at least one member selected from the group consisting of the above-mentioned antihypertensive agents, and at least one member selected from the group consisting of the above-mentioned anti-diabetic agents. A preferred combination is EPA, at least one member selected from the group consisting of the above-mentioned antihypertensives and tocopherols (vitamin E). A preferred combination is EPA, at least one member selected from the group consisting of the above-mentioned antihypertensive agents, and at least one member selected from the group consisting of blood flow improvers. A preferred combination is EPA, at least one member selected from the group consisting of the above-mentioned antihypertensive agents, and at least one member selected from the group consisting of the above-mentioned bile acid derivatives (including FXR ligands).

A preferred combination is EPA, at least one member selected from the group consisting of the anti-diabetic agents mentioned above and tocopherol (vitamin E). A preferred combination is EPA, at least one member selected from the group consisting of the above-mentioned anti-diabetic agents, and at least one member selected from the group consisting of blood flow improvers. A preferred combination is EPA, at least one member selected from the group consisting of the above-mentioned anti-diabetic agents, and at least one member selected from the group consisting of the above-mentioned bile acid derivatives (including FXR ligands). A preferred combination is EPA, tocopherol (vitamin E) and at least one member selected from the group consisting of blood flow improvers. A preferred combination is EPA, tocopherol (vitamin E) and at least one member selected from the group consisting of the bile acid derivatives mentioned above, including FXR ligands. A preferred combination is EPA, at least one member selected from the group consisting of blood flow modifiers, and at least one member selected from the group consisting of the bile acid derivatives (including FXR ligands) mentioned above.

A preferred combination is EPA, at least one member selected from the group consisting of the above-mentioned agents for hyperlipidemia, at least one selected from the group consisting of the above-mentioned antihypertensive drugs a member, at least one member selected from the group consisting of the above-mentioned anti-diabetic agent and tocopherol (vitamin E). A preferred combination is EPA, at least one member selected from the group consisting of the above-mentioned agents for hyperlipidemia, at least one member selected from the group consisting of the above-mentioned antihypertensive drugs, at least one A member of the group consisting of the above-mentioned antidiabetic agents and at least one member selected from the group consisting of the above-mentioned bile acid derivatives (including FXR ligands) are selected. Preferably, the combination is EPA, at least one member selected from the group consisting of the above-mentioned agents for hyperlipidemia, at least one selected from the group consisting of the above-mentioned antihypertensive drugs, tocopherol (vitamin E) A member of the group and at least one member selected from the group consisting of the bile acid derivatives mentioned above, including FXR ligands. Preferably, the combination is EPA, at least one member selected from the group consisting of the above-mentioned agents for hyperlipidemia, at least one selected from the group consisting of the above-mentioned anti-diabetic agent, tocopherol (vitamin E) A member of the group and at least one member selected from the group consisting of the bile acid derivatives mentioned above, including FXR ligands. Preferably, the combination is EPA, at least one member selected from the group consisting of the above-mentioned agents for hyperlipidemia, at least one selected from the group consisting of the above-mentioned anti-diabetic agent, tocopherol (vitamin E) A member of the group and at least one member selected from the group consisting of the bile acid derivatives mentioned above, including FXR ligands. A preferred combination is EPA, at least one member selected from the group consisting of the above-mentioned antihypertensive drugs, at least one member selected from the group consisting of the above-mentioned antidiabetic agent, tocopherol (vitamin E), and At least one member selected from the group consisting of the bile acid derivatives mentioned above, including FXR ligands.

A preferred combination is EPA, at least one member selected from the group consisting of the above-mentioned agents for hyperlipidemia, at least one member selected from the group consisting of the above-mentioned antihypertensive drugs, at least one The members of the group consisting of the antidiabetic agent, tocopherol (vitamin E), and at least one member selected from the group consisting of the above-mentioned bile acid derivatives (including FXR ligands) are selected.

EPA (first component) and second effective component (eg, agent for hyperlipidemia, anti-drug The combination of a hypertensive drug, an anti-diabetic agent, and a farnesoid X receptor (FXR) ligand) achieves a degree of safety and significant efficiency that is not observed by a single administration of the corresponding agent. The combined use of EPA (first component) and the second effective component is expected to exhibit synergistic prevention/improvement or therapeutic effects for NASH. The combination of EPA (first ingredient) and the second effective ingredient can reduce the dosage of the agent and the side effects of the agent. Therefore, it can also be administered to a patient who is unacceptable for treatment or who has to stop treatment due to side effects of the second effective component.

D. Therapeutic effect

The compositions of the present invention are useful as therapeutic agents for various diseases of animals, and in particular mammals, such as NASH and therapeutic agents for related disorders. In particular, it is contemplated that the compositions of the invention exhibit an ameliorating or therapeutic effect in a NASH individual without diabetes, or with pre-diabetes or mild or no biliary disease, or in the early stages of the disease. NASH individuals may ameliorate or maintain a variety of symptoms including, but not limited to, increased lipids, insulin resistance, increased blood pressure, abnormal liver function tests, abnormal liver enzyme activity, elevated glucose levels, liver dysfunction, hyperlipemia Symptom or any abnormality criteria as found in Figure 5. In some cases, a pharmaceutical composition can assist in maintaining the function, extent or activity present in an individual.

In some cases, the composition can reduce the fasting glucose content by a method as provided by the present disclosure. In some cases, the composition can reduce the glucose content determined to be higher than normal as found in pre-diabetic and mildly diabetic individuals. In some cases, the composition can reduce the high glucose content of individuals not considered to have diabetes. In some cases, the pharmaceutical composition can assist in maintaining the amount of glucose present in the individual.

In some cases, the composition can reduce the GGT content below the threshold as provided by the present disclosure. In some instances, the composition can reduce the GGT content determined to be higher than normal as found in NASH individuals having or at risk of developing the disease. In some cases, the composition can reduce the GGT content of an individual who is not considered to have a biliary tract disease. In some cases, the pharmaceutical composition can assist in maintaining the GGT content present in the individual.

In some cases, the composition can reduce the sFas, M30, or NASH risk score values below the threshold as provided by the present disclosure. In some cases, the composition can reduce the sFas, M30, or NASH risk score values determined to be higher than normal, as found in NASH individuals with hepatocyte apoptosis or at risk of indication. In some cases, the composition reduces the sFas, M30 or NASH risk score values for individuals not considered to have hepatocyte apoptosis. In some cases, in some cases, the pharmaceutical composition can assist in maintaining the sFas, M30, or NASH risk score values present in the individual. In addition, in some cases, the patient's EPA/AA ratio may be modified to be equal to or greater than 0.1, 0.2, 0.3, or 0.4 compared to the baseline EPA/AA ratio.

The compositions of the present invention can reduce the burden on a patient by reducing the dosage and daily frequency of administration and thus by improving drug compliance. This also causes a higher improvement or therapeutic effect.

IV example Example 1: Preclinical experience

In animal and in vitro model studies, EPA-E (all- cis- 5,8,11,14,17-eicosapentaenoate) has been shown to reduce lipids in rats, hamsters and rabbits. It has an anti-aggregation effect on platelets of rats, rabbits and humans; and preserves the elasticity of the sputum in rabbits. In other studies, polyunsaturated fatty acids (PUFAs) have been shown to improve hepatic steatosis in ob / ob mice by down-regulating hepatic steroid modulating element binding protein-1c (SREBP-1c). In a similar way, 0.1 mg/g repeated oral administration of EPA-E inhibits the synthesis of SREBP-1c by the liver and synthesis of monounsaturated fatty acids (MUFA) by stearyl-coenzyme A desaturase 1 (SCD1) Fat accumulation in a mouse diet induced hepatic steatosis model. In a mouse model of galactosamine-induced steatohepatitis, oral administration of EPA-E at 1000 mg/kg delayed the progression of steatohepatitis by suppressing triglyceride (TG) accumulation. In a rat model of methionine-choline-deficient diet of nonalcoholic steatohepatitis, repeated administration of EPA-E at 1000 mg/kg orally inhibited fibrosis by suppressing inflammation and oxidative stress.

