TW548105B - Composition and method for treating nonalcoholic steatohepatitis - Google Patents

Abstract

Nonalcoholic steatohepatitis (NASH) is a disease of the liver characterized by inflammation and damage to the liver cells. Typically, steatohepatitis involves inflammation of the liver related to fat accumulation, and mimics alcoholic hepatitis but is observed in patients who seldom or never consume alcohol. Nonalcoholic steatohepatitis can lead to serious liver damage, and ultimately cirrhosis. The present invention provides methods and compositions useful for the treatment or alleviation of nonalcoholic steatohepatitis and the pharmaceutical formulations for their administration to a human. Specifically, compositions comprised of lecithin, antioxidants and vitamin B complex are administered parenterally, most preferably by oral administration. Specific therapeutic formulations include admixtures of these compounds and specific dosage formulations include daily oral administrations of these compounds in tablet or powder forms.

Description

548105 Case No. 87120265 Amended 5. Description of the invention (1) Scope of the invention-The present invention generally relates to the treatment of liver diseases with dietary supplements containing lecithin, antioxidants and / or vitamin B complex. A preferred embodiment is the use of a composition and a dietary supplement comprising oral administration of egg filling month purpose, at least one antioxidant, and a vitamin B complex to treat or alleviate non-alcoholic steatohepatitis. BACKGROUND OF THE INVENTION The liver is the largest organ in the human body and is located above the right upper abdomen. This organ is quite complex and highly specialized, and performs many important biochemical functions. One of the important functions of the liver involves removing toxins from the body and making proteins (including energy storage and coagulation factors). The liver can also store minerals, vitamins and glucose in the form of glycogen (which can be metabolized in large quantities to provide energy). The liver also plays an important role in red blood cell metabolism and breaking down by-products of metabolism in certain bloodstreams. Nonalcoholic steatohepatitis (NASΗ) is a common liver disease for both men and women. However, it occurs most often in women and is particularly common in obese people. Although it has been observed that the disease is accompanied by several other pathological conditions (including diabetes, hyperlipidemia, and hyperglycemia), the cause and development of this disease and its causal or temporal relationship with other conditions are not fully understood . However, in NASH patients, certain liver tissue characteristics and dysfunctions are common. In particular, non-alcoholic steatohepatitis is associated with fatty deposits, tissue degeneration, inflammation, cell degeneration, liver cirrhosis, elevated free fatty acids, and other abnormalities and is often seen in patients with NASH. Steatohepatitis, which is an excess of fat in the liver, is often seen in hunger, excessive intake of carbohydrates, lack of protein-type energy, obesity, and steroid therapy.

O: \ 56 \ 56227.ptc Page 6 2001.02.16.006 548105 _Case No. 87120265_ Year Month Day__ 5. Description of the invention (2) The status of the law. The hypothesis explaining liver fat accumulation is the result of an increase in free fatty acid accumulation, an increase in fatty acids produced by the liver, and a decrease in free fatty acid oxidation or L D L cholesterol production or secretion. In some cases of steatohepatitis, increased concentrations of free fatty acids may involve the reaction of free fatty acids with biofilms. Patients with NASA rickets showed increased activity of aspartate transaminase and / or alanine transaminase, which is characterized by an activity of at least 150% of normal. In order to confirm the clinical diagnosis of NASH, it is necessary to determine the absence of alcohol intake to low levels of alcohol intake, and confirm that they have not previously been infected with hepatitis B virus or hepatitis C. Non-alcoholic fatty liver * Specific diagnosis of inflammation can also rely on detailed analysis of liver biopsy samples. Histologically confirmed features may include giant vesicular fat, liver cirrhosis, parenchymal inflammation, and the appearance of II Marrow (M a 1 10 r y) vitreous. Nearly 8% of patients undergoing a liver biopsy will show histological evidence of NAS. The most common physiological condition associated with NASH is obesity, and about 70% of NASH patients are clinically diagnosed as obese. NA is particularly common in obese patients undergoing jejunal shunt to treat obesity. In patients with NASA, the general tendency of the degree of obesity is related to the amount of steatosis and has nothing to do with non-insulin-dependent diabetes. However, non-insulin-dependent diabetes mellitus increases the prevalence of steatohepatitis, especially in patients who require insulin. Patients who lost weight before death did not appear to alleviate steatosis, and, paradoxically, obese patients who lost weight before death actually had a higher incidence of steatohepatitis. The disease is rare in patients under 30 years of age, but it is particularly common in patients in their 50s and 60s. · Liver biopsy samples tend to be similar to those seen in patients with alcoholic hepatitis, even in patients with NASA rickets who do not consume any alcohol. However, in comparison, NASH showed higher rates of cavitation (indicating diabetes) and steatosis than alcoholic hepatitis. Patients with alcoholic hepatitis also have higher levels