In the safety pharmacology study, EPA-E has no effect on the central nervous system, autonomic nerve, respiratory and cardiovascular system at an oral dose of up to 3000 mg/kg, but only after 3,000 mg/kg oral dose, pyloric-linked rats The gastric juice content is reduced. The metabolites and impurities of EPA-E and the effect of oxidized EPA-E on the above system are not significant and do not seem to promote the general pharmacological effects of EPA-E.

Pharmacokinetics and product metabolism in animal overview

EPADEL is a product of all- cis-- 5,8,11,14,17-eicosapentaenoic acid ethyl ester (EPA-E) (one of the n-3 essential fatty acids). The preclinical absorption, distribution, metabolism, and excretion (ADME) characteristics of EPA-E were primarily determined in rats.

Oral administration of a single dose of radioactive ¹⁴ C-EPA-E at a dose of 30-1000 mg/kg in rats showed sufficient absorption of EPA-E primarily via the lymphatic route. After administration of ¹⁴ C-EPA-E to the connective intestine of the rat, the residual radioactivity in the intestine at 24 hours was only 4.6% of the administered dose. The radioactivity transferred to plasma and lymph was detected mainly in the early triglyceride (TG) fraction after administration, while the distribution of free fatty acid (FFA) fraction was traced at all time points. Radioactivity is widely distributed in body tissues; relatively high levels are observed especially in brown fat, adrenal gland, liver and pancreas. Within the tissue, radioactivity is primarily distributed in the TG and/or phospholipid (PL) fraction. ¹⁴ C-EPA-E rapidly decomposes in the intestinal homogenate, lymph, plasma and liver homogenates of rats. Oral administration of EPA-E is mainly incorporated into adrenal lipids in the form of cholesterol esters of fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA). in.

The uptake of ¹⁴ C-EPA-E derived radioactivity in the above rats is compatible with the absorption process of essential fatty acids in the following animals and humans. In addition, esterases are also distributed in most organs of humans). Therefore, the absorption and distribution characteristics after oral administration of EPA-E should be qualitatively similar to those observed in rats in humans and dogs.

It is known that the digestion and absorption of essential fatty acids, mainly in the form of TG, involve several processes.

‧ Fatty acids are rapidly hydrolyzed from TG to FFA by lipase in the intestine.

‧ FFA is absorbed by intestinal cysts, where it is re-esterified into TG and enters the blood circulation in the form of chylomicrons mainly via the lymphatic route.

‧ In tissue, TG of chylomicrons is hydrolyzed again by lipoprotein lipase to FFA and absorbed by tissues.

Therefore, when EPA-E is orally administered to humans, it exhibits sufficient absorption even if an unaltered ethyl ester form is not detected in the blood, and only a very low content of free form (EPA) is detected. Due to this absorption mechanism of essential fatty acids, the EPA-E administered is in the form of blood-component fatty acids in the total lipid. In fact, according to the approval of packaging Lovaza ^® file, after 4g Omacor ^® (a mixture of EPA and DHA ethyl esters of) the oral dosage, in free form in the circulation of EPA undetectable (<1μM). After oral administration of EPA-E, EPA, DPA, and DHA were isolated and identified as metabolites in tissues and plasma. EPA, DPA and DHA are included in TG and PL. After a single oral administration of 30 mg/kg EPA-E, radioactivity was mainly excreted in exhaled breath (44%) with minimal excretion in bile and urine (about 3%) and excretion in feces by about 20%. Therefore, the respiratory pathway (in the form of ¹⁴ CO2) is considered to be the major elimination pathway for ¹⁴ C-EPA-E. The radioactive excretion was lower in the dog after 30 mg/kg single oral administration, 1.0% of which was excreted in the urine and 19.2% was recovered in the feces after 1 week.

Renal excretion is the elimination of several traces of highly polar metabolites (<0.4%), but no EPA-E, EPA, DPA or DHA is detected in the urine. In feces, EPA-E and EPA, which ultimately originated from unabsorbed drugs, were detected; however, no DPA or DHA was detected in the feces.

In a metabolic study performed in vitro, when ¹⁴ C-EPA-CoA was incubated with the rat liver mitochondrial fraction, 17.1% of the radioactivity added to the incubation mixture was detected as ¹⁴ CO2 and a product which formed a carbon chain shortening was observed. ¹⁴ CEPA-CoA can also form a carbon chain shortening product by incubation with the rat peroxisome fraction. These results show that after absorption by rat tissue, EPA is eventually almost completely oxidized to CO2 by mitochondrial and catalase β-oxidation.

After oral administration of ¹⁴ C-EPA-E to rats, EPA, DPA and DHA were detected as metabolites in the total lipid fraction of plasma and tissues (liver, fat, heart and brain). However, no altered EPA-E was found in plasma or any tissue. In the total lipid fraction of the liver, radioactivity is mainly derived from EPA, DPA and DHA. Therefore, the main metabolite of ¹⁴ C-EPA-E in the tissues of EPA, DPA and DHA is considered to be a constituent fatty acid of the total lipid fraction. When ¹⁴ C-EPA‧K was incubated with the microsome fraction, DPA and DHA were detected. These results show that EPA absorbed by rat tissue extends into microparticles into DPA and DHA.

Plasma protein binding in rats and dogs was >86% and >96%, respectively. The foregoing studies have shown that EPA is unlikely to inhibit CYP450 at free concentrations observed in humans.

Example 2: Clinical trial data Research design

This example provides a protocol for a phase II clinical trial, a double-blind, placebo-controlled study being conducted to study the safety, efficacy, and pharmacokinetic properties of two doses of EPA-E in individuals with NASH. A maximum of 70 individuals were recruited from each treatment group and a total of 210 individuals were recruited. Patients were assigned a combination of two active doses and a placebo at a 1:1:1 ratio using block randomization using an interactive voice response system (IVRS). Patients are stratified by the presence or absence of diabetes. The number of patients with diabetes does not exceed 25% of the total number of patients recruited. Individuals were treated three times a day with 600 mg EPA-E, 900 mg EPA-E or placebo for one year.

‧ Study Group 1: 600mg EPA-E (3 capsules), TID

‧ Study Group 2: 900mg EPA-E (3 capsules), TID

‧ Study Group 3: Placebo (3 capsules), TID

A liver biopsy is required for the individual to demonstrate NASH during the 6 month period prior to screening. The pharmacokinetic properties of EPA-E were assessed in a subgroup of individuals at designated sites. Individuals are contacted prior to providing informed consent to determine if they will participate in the PK subgroup. Approximately 36 individuals participated in the PK subgroup assessment (12 in each treatment group to include 6 males and 6 females).

A schematic of the study is provided in Figure 6. The overall research continuation plan is 2 years.

Research drug

To support the trial, EPA-E capsules and matching placebo capsules were prepared. The EPA-E capsule contains 300 mg of an EPA-E oval soft gelatin capsule as an active ingredient. Placebo capsules contain oval soft gelatin capsules as an inactive ingredient in olive oil. These capsules are not identifiable as EPA-E capsules or placebo capsules.

Immediately after the individual meal, 3 capsules were administered orally, 3 times a day.

Qualification criteria

Individuals with histological diagnosis of NASH are eligible.

Inclusion criteria

The inclusion criteria are designed to ensure that individuals who have been certified to have NASH are included in the biopsy and avoid potential harm to the individual as a result of participating in the study.

If an individual satisfies the following criteria, the study potentially includes such individuals:

1. Diagnosing NASH by a central reading pathologist: Submitting a liver biopsy slide according to one of the following criteria is evaluated by a central pathologist: a. The aforementioned liver biopsy must be obtained within 6 months prior to informed consent and Should be judged by a local pathologist, such as showing NAS 4, wherein the minimum score for steatosis and lobular inflammation plus bloating is 1 or for sinus fibrosis at least 1a and the discovery of possible or clear steatohepatitis b. For liver biopsy performed after obtaining informed consent, submit all Slides are used to read by the central pathologist in accordance with the independent pathology review charter (IPRC)

2. Patients older than 18 years of age

3. Can recruit diabetic patients who take a stable dose of anti-diabetic agent at least 6 months before liver biopsy

4. Females must have no fertility (surgery infertility or at least 2 years after menopause) or if they have fertility potential, they must have a negative pregnancy test at screening and agree to use an effective form of contraception during the study and in the last dose study After medicine for at least 30 days

5. Normal ECG or clinically inconspicuous findings during screening and baseline visits

6. No obvious accompanying medical disease, no clinically obvious physical findings and no clinically obvious laboratory findings, as determined by the main investigator

7. Sign an informed consent form instructing them to understand the purpose and procedures required for the study and to participate in the research and to abide by the procedures and restrictions

Exclusion criteria

Exclusion criteria are designed to exclude individuals from the study, and the condition is that the primary endpoint cannot be assessed, provided that it has an analysis that can interfere with the end of the study or a disease state that would put the individual at risk of serious adverse events associated with their participation.

If the potential individual satisfies any of the following exclusion criteria, then the individuals are excluded from the study:

1. Can't or don't want to have liver biopsy

2. Diagnosis of sclerosis by central pathologists

3. Previous obesity treatment surgery or biliary shunt (ie gastric bypass), esophageal hysterectomy and gastric anterior surgery

4. Serum ALT>300U/L

5. Within 6 months prior to screening, individuals have used drugs associated with steatohepatitis (corticosteroids, high-dose estrogens, methotrexate, amiodarone, anti-HIV drugs, tamoxifen, and diltiazem) )

6. Use the following anti-NASH agents for more than 2 weeks within 3 months prior to liver biopsy or within 3 months prior to screening.

a. Vitamin E>60IU/day

b.>200mg supplement containing omega-3-acid ethyl ester or omega-3-PUFA/day

c. thiazolidinedione (eg pioglitazone)

7. Patients taking unstable doses of the following anti-NASH agents within 6 months of liver biopsy or within 6 months of screening visits: HMG-CoA reductase inhibitors (statins), fibrates, probucol, Ezetimibe, ursodeoxycholic acid (UDCA), taurine, betaine, N-acetylcysteine, s-adenosylmethionine (SAM-e), milk thistle ( Milk thistle), anti-TNF therapy or probiotics

8. Weight loss is greater than 10% within 8 weeks of baseline visit

9. Alcohol accumulation > 30g/day for 3 consecutive months or for 5 consecutive years after screening

10. Blood alcohol content greater than 0.02% and/or baseline at screening

11. Evidence of active substance abuse, including prescription and recreational drugs

12. Other liver diseases (hepatitis C, hepatitis B, Wilson's disease, autoimmune, alpha-1-antitrypsin and hemochromatosis) or known HIV infection

13. Pregnancy or lactation during screening visits

14. Renal insufficiency (creatinine > 2 mg / dL), symptomatic coronary, peripheral or neurovascular disease, symptomatic heart failure (NYHA 2-4) or complete respiratory disease requiring oxygen therapy

15. Brain or retinal hemorrhage or other history of bleeding

16. For male QTc > 450 msec and for female > 470 msec, as corrected by Fridericia

17. Cannot provide written informed consent

18. Take any study agent or participate in any clinical study of the study agent or study therapy within 3 months prior to screening visits.

19. In the opinion of the main investigator, any condition in which the patient can be contraindicated

Prohibition and accompanying medicine

All prescription and over-the-counter medicines taken by the individual during the 30 days prior to screening until the start of treatment are recorded. The following medicines are banned during the study period:

‧Supplier containing omega-3-acid ethyl ester and omega-3-PUFA, >200mg/day

‧Vitamin E>60IU/day

‧ Thiazolidinedione (eg pioglitazone)

The following medicines are allowed during the study period according to specified limits:

‧ Individuals can continue prescription or over-the-counter medicine or herbal medicine (HMG-CoA reductase inhibitors [statins], fibrates, probucol, ezetimibe, ursodeoxycholic acid (UDCA), taurine , betaine, N-acetylcysteine, s-adenosylmethionine [SAM-e], milk thistle, anti-TNF therapy or probiotics, only if it is administered at a stable dose before screening 6 months

‧ Individuals may continue the following anti-diabetic medicines if they take a stable dose at least 6 months prior to liver biopsy: biguanide (metformin), insulin, sulfonylurea, alpha-glucosidase inhibitor (acarbose) and benzene Alanine derivative (nateglinide)

‧ Any individual receiving antiplatelet therapy or antithrombotic agents (eg warfarin, ASA and clopidogrel) should be closely monitored during the study period

preliminary result

A) A subpopulation of NASH patients is counted and classified as responders or non-responders as shown in FIG. Preliminary data indicated that the pharmaceutical composition was more potent in patients who were determined to have no diabetes or showed mild diabetes compared to diabetic patients in Study Group 1 (600 mg EPA-E, TID). The efficacy of Study Group 2 (900 mg EPA-E, TID) was also equivalent to the efficacy of Study Group 1.

Further characterizing the same subpopulation of patients. The patient's HbA1c content was measured and its HbA1c = < 6.4, as shown in FIG. Preliminary data indicates that the pharmaceutical composition is in all cases HbA1c content = < 6.4 and especially in study group 1 based on patients as may be classified as non-diabetic (including pre-diabetes) as set forth by the ADA and as described herein. High efficiency. The efficacy of Study Group 2 is also equivalent to the efficacy of Study Group 1.

Or use the test of fasting glucose to measure diabetes in the same subpopulation of patients. the amount The glucose content of the patient was measured, and its glucose content = <125 mg/dL, and is shown in FIG. Preliminary data indicates efficacy of the pharmaceutical composition in patients with = < 125 mg/dL and based in the study group 1 as stipulated by the ADA and as described herein can be classified as non-diabetic (including pre-diabetes) or diabetes high. The efficacy of Study Group 2 is also equivalent to the efficacy of Study Group 1.

The graph in Figure 4 indicates that in Study Group 1, non-diabetes (including pre-diabetes) or diabetes, as measured by both fasting glucose = <125 mg/dL and HbA1c = < 6.4, indicates a higher EPA-E. Reaction rate. The efficacy of Study Group 2 is also equivalent to the efficacy of Study Group 1.

B) The second subpopulation of NASH patients is counted and classified as responders or non-responders as shown in FIG. Preliminary data indicated that study group 1 (600 mg EPA-E, TID) and study group 2 (900 mg EPA-E, TID) were more potent in patients with no disease-associated biliary disease markers.