O: \ 56 \ 56227.ptc Page 7 2001.02.16.007 548105 _Case No. 87120265__Year Month_a_Amendment____ V. Description of the invention (3) The incidence of fibrosis around the veins and around the cells and the proliferation of the bile ducts. In general, the symptoms and histological damage seen in patients with alcoholic hepatitis are much more severe than those in NAS. There have been many experimental studies to improve understanding of NASH. For example, Susumu I toh and others studied 16 patients with non-alcoholic steatohepatitis and 22 patients with alcoholic hepatitis and found that these two liver-like diseases are different. Susumuto et al. Comparison between Nonalcoholic Steatohepatitis and Alcoholic Hepatitis, 82 The American Journal of G astroenterology L. 6 5 0 (1 9 8 July 7). Other examples are Ian R. ^

Wanless) and John S. Lentz, Fatty Liver Hepatitis (Steatohepatitis) and Obesity: An Autopsy Study with Analysis of Risk Factors, 12 -(Hepatology) 5: 1106 (1990) (concluded that fatty acids can cause necrosis of hepatocytes found in some obese individuals) and Bruce R. Bacon et al., Non-alcoholic Steatohepatitis: clinically extended, qualitative (Nonalcoholic Steatohepatitis: An Expanded Clinical Entity), 107 Gastroenterology 1 1 0 (1 994 years) (concluded that NASH should not be considered to be only seen in obese sugar 0 Diseases of women with urine). Bile deficiency is known to cause liver fat infiltration in animals such as rats, mice, pigs, and dogs. As a result, choline deficiency can prevent the liver from transporting fatty acids (such as triglycerides). Indeed, a recent study has shown

O: \ 56 \ 56227.ptc Page 8 2001.02.16.008 548105 Case No. 87120265 Revised _____ --- V. Description of the invention (4) Patients who receive nutrition parenterally may lack plasma-free choline And the formation of hepatic steatosis, and this deficiency can be reversed by egg androgen (androgen test) supplements. Alan Buchman et al., That squamous fat can increase the level of plasma free choline and reduce liver fatty degeneration in patients with long-term complete parenteral nutrition (Lecithin Increases Plasma Free Choline

Decreases Hepatic Steatosis in Long-Term Total Parenteral Nutrition Patients), 102 Gastroenterology 1363k (1922 years). Although nonalcoholic steatohepatitis is generally considered a progressive liver disease, the patient's condition tends to stabilize for several years after the patient shows the most common clinical manifestations of the disease. Most patients who had repeated biopsies over a period of many years generally showed no significant morphological changes during this period. To date, scientists have not found any biochemical, clinical, or histological tests that can distinguish patients with NASH as an appropriate type or a precursor to more severe liver disease (and even death). There is currently no fixed therapy for NASH patients. Weight loss is a common prescription because obesity is common in patients with NASH. The weight loss effect of weight loss has not been determined, however, because obese patients rarely maintain significant weight loss. · Description of the invention The present invention includes a method and a composition for treating or alleviating non-alcoholic steatohepatitis 'specifically' is a pharmaceutical preparation and method that can be administered to humans 311 as a part of the method of treating health, Alleviate or at least remedy the disease. The composition preferably contains dietary lecithin, antioxidant compounds, and / or vitamin complexes. The pharmaceutical composition is preferably formulated to be administered orally. The dosage range should cause liver Decrease in steatosis (indicated by increased liver density). For better clinical application of the present invention, NAS Η patients take regularly

2001.02.16.009 548105 _Case No. 87120265_Year Month__ V. Description of the invention (5) Good oral tolerated dose, monitor its liver function and histology to study its response to the formulation. DETAILED DESCRIPTION OF THE INVENTION The present invention is a pharmaceutically acceptable composition, usually administered as a dietary supplement, for the treatment or alleviation of non-alcoholic steatohepatitis, the main purpose of which is to reduce hepatic steatosis. In a preferred embodiment, the composition includes a dietary lecithin supplement and a dietary supplement containing an antioxidant and a vitamin B complex. Dietary lecithin supplements are preferably prepared in powder form. Antioxidant compound and vitamin B complex can be mixed into separate dosages, and are preferably made into tablets together. The preferred dosage range is 15 to 50 grams of dietary lecithin supplement and 675 to 4050 mg (1 to 6 tablets) of antioxidant / vitamin B complex supplements per day. However, it is best to take 20 grams of a dietary lecithin supplement and 1,350 mg (2 tablets) of an antioxidant / vitamin B complex supplement twice daily. As used herein, the term π lecithin π includes choline and choline phospholipids (such as phospholipids), and naturally occurring general choline-containing compounds (including printed lipid derivatives such as phospholipid serine). Lecithin is mainly composed of choline and inositol; these two compounds are used in the body to break down cholesterol and dietary fat. 1 _ Once lecithin is reduced to these two components, choline can be converted to ethylcholine, which is used for neuroactive (including brain and muscle functions) compounds. Lecithin can also help the body absorb vitamin A, vitamin D, and vitamin B1 in the digestive tract. Generally speaking, the dietary egg-filling supplements contain egg-filling / fat-filled choline / choline at a ratio of 1.1: 1 0: 50 and are often ingested to reduce triglycerides and cholesterol in the blood. In addition, lecithin has been studied as an agent to treat many different liver diseases, ranging from alcoholism to exposure to radiation and toxicity

〇- \ 56 \ 56227.ptc Page 10 2001.02.16.010 548105 Case No. 87120265 _5 Amendment 5. Description of the invention (6) Chemicals. -Phospholipid serine is a phospholipid related to the structural integrity and chemical function of cell membranes. Phospholipid serine can also be ingested as a supplement, and in patients lacking a phosphonium-based donor (ie, folic acid, vitamin B 12 and essential fatty acids), the ability of the brain to synthesize phospholipid serine is weakened, Instructed to be taken. Although dietary lecithin has been studied as a treatment for certain liver diseases as mentioned above, its dietary sources are more common in high-fat, high-cholesterol foods such as meat, liver, and eggs, and should be prone to obesity Avoidance of typical NAS sickness. Therefore, according to the present invention, the dietary lecithin is preferably taken orally as a supplement. Dietary lecithin supplements may be obtained from commercially available products or manufactured by techniques known in the art. In a preferred embodiment, granular phospholipid fragments from soybean lecithin rich in phospholipids choline are used. The supplement includes phospholipids choline (minimum 50%), phospholipids monoethanolamine (maximum 30%), lysophospholipids choline (maximum 5%), and other phospholipids (maximum 9%). The vitamin B complex of the present invention is a combination of two or more vitamin B, like all vitamins, which is necessary for the metabolism of higher organisms and other essential biological functions. Vitamin B is one of the water-soluble vitamins, and its typical functions such as coenzyme can interact with metabolic enzymes to complete certain specific biochemical functions. Vitamin B-1 (Thiamine) functions to release energy from carbohydrates, alcohol, and fat. One of the biochemically active forms of Beta -1, thiamine pyrollin, is a coenzyme for certain metabolic steps, including the citric acid cycle and the conversion of alanine to ethyl coenzyme. Thiamine can form coenzyme after phosphorylation by ATP-dependent pyrophosphatase. Thiamine pyrophosphate contains substituted pyrimidine nitrogen-containing isomers and thiazole nitrogen-sulfur-containing isomers. Thiazole partially provides pyruvate metabolism activity to provide non-oxidative decarboxylation.