The initial endpoint achievement rate of gamma-glutaminyl transferase (GGT) is reflected in Figure 8. Preliminary data indicated that the pharmaceutical composition was more potent in patients with GGT content = <60 IU/L in Study Groups 1 and 2.

Further characterizing the same subpopulation of patients. The patient's NASH response (NAS score change) was measured and its GGT content = <33 IU/L, as shown in the table of Figure 9. Preliminary data indicate that the pharmaceutical composition is more potent in patients with GGT content = <33 IU/L and can be classified as having no biliary disease in study groups 1 and 2.

Alternatively, the gamma-glutamine thiotransferase (GGT) content on day 365 is also measured. A modification of the serum EPA/AA ratio of patients at 33 IU/L is shown in the table of FIG. Preliminary data indicating that the pharmaceutical composition has 33 IU/L is more effective in patients in study group 2 who can be classified as having no biliary disease.

The table in Figure 11 provides the content of γ-glutamine thiotransferase (GGT). 33 IU/L patients and γ-glutamine thiotransferase (GGT) content Corresponding reference values for parameters of liver function in patients 33 IU/L. Also analyzed the content of γ-glutamine thiotransferase (GGT) Serum direct bilirubin content in a subgroup of 33 IU/L patients. All patients were observed to be within the reference (normal) value of direct bilirubin content. Serum GGT content The serum direct bilirubin ranged from 0.03 to 0.17 for patients at 33 IU/L.

Figure 12 is a graph representing the serum EPA/AA ratio of EPA-E administered at different doses over time. The chart indicates the content of γ-glutamine thiotransferase (GGT) in Study Group 2. The EPA/AA ratio was significantly increased in patients 33 IU/L. For the EPA-E dose of 2700 mg/day, serum GGT content was observed on day 365. The improvement range for this ratio of patients with 33 IU/L is between 0.0406 and 1.637.

Also in γ-glutamine thiotransferase (GGT) content 33 IU/L patients and γ-glutamine thiotransferase (GGT) content ALP levels were analyzed in a subgroup of 33 IU/L patients. Some patients with GGT >= 33 IU/L and placebo groups showed ALP values above the reference (normal) values, as shown in FIG.

C) The third subpopulation of NASH patients is counted and classified as responders or non-responders as shown in FIG. Preliminary data indicates that the pharmaceutical composition is more potent in patients who have been determined to have a serum content of sFas equal to or less than 9.5 ng/mL (1800 mg EPA-E, TID) associated with NASH.

The ratio of sFas content to responder is reflected in Figure 15. Preliminary data indicates that the pharmaceutical composition is more potent in patients having a serum content (1800 mg EPA-E, TID) having an sFas associated with NASH equal to or less than 10.0 ng/mL, particularly equal to or less than 9.5 ng/mL.

Further characterizing the same subpopulation of patients. The NASH response (NAS score change) of a patient having a serum content of sFas equal to or less than 9.5 ng/mL was measured as shown in the table of FIG. Preliminary data indicates that the pharmaceutical composition has been determined to have a serum content of sFas equal to or less than 9.5 ng/mL and that study group 1 (1800 mg EPA-E, TID) can be classified as having no hepatocyte apoptosis or early hepatocyte apoptosis. The efficacy in patients is higher.

Subpopulations of NASH patients were counted and classified as responders or non-responders as shown in FIG. Preliminary data indicates that the pharmaceutical composition is determined to have a serum content of M30 equal to or less than 1500 U/L, particularly equal to or less than 900 U/L, and particularly equal to or less than 500 U/L (1800 mg EPA-E, TID) associated with NASH. The performance is higher.

The ratio of sFas and M30 content to the responder is reflected in FIG. Preliminary data indicates that the pharmaceutical composition has been determined to have an sFas associated with NASH equal to or less than 10.0 ng/mL, particularly equal to or less than 9.7 ng/mL, more specifically equal to or less than 9.5 ng/mL, and/or M30 equal to or less than 1500 U/ L, especially in patients with serum levels equal to or less than 600 U/L, more particularly equal to or less than 500 U/L (1800 mg EPA-E, TID and 2700 mg EPA-E, TID) are more potent.

Subpopulations of NASH patients were counted and classified as responders or non-responders as shown in FIG. Preliminary data indicates that the pharmaceutical composition is more potent in patients whose NASH risk score associated with NASH is determined to be equal to or less than 4.0, particularly equal to or less than 3.0 (1800 mg EPA-E, TID).

Figure 20 provides reference values for parameters of hepatocyte apoptosis in patients with sFas 9.5 ng/mL and reference values as determined by Tamimi TI. et al, J. Hepatol., 54, 1224-1229, 2011. Preliminary data indicated that the M30 levels in patients with sFas 9.5 ng/mL were lower than those of sFas > 9.5 ng/mL and were almost identical to the reference values for NASH patients in the Tamimi article.

Alternatively, the improvement of the serum EPA/AA ratio of the patient-associated serum sFas equal to or less than 9.5 ng/mL on day 365 was also measured, as shown in the graph of FIG. Preliminary data indicates that the EPA/AA ratio in patients with sFas 9.5 ng/mL is higher than in patients with sFas > 9.5 ng/mL, which have higher efficacy of the pharmaceutical composition and can be classified as non-hepatocytes Apoptosis or has early hepatocyte apoptosis.

The table in Figure 22 provides the corresponding EPA/AA ratio results for patients with sFas equal to or less than 9.5 ng/mL and which can be classified as having no hepatocyte apoptosis or having early hepatocyte apoptosis. Preliminary number The EPA/AA ratio in patients with sFas ≦ 9.5 ng/mL was higher than those in patients with sFas > 9.5 ng/mL.

Example 3: Self-Emulsifying Formulation

0.5 g of soy lecithin, 1.0 g of polyoxyethylene (60) hydrogenated castor oil, 0.4 g of propylene glycol and 3.1 g of EPA-E were weighed and mixed while heating to a temperature of about 70 ° C to prepare a self-emulsifying composition. After substituting with nitrogen, the self-emulsifying composition was hermetically sealed and stored at room temperature until evaluation. The formulation of the self-emulsifying composition is shown below:

Example 4: Self-Emulsifying Formulation

0.5 g of soy lecithin, 1.0 g of polyoxyethylene (50) hydrogenated castor oil, 0.4 g of propylene glycol and 3.1 g of EPA-E were weighed, and the self-emulsified composition was prepared and stored by repeating the procedure of Example 3. The formulation of the self-emulsifying composition is shown below:

Example 5: Self-Emulsifying Formulation

0.5 g of soy lecithin, 0.9 g of polyoxyethylene castor oil, 0.6 g of propylene glycol and 3.0 g of EPA-E were weighed, and a self-emulsified composition was prepared and stored by repeating the procedure of Example 1. The formulation of the self-emulsifying composition is shown below:

Example 6: Self-Emulsifying Formulation

0.6 g of soy lecithin, 0.6 g of polyoxyethylene (60) hydrogenated castor oil, 0.5 g of propylene glycol and 3.3 g of EPA-E were weighed, and a self-emulsified composition was prepared and stored by repeating the procedure of Example 1. The formulation of the self-emulsifying composition is shown below:

Example 7: Self-Emulsifying Formulation

0.5 g of soy lecithin, 0.5 g of polyoxyethylene (50) hydrogenated castor oil, 0.5 g of propylene glycol and 3.5 g of EPA-E were weighed, and a self-emulsified composition was prepared and stored by repeating the procedure of Example 3. The formulation of the self-emulsifying composition is shown below:

Example 8: Self-Emulsifying Formulation

Weigh 0.3 g soy lecithin, 0.3 g polyoxyethylene (20) sorbitan monooleate, 0.9 g polyoxyethylene (60) hydrogenated castor oil, 0.4 g propylene glycol and 3.1 g EPA-E, and repeat The procedure of Example 3 prepared and stored a self-emulsifying composition. The formulation of the self-emulsifying composition is shown below:

Example 9: Self-Emulsifying Formulation

Weigh 0.22 g of soy lecithin, 0.36 g of polyoxyethylene (20) sorbitan monooleate, 0.36 g of polyoxyethylene 35 castor oil, 1.2 g of purified water, and 4.0 g of EPA-E, and repeat Example 3. The procedure prepares and stores a self-emulsifying composition. The formulation of the self-emulsifying composition is shown below:

Claims (107)

A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: a. selecting an individual having or suspected of having a fatty liver disease or condition, wherein the system is free of diabetes, pre-diabetes or Mild diabetes; and b. administration of a therapeutically effective amount of ethyl eicosapentaenoate (EPA-E), eicosapentaenoic acid (EPA) or a pharmaceutically acceptable indoleamine, salt or ester thereof Or a pharmaceutical composition of a phospholipid. A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: a. selecting an individual having or suspected of having a fatty liver disease or condition, wherein i. the serum HbA1c content of the individual is equal to Or less than 6.4% or ii. the individual has a fasting serum glucose content of 125 mg/dl or less; and b. administering a therapeutically effective amount of ethyl eicosapentaenoate (EPA-E), eicosapentaene A pharmaceutical composition of an acid (EPA) or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof. A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: a. selecting an individual having or suspected of having a fatty liver disease or condition, wherein i. the serum HbA1c content of the individual is equal to Or less than 6.4% or ii. the individual has a fasting serum glucose content of 125 mg/dl or less; and b. administering a therapeutically effective amount of ethyl eicosapentaenoate (EPA-E), eicosapentaene Acid (EPA) or its pharmaceutically acceptable indoleamine, salt, ester or phospholipid The pharmaceutical composition; and c. administration in step b causes the serum EPA/AA ratio in the individual to be equal to or greater than 0.4 compared to the baseline EPA/AA ratio. A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: a. selecting an individual having or suspected of having a fatty liver disease or condition, wherein i. the serum HbA1c content of the individual is equal to Or less than 6.4% or ii. the individual has a fasting serum glucose content equal to or less than 125 mg/dl; iii. wherein the individual has not been treated with an anti-diabetic agent or has been previously treated with an anti-diabetic agent; and b. administration of a therapeutically effective amount comprises A pharmaceutical composition of ethyl eicosapentaenoate (EPA-E), eicosapentaenoic acid (EPA) or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof. A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: a. selecting an individual having or suspected of having a fatty liver disease or condition, wherein i. the serum HbA1c content of the individual is equal to Or less than 6.4% or ii. the individual has a fasting serum glucose content of 125 mg/dl or less; and b. administering a therapeutically effective amount of ethyl eicosapentaenoate (EPA-E), eicosapentaene A pharmaceutical composition of an acid (EPA) or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof in combination with one or more anti-diabetic agents. A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: (a) selecting an individual having: i.NAS score greater than or equal to 3; or ii. steatosis score equal to or greater than 1; or iii. lobular inflammatory score equal to or greater than 1; or iv. flatness score equal to or greater than 1; or v. fibrosis score equal to or Greater than 1; (b) administering to the individual a therapeutically effective amount of ethyl eicosapentaenoate (EPA-E), eicosapentaenoic acid (EPA) or a pharmaceutically acceptable indoleamine or salt thereof a pharmaceutical composition of an ester or a phospholipid; and wherein the individual has a serum HbA1c content of 6.4% or less or ii) the individual has a fasting serum glucose content of 125 mg/dl or less. The pharmaceutical composition according to any one of claims 1 to 6, wherein the system is free from diabetes. The pharmaceutical composition according to any one of claims 1 to 6, wherein the system is pre-diabetes. The pharmaceutical composition according to any one of claims 1 to 6, wherein the system is mildly diabetic. A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: selecting an individual having or suspected of having a fatty liver disease or condition, wherein the individual exhibits normal or substantially normal bile function Or the serum gamma glutamine thiol transferase (GGT) content is normal or substantially normal; and administration of a therapeutically effective amount of ethyl eicosapentaenoate (EPA-E), eicosapentaenoic acid (EPA) Or a pharmaceutically acceptable pharmaceutical composition of a guanamine, salt, ester or phospholipid. A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: selecting an individual having or suspected of having a fatty liver disease or condition, wherein the individual exhibits normal or substantially normal bile function Or the serum γ-glutaminyl transferase (GGT) content is equal to or less than 78 IU/L, or the male GGT content is equal to Or less than 85 IU/L and the female GGT content is equal to or less than 55 IU/L. A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: selecting an individual having or suspected of having a fatty liver disease or condition, wherein the individual exhibits normal or substantially normal bile function Or the serum γ-glutaminyl transferase (GGT) content is equal to or less than 33 IU/L, or the male GGT content is equal to or less than 30 IU/L and the female GGT content is equal to or less than 24 IU/L; and administering a therapeutically effective amount A pharmaceutical composition comprising ethyl eicosapentaenoate (EPA-E), eicosapentaenoic acid (EPA) or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof. A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: selecting an individual having or suspected of having a fatty liver disease or condition, wherein the individual exhibits normal or substantially normal bile function Or the serum γ-glutaminyl transferase (GGT) content is equal to or less than 33 IU/L, (a) administering to the individual an effective amount of ethyl eicosapentaenoate (EPA-E), eicosapentaene a pharmaceutical composition of an acid (EPA) or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof; (b) improving the steatosis and lobular inflammatory condition of the individual, and the fibrosis stage score does not deteriorate; c) The individual exhibits at least one of the following changes in labeling compared to the pre-treatment baseline: ALT, AST, TG, TG/HDL ratio, free fatty acid, AA, MUFA, palmitoleic acid, oleic acid, oleic acid/ Stearic acid ratio, palmitoleic acid/palmitic acid ratio, stearic acid/palmitic acid ratio, γ-linolenic acid/linolenic acid ratio, adrenal acid/AA ratio, ferritin, thioredoxin, TNFα, sTNF -R1, sTNF-R2, Hs-CRP, CTGF, sCD40, leptin, complement factor D, CK18 , serum HMGB1, Fas, hyaluronic acid, type IV collagen (7s domain), procollagen III peptide or PAI-1 reduced by at least 1%; EPA or EPA / AA ratio increased by at least 5%; DPA, AA / high - γ -linolenic acid ratio or serum adiponectin Increase by at least 1%; ALP, bilirubin, GGT, albumin, HDL-C, LDL-C, TC, non-HDL-C, HOMA-IR, HbA1c, glucose, fasting plasma glucose, postprandial plasma glucose, OGTT, Platelet count or BMI does not worsen. A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: (a) selecting an individual, at least one selected from the group consisting of a NAS score, a steatosis score, a lobular inflammatory score, a bloating score, and a fiber The criteria for the group consisting of fatty phase shows fatty liver disease; and wherein the individual exhibits a serum gamma glutamine thiotransferase (GGT) content of 33 IU/L or less; and (b) administration of a therapeutically effective amount comprising twenty carbon five A pharmaceutical composition of ethyl enoate (EPA-E), eicosapentaenoic acid (EPA) or a pharmaceutically acceptable guanamine, salt, ester or phospholipid thereof. A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: (a) selecting