O: \ 56 \ 56227.ptc Page 11 2001.02.16.011 548105 _ Case No. 87120265_Year Month Day__ V. Description of the invention (7) Vitamin B-2 (riboflavin) can be metabolized to flavin adenine sigmaline Dinucleotide (FAD) and flavin mononucleotide (F MN) coenzymes. Both coenzymes have an isopyridine ring that can accept two electrons in an enzyme reaction. Biochemically, vitamin B-2 can release energy from proteins, fats, and carbohydrates. Vitamin B-3 (nicotinic acid or nicotinamide) is involved in the synthesis of pyridine nucleotide. Nicotinic acid reacts with adenosine to form nicotinamide adenine dinucleotide (NAD), which plays an important electron carrier function in certain biochemical steps. Niacin also plays an important role in digestive function and maintaining blood ‘clear cholesterol concentration. Biochemically, vitamin B-3 is related to the oxidative metabolism of food intake and has been shown to play an important role in maintaining the circulatory system. Vitamin B-6 (pyridoxine) is similar in structure to pyridine, but contains a hydroxymethyl group in the para position. Biochemically, p-hydroxymethyl is oxidized to form an aldehyde, and the meta-hydroxyl group is phosphorylated to obtain pyridoxal phosphate. Vitamin B-6 is involved in amino acid transfer, ν decarbonylation, and chemical modification. Vitamin B-6 has also been shown to promote the formation of blood cells and heme, as well as carbohydrate, protein and fat metabolism. Vitamin B-12 (cyanocobalamin) contains a monovalent cobalt metal located in the center of a tetrapyrrole-like oxoporphyrin structure. Biochemically, vitamin B-1 2 provides a 基 group in many biochemical reactions (especially including the synthesis of choline and methionine) to synthesize certain compounds. Vitamin B-9, folic acid, which functions as an amidine-based donor after being reduced to tetrahydrofolate by the enzyme after interacting with the enzyme dihydrofolate reductase. Vitamin B-9 is reported to promote red blood cell formation and plays an important role in maintaining the nervous system > The antioxidant of the present invention contains at least one vitamin C or E and preferably contains other known antioxidants such as vitamin A and certain types of vitamins. It is preferred to use a selenium yeast composition to promote the bioavailability of selenium. This combination

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Mark W ^ HI, Costa Mesa, California]. According to the knowledge, Ben Sheming, the anti-emulsifier and the vitamin W complex are preferably administered together with the fat as part of a dietary supplement. The composition of a suitable composition containing a mixed antioxidant / vitamin B complex supplement is shown in Table 1. _ Describe the unit of each tablet (mg) Thiamine nitrate (vitamin B-1) 1.500 riboflavin (vitamin B-2) 1.753 nicotinamide (vitamin B-3) 20.101 pyridoxine HCL (vitamin B-6) 2.062 Cyanomethoxin (Vitamin B-12) ^ 0.600 D-Calcium Pantothenate 10.870 Folic Acid (Vitamin B-9) 0.408 D-Biotin (Vitamin H) __ 30.000 Barley Juice Powder _ 215.154 Wheat Germ Powder __ 100.000 Cold Carotene ___ 5.000 Ascorbic acid 50.000 Vitamin E acetate 71.429 Selenium yeast 1,600 μg / g 15.625 Stearic acid powder 3.250 Sylox (silicon dioxide) 9.750 Magnesium stearate ___ 6.500 MCC (methyl crystalline cellulose) 131.202 Total-675.200 # _

O: \ 56 \ 56227.ptc Page 13 2001.02. 16.013 548105 Case No. 87120265 Month Amendment V. Description of the invention (9) All other antioxidant / vitamin B complex compositions are from commercial products. After the general description of the present invention, further understanding can refer to the following examples, which are experimental studies to study the effects of dietary supplements (lecithin, antioxidants and vitamin B complex) on NASH patients. Example 1 Four patients (one male and three females) were recruited, and their aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) rose at least one and a half times the normal high value, and Liver biopsy in the first three months of the study has proven NASH. These patients did not have other chronic liver diseases and did not use complete parenteral nutrition or lipid-lowering agents. Each patient was given 20 grams of lecithin supplements and antioxidants (vitamins A, C, and E and selenium) and 300% twice the recommended daily dosage (RD A) twice daily. -Vitamin B complex for 12 weeks. AST, ALT, GGT (r-glutamine transpeptidase), alkaline phosphatase, total bilirubin, fat profile, and free choline were measured at the beginning of the experiment, 4th week, 8th week, and 12th week Serum concentrations, and plasma phospholipids bind choline and red blood cells. A computed tomography (CT) scan of the liver was obtained at the beginning of the experiment and at 12 weeks. Another liver biopsy was performed after treatment to confirm changes in fat infiltration measured by computed tomography. Portal inflammation, lobular activity, steatosis, and fibrosis were classified on a scale of 0 to 4. The average computerized tomographic tissue density of the liver and spleen was obtained from a number of representative cuts, and the unit was Hansfeld (Η 〇 n s f i e 1 d) (HU). Liver density is measured by the liver-spleen boundary, with 0 to 8 HU representing sideline fat changes, while negative HU values indicate significant fat infiltration. All the four patients had no drug side effects after the study. Furthermore, liver density increased by CT scan (4.9 9 ± 4. 6 5 H U before treatment compared with treatment

O: \ 56 \ 56227.ptc Page 14 2001.02. 16.014 548105 _ Case No. 87120265_Year Month and Day__ V. Description of the invention (10) -5 2 1 ± 8 · 0 7 HU after treatment; p < 0 · 0 5) indicates that all four patients showed a statistically significant reduction in hepatic steatosis. Histologically, steatosis was reduced in two of the four patients. No change in portal inflammation was observed, however, lobular activity increased slightly in two of the patients. Although a small increase in fibrosis can be seen, it cannot be judged as a positive or negative effect. The increase in fibrosis may result from local sampling deviations. In addition, a correlation between fibrosis and the degree of obesity has been observed, and the presence or development of fibrosis has not been shown to be directly related to the development or progression of NASH. The detailed biopsy results are shown in Table 2 below. 0 Table 2 Patent No. Portal inflammation Lobules Active steatosis Fibrosis Iron Liver Glycated core # 1 Before treatment 1 0 2 2 1 1 After treatment 1 1-1 3 1 1 # 2 Before treatment 2 1 2 2 0 0 After treatment 2 2 1 2 0 0 # 3 Before treatment 0 2 3 0 0 0 After treatment 0 2 3 2 0 0 # 4 Before treatment 0 1 1 0 0 1 After treatment 0 1 1 1 0 0 For those skilled in the art, it is obvious that the disclosed invention still has various changes, improvements, and application methods, and this application contains the scope allowed by law to be extended by specific embodiments. Although the present invention has been described with reference to certain preferred embodiments, the full scope of the present invention is not limited thereby, but is based on the scope of the following patent applications.

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Claims (1)

548105 Case No. 87120265 Amendment 6. Scope of Patent Application 1 1 · If the composition of the scope of patent application No. 1, 2, 3, 4, 5 or 6 is applied, it is used as an oral dietary supplement. 1 2. The composition according to item 7 of the patent application, wherein the lecithin dosage is 20 grams. 13. The composition according to item 8 of the scope of patent application, wherein the dosage of the combination of the antioxidant and the biotin B complex is 1375 mg. O: \ 56 \ 56227.ptc Page 18 2001.02.19.018 Page 1 2001.02.16.001 548105 _Case No: 87120265_ Year Month_ Xiu Wang.,, 4 .. y 1 ―,: .Γ H 6. Application for patent scope \ 1. A treatment for human non-alcoholic steatohepatitis A composition containing one dose of a pharmaceutically acceptable composition, which is composed of a combination of 15 to 50 grams of egg scale fat and 675 to 4050 mg of a vitamin B complex and an antioxidant . 2. The composition according to item 1 of the patent application, wherein lecithin is a dietary supplement. _ 3. The composition according to item 2 of the patent application scope, wherein the antioxidant is composed of vitamin C. 4. The composition according to item 2 of the patent application scope, wherein the antioxidant is composed of vitamin E. Paralysis 5. The composition according to item 2 of the patent application, wherein the antioxidant is composed of vitamin C or E and selenium. 6. The composition as claimed in item 5 of the scope of patent application, further comprising vitamin A 〇7. The composition as claimed in item 1, 2, 3, 4, 5 or 6 of the scope of patent application, wherein the dosage of dietary lecithin is It is between 15 and 50 grams. 8. For the composition of claim 1, 2, 3, 4, 5 or 6, the dosage of the antioxidant and vitamin B complex is between 675 and 4050 milligrams. 9. If the composition of the scope of patent application No. 1, 2, 3, 4, 5 or 6, is made daily containing 20 grams of lecithin and 135 milligrams of antioxidants and vitamin B complex _ Dosage form. 10. The composition according to item 2 of the scope of patent application, wherein the lecithin dietary supplement is rich in fat-filling biliary test. O: \ 56 \ 56227.ptc Page 17 2001.02.19.017