an individual having the following: vi. NAS score greater than or equal to 3; or vii. fat degeneration score equal to or greater than 1; or viii. the lobular inflammatory score is equal to or greater than 1; or ix. the swell index is equal to or greater than 1; or x. the fibrosis score is equal to or greater than 1; (b) determining the individual's gamma glutamine thiotransferase ( GGT) serum content; and (c) if i) shows a serum gamma glutamine thiotransferase (GGT) content of 33 IU/L or less, administering to the individual a therapeutically effective amount comprising eicosapentaenoic acid B A pharmaceutical composition of an ester (EPA-E), eicosapentaenoic acid (EPA) or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof. A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: selecting an individual having or suspected of having a fatty liver disease or condition, wherein the individual exhibits no hepatocyte apoptosis or early liver Apoptosis; and administering to the individual a therapeutically effective amount of ethyl eicosapentaenoate (EPA-E), eicosapentaenoic acid (EPA) or a pharmaceutically acceptable indoleamine, salt thereof, A pharmaceutical composition of an ester or phospholipid. A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: selecting an individual having or suspected of having a fatty liver disease or condition, wherein the individual exhibits no hepatocyte apoptosis or early liver Apoptosis or serum soluble Fas (sFas) content equal to or less than 10.0 ng / mL and / or serum cytokeratin -18M30 (M30) content is equal to or less than 1500 U / L or NASH risk score is equal to or less than 3.0; and administration An effective amount of a pharmaceutical composition comprising ethyl eicosapentaenoate (EPA-E), eicosapentaenoic acid (EPA) or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof. A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: selecting an individual having or suspected of having a fatty liver disease or condition, wherein the individual exhibits no hepatocyte apoptosis or early liver Apoptosis or serum soluble Fas (sFas) content is equal to or less than 10.0 ng / mL and / or serum cytokeratin -18M30 (M30) content is equal to or less than 1500 U / L or NASH risk score is equal to or less than 3.0, (a) direction The individual is administered an effective amount of a pharmaceutical composition comprising ethyl eicosapentaenoate (EPA-E), eicosapentaenoic acid (EPA) or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof; (b) improving the steatosis and lobular inflammatory condition of the individual and the fibrosis stage score does not deteriorate; and (c) the individual exhibits at least one of the following compared to the pre-treatment baseline content Marker changes: ALT, AST, TG, TG/HDL ratio, free fatty acids, AA, MUFA, palmitoleic acid, oleic acid, oleic acid/stearic acid ratio, palmitoleic acid/palmitic acid ratio, stearic acid/palm Acid ratio, γ-linolenic acid/linolenic acid ratio, adrenal acid/AA ratio, ferritin, thioredoxin, TNFα, sTNF-R1, sTNF-R2, Hs-CRP, CTGF, sCD40, leptin, Complement factor D, CK18 fragment, serum HMGB1, Fas, hyaluronic acid, type IV collagen (7s domain), procollagen III peptide or PAI-1 reduced by at least 1%; EPA or EPA/AA ratio increased by at least 5%; DPA , AA/high-γ-linolenic acid ratio or serum adiponectin increased by at least 1%; ALP, bilirubin, GGT, albumin, HDL-C, LDL-C, TC, non-HDL-C, HOMA-IR , HbA1c, glucose, fasting plasma glucose, postprandial plasma glucose, OGTT, platelet count, M30, sFas, NASH risk score or BMI did not worsen. A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: (a) selecting an individual, at least one selected from the group consisting of a NAS score, a steatosis score, a lobular inflammatory score, a bloating score, and a fiber The criteria for the group consisting of fatty phase showed fatty liver disease; and wherein the individual showed no hepatocyte apoptosis or early hepatocyte apoptosis or serum soluble Fas (sFas) content equal to or less than 10.0 ng / mL and / or serum cytokeratin - 18M30 (M30) content equal to or less than 1500 U / L or NASH risk score equal to or less than 3.0; and (b) administration of a therapeutically effective amount of ethyl eicosapentaenoate (EPA-E), eicosapentaene A pharmaceutical composition of an acid (EPA) or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof. A pharmaceutical composition for treating a fatty liver disease or condition in an individual in need thereof, the treatment comprising: (a) selecting an individual having: xi.NAS score greater than or equal to 3; or xii. steatosis score equal to or greater than 1; or xiii. lobular inflammatory score equal to or greater than 1; or xiv. swell score equal to or greater than 1; or xv. fibrosis score equal to or Greater than 1; (b) determining the soluble Fas (sFas) serum content and/or serum cytokeratin-18M30 (M30) content or NASH risk score of the individual; and (c) if i) exhibits sFas content equal to or less than 10.0 ng If the /mL and/or M30 content is equal to or less than 1500 U/L or the NASH risk score is equal to or less than 3.0, then the subject is administered a therapeutically effective amount of ethyl eicosapentaenoate (EPA-E), twenty carbons. A pharmaceutical composition of pentaenoic acid (EPA) or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the individual does not receive a diabetes treatment or an anti-diabetic agent. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the individual receives at least one diabetes treatment or at least one anti-diabetic agent. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the individual receives at least one diabetes treatment or at least one anti-diabetic agent administered concurrently with the pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the antidiabetic agent is selected from the group consisting of PPARγ agonist, biguanide, protein tyrosine phosphatase-1B (PTP-1B) Inhibitors, meglitinide, alpha glucoside hydrolase inhibitors, insulin secretagogues, A2 antagonists, insulin and related compounds, PPAR dual agonists, SGLT2 inhibitors, GSK 3β/GSK 3 inhibitors, Dipeptidyl peptidase IV (DP-IV) inhibitors, peptides, sulfonamides, and non-sulfonylurea secretagogues. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the individual Diabetic diet. The pharmaceutical composition of any one of claims 1 to 6 and 10 to 20, wherein the individual consumes a Western diet. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the fatty liver disease or condition is selected from the group consisting of non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) ). The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the individual having or suspected of having a fatty liver disease or disorder comprises selecting an individual having a score selected from the group consisting of: greater than or A NAS score equal to 3, a steatosis score equal to or greater than 1, a lobular inflammatory score equal to or greater than 1, a swell score equal to or greater than 1, and a fibrosis score equal to or greater than one. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the individual selected to have or suspected of having a fatty liver disease or condition comprises an individual who is overweight. The pharmaceutical composition of claim 29, wherein the individual having or suspected of having a fatty liver disease or condition further comprises selecting an individual having a body mass index (BMI) greater than or equal to 25 kg/m ² . The pharmaceutical composition of any one of claims 1 to 6 and 10 to 20, wherein the individual selected to have or suspected of having a fatty liver disease or condition further comprises selecting an individual having a family history of fatty liver disease. The pharmaceutical composition of any one of claims 1 to 6 and 10 to 20, wherein the individual having or suspected of having a fatty liver disease or condition comprises selecting an individual having a NAS score greater than or equal to 4. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the individual is characterized by at least one criterion selected from the group consisting of: a baseline ALT value of from about 10 to about 300 IU/L; a baseline AST Values range from about 10 to about 250 IU/L; baseline steatosis grades range from about 2 to 3; and baseline lobular inflammatory grades range from about 2 to 3. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the fatty liver disease is characterized by a pre-treatment baseline content of at least one of the individuals selected from the group consisting of: ALT at 10 IU/L In the range of 300 IU/L, AST is in the range of 10 IU/L to 250 IU/L, HDL/C is in the range of 25 mg/dl to 55 mg/dl, and LDL-C is in the range of 100 mg/dl to 200 mg/dl, triglyceride. In the range of 100 mg/dl to 1000 mg/dl, TC is in the range of 170 mg/dl to 300 mg/dl, high TG and low HDL-C, TG/HDL-C ratio is in the range of 3.75 to 10, and non-HDL-C is in 100 mg. In the range of /dl to 250mg/dl, free fatty acids range from 400μ Eq/L to 1000μ Eq/L, HOMA-IR ranges from 1.5 to 5, HbA1c ranges from 5.7% to 10%, and fasting plasma glucose is 100mg/ Glucose intolerance and metabolic syndrome in the range of dl to 200 mg/dl. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the fatty liver disease is characterized in that at least one selected from the group consisting of individuals having fatty liver disease Pre-treatment baseline levels of the following group of criteria: low levels of EPA, DPA, DHA, EPA/AA, DHA/AA, DHA/DPA, AA/high-gamma-linolenic acid; and high levels of AA, MUFA , palmitoleic acid, oleic acid, oleic acid/stearic acid, palmitoleic acid/palmitic acid, gamma-linolenic acid/linolenic acid, adrenal acid/AA. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the EPA-E, eicosapentaenoic acid (EPA) or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof After about one year of administration, the individual exhibits at least one improvement selected from the group consisting of: a decrease in ALT value compared to the baseline ALT value; a decrease in AST value compared to the baseline AST value; The grade of steatosis was reduced compared to the baseline steatosis grade; and the lobular inflammatory grade was reduced compared to the baseline lobular inflammatory grade. The pharmaceutical composition of any one of claims 1 to 6 and 10 to 20, wherein the therapeutically effective amount of EPA-E administered to the individual is between about 1800 mg/day and about 2700 mg/day. The amount between. The pharmaceutical composition of any one of claims 1 to 6 and 10 to 20, wherein the therapeutically effective amount of EPA-E administered to the individual is at least 1800 mg/day. The pharmaceutical composition of any one of claims 1 to 6 and 10 to 20, wherein the therapeutically effective amount of EPA-E administered to the individual is at least 2700 mg/day. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the individual is further characterized by having at least one condition selected from the group consisting of high triglycerides and low HDL-C, glucose tolerance Suffering from bad and metabolic syndrome. The pharmaceutical composition of any one of claims 1 to 6 and 10 to 20, wherein the reduced ALT value is at least 5% lower than the baseline ALT value and/or the reduced AST value is at least 5 lower than the baseline AST value %. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, further comprising determining, prior to treatment, a baseline serum content of at least one member selected from the group consisting of: ALT at 10 IU/L to In the range of 300 IU/L, AST is in the range of 10 IU/L to 250 IU/L, HDL-C is in the range of 25 mg/dl to 55 mg/dl, LDL-C is in the range of 100 mg/dl to 200 mg/dl, and triglyceride is in the range of 100 IU/L to 250 IU/L. In the range of 100 mg/dl to 1000 mg/dl, TC is in the range of 170 mg/dl to 300 mg/dl, high TG and low HDL-C, TG/HDL-C ratio is in the range of 3.75 to 10, and non-HDL-C is in 100 mg/ In the range of dl to 250 mg/dl, free fatty acids range from 400 μEq/L to 1000 μEq/L, HOMA-IR ranges from 1.5 to 5, HbA1c ranges from 5.7% to 10%, and fasting plasma glucose is 100 mg/dl. Up to 200 mg / dl. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein after administration of ethyl eicosapentaenoate for at least 3 months, the individual exhibits at least the following baseline content A change in label: ALT, AST, TG, TG/HDL ratio, free fatty acid, AA, MUFA, palmitoleic acid, oleic acid, oleic acid/stearic acid ratio, palmitoleic acid/palmitic acid ratio, adrenal acid/AA Ratio, ferritin, sulphur Also protein, TNFα, sTNF-R1, sTNF-R2, Hs-CRP, CRGF, sCD40, leptin, complement factor D, CK18 fragment, serum HMGB1, Fas, hyaluronic acid, type IV collagen (7s domain), Procollagen III peptide or PAI-1 reduced by at least 1%; EPA or EPA/AA ratio increased by at least 5%; DPA, AA/high-γ-linoleic acid ratio or serum adiponectin increased by at least 1%; ALP, bilirubin , GGT, albumin, HDL-C, LDL-C, TC, non-HDL-C, HOMA-IR, HbA1c, glucose, fasting plasma glucose, postprandial plasma glucose, OGTT, platelet count or BMI do not worsen. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, which further comprises modifying the steatosis and lobular inflammatory condition of the individual, and the fibrosis stage score does not deteriorate. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, further comprising: improving the synthetic score of the NAS score (i) to ≦3 of the individual and the score of the fibrosis stage does not deteriorate, or (ii) At least two of the NAS components have a total improvement of ≧2 and the fibrosis stage score does not deteriorate. The pharmaceutical composition of any one of claims 1, 2, 4, 5, 6 or 14 to 20 further comprising an improvement in serum EPA/AA ratio compared to a baseline EPA/AA ratio. The pharmaceutical composition of claim 46, wherein the improvement in serum EPA/AA ratio is equal to or greater than 0.4 compared to the baseline EPA/AA ratio. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the pharmaceutical composition is administered to the individual 1 to 4 times a day. The pharmaceutical composition of any one of claims 1 to 6 and 10 to 20, wherein the composition is present in one or more capsules. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the composition comprises a self-emulsifying composition comprising 50% by weight to 95% by weight of omega-3 polyunsaturated fatty acid or Its pharmaceutically acceptable indoleamine, salt, phospholipid or ester. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the composition comprises a self-emulsifying composition comprising 50% by weight to 95% by weight of EPA-E, EPA or a pharmaceutical thereof An acceptable guanamine, salt, ester or phospholipid. A pharmaceutical composition according to claim 51, wherein the composition comprises a self-emulsifying composition comprising at least 60% by weight of EPA-E, EPA or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof. A pharmaceutical composition according to claim 51, wherein the composition comprises a self-emulsifying composition comprising at least 70% by weight of EPA-E, EPA or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof. The pharmaceutical composition of claim 51, wherein the composition comprises a self-emulsifying composition comprising at least 80% by weight of EPA-E, EPA or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof. A pharmaceutical composition according to claim 51, wherein the composition comprises a self-emulsifying composition comprising at least 90% by weight of EPA-E, EPA or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof. The pharmaceutical composition of claim 51, wherein the composition comprises a self-emulsifying composition comprising at least 95% by weight of EPA-E, EPA or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof. A pharmaceutical composition according to claim 51, wherein the composition comprises a self-emulsifying composition comprising at least 96% by weight of EPA-E, EPA or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid thereof. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the composition comprises from 5% by weight to 50% by weight of an emulsifier having a hydrophilic lipophilic balance of at least 10. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the composition comprises 10% to 50% by weight of an emulsion having a hydrophilic lipophilic balance of at least 10 Agent. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the composition comprises 20% to 50% by weight of an emulsifier having a hydrophilic lipophilic balance of at least 10. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the composition comprises 30% to 50% by weight of an emulsifier having a hydrophilic lipophilic balance of at least 10. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the composition comprises 40% to 50% by weight of an emulsifier having a hydrophilic lipophilic balance of at least 10. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the composition comprises an ethanol content of up to 4% by weight relative to the total content of the compound and the emulsifier. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the composition is free of ethanol. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the composition comprises from 5% by weight to 50% by weight of at least one emulsifier selected from the group consisting of polyoxyethylene hydrogenated castor oil , polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester And lecithin. The pharmaceutical composition of claim 65, wherein the emulsifier is at least one member selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, sucrose fat Acid esters, sorbitan fatty acid esters and glycerin fatty acid esters. The pharmaceutical composition of claim 66, wherein the polyoxyethylene hydrogenated castor oil is at least one member selected from the group consisting of polyoxyethylene (20) hydrogenated castor oil, poly Oxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, and polyoxyethylene (100) hydrogenated castor oil. The pharmaceutical composition of claim 66, wherein the polyoxyethylene sorbitan fatty acid ester is at least one member selected from the group consisting of polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan III Stearate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate and polyoxyethylene sorbitan monolaurate. The pharmaceutical composition of claim 66, wherein the sucrose fatty acid ester is at least one member selected from the group consisting of sucrose laurate, sucrose myristate, sucrose palmitate, sucrose stearate, and sucrose. Oleate. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the composition contains lecithin. The pharmaceutical composition of claim 70, wherein the lecithin is at least one member selected from the group consisting of soy lecithin, enzymatically degraded soy lecithin, hydrogenated soy lecithin, and egg yolk lecithin. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the composition contains a polyol. The pharmaceutical composition of claim 72, wherein the polyol is propylene glycol or glycerin. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the composition contains at least one member selected from the group consisting of eicosapentaenoic acid, docosahexaenoic acid and Its pharmaceutically acceptable indoleamines, salts, esters and phospholipids. The pharmaceutical composition of claim 74, wherein the composition contains less than 5% eicosapentaenoic acid and pharmaceutically acceptable indoleamines, salts, esters and phospholipids thereof. The pharmaceutical composition of claim 74, wherein the composition contains less than 3% eicosapentaenoic acid and pharmaceutically acceptable indoleamines, salts, esters and phospholipids thereof. The pharmaceutical composition of claim 74, wherein the composition contains less than 5% twenty-two carbon Hexenoic acid and its pharmaceutically acceptable indoleamines, salts, esters and phospholipids. The pharmaceutical composition of claim 74, wherein the composition contains less than 3% docosahexaenoic acid and pharmaceutically acceptable indoleamines, salts, esters and phospholipids thereof. The pharmaceutical composition of claim 50, wherein the composition comprises ethyl eicosapentaenoate and/or ethyl docosahexaenoate. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the composition comprises 5 to 50% by weight of an emulsifier, and the total content of the emulsifier is at least one selected relative to 100 parts by weight The compound of the group consisting of the following groups is 10 to 100 parts by weight: an omega-3 polyunsaturated fatty acid and pharmaceutically acceptable indoleamine, salt, ester and phospholipid thereof. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein the composition comprises 5 to 50% by weight of an emulsifier, and the total content of the emulsifier is at least one selected relative to 100 parts by weight The compound of the group consisting of free consisting of 10 to 50 parts by weight: EPA-E, EPA and its pharmaceutically acceptable indoleamines, salts, esters and phospholipids. The pharmaceutical composition according to any one of claims 1 to 6 and 10 to 20, wherein EPA-E, EPA or a pharmaceutically acceptable indoleamine, salt, ester or phospholipid present in the composition accounts for such a total At least 40% by weight of the fatty acid and its derivative. The requested item 1 to 6 and 10 to 20. The pharmaceutical composition according to any one of, wherein the pharmaceutical composition based ^{Epadel TM, Lovaza TM, Omacor TM} , Lotriga TM or Vascepa ^TM. The pharmaceutical composition according to any one of claims 1 to 6, wherein the individual has a serum HbA1c content of 6.4%. The pharmaceutical composition according to any one of claims 1 to 6, wherein the individual has a serum HbA1c content of between 5.7% and 6.4%. The pharmaceutical composition according to any one of claims 1 to 6, wherein the individual has a serum HbA1c content of 5.6%. The pharmaceutical composition according to any one of claims 1 to 6, wherein the individual's serum HbA1c The content is less than 5.6%. The pharmaceutical composition according to any one of claims 1 to 6, wherein the individual has a fasting glucose content equal to 125 mg/dL. The pharmaceutical composition according to any one of claims 1 to 6, wherein the individual has a fasting glucose content of less than 125 mg/dL. The pharmaceutical composition according to any one of claims 1 to 6, wherein the individual has a fasting glucose content of between 100 mg/dL and 125 mg/dL. The pharmaceutical composition according to any one of claims 1 to 6, wherein the individual has a fasting glucose content equal to 100 mg/dL. The pharmaceutical composition according to any one of claims 1 to 6, wherein the individual has a fasting glucose content of less than 100 mg/dL. The pharmaceutical composition according to any one of claims 1 to 6, wherein the serum HbA1c content of the individual is measured using a technique selected from the group consisting of high performance liquid chromatography (HPLC); immunoassay; enzyme analysis; colorimetric analysis Capillary electrophoresis and boric acid affinity chromatography. The pharmaceutical composition according to any one of claims 1 to 6, wherein the glucose content of the individual is measured using a method selected from the group consisting of FPG, RPG and OGTT. The pharmaceutical composition according to any one of claims 1 to 10, wherein the individual exhibits a serum γ-glutaminyl transferase (GGT) content of 24 IU/L or less. The pharmaceutical composition according to any one of claims 1 to 10, wherein the individual has no condition selected from the group consisting of alcoholic liver injury, drug-induced liver injury, chronic active hepatitis, cirrhosis, liver cancer, Hepatic steatosis and biliary tract disease. The pharmaceutical composition according to any one of claims 1 to 10, wherein the individual exhibits unobstructed or normal excretion of bile. The pharmaceutical composition according to any one of claims 1 to 10, wherein the individual does not have liver damage. The pharmaceutical composition according to any one of claims 1 to 10, wherein the individual does not exhibit Liver dysfunction. The pharmaceutical composition according to any one of claims 1 to 10, wherein the individual exhibits a normal amount of direct bilirubin. The pharmaceutical composition according to any one of claims 1 to 10, wherein the individual shows no biliary tract disease or the individual has an early biliary tract disease. The pharmaceutical composition according to any one of claims 1 to 10, wherein the individual selected to have or suspected of having a fatty liver disease or disorder comprises an individual selected to have a normal serum direct bilirubin content equal to or less than 0.4 . The pharmaceutical composition according to any one of claims 1 to 16 wherein the NASH risk score is calculated using the following formula: NASH risk score = -6.4894 + 0.0078 x M30 (U/L) + 0.4668 x sFas (ng/mL) ). The pharmaceutical composition according to claims 1 and 16 to 20, wherein the individual has no condition selected from the group consisting of alcoholic liver injury, drug-induced liver damage, chronic active hepatitis, cirrhosis, liver cancer, hepatic steatosis and Hepatocyte apoptosis. The pharmaceutical composition of claim 1 and 16 to 20, wherein the individual does not have liver damage. The pharmaceutical composition of claims 1 and 16 to 20, wherein the individual does not exhibit liver dysfunction. The pharmaceutical composition according to claims 1 and 16 to 20, wherein the individual exhibits no hepatocyte apoptosis or early hepatocyte apoptosis, or the subject has no hepatocyte apoptosis or is at an early stage of early hepatocyte apoptosis.