Method of treating non-alcoholic steatohepatitis (nash) with using cysteamine products. RU patent 2498795.

FIELD: medicine.

SUBSTANCE: group of inventions refers to treating fatty liver degeneration. The method of treating a patient suffering fatty liver degeneration involves administering a therapeutically effective amount of cysteamine or cystamine, or a pharmaceutically acceptable salt thereof as a part of a composition. The method of treating the patient suffering non-alcoholic fatty liver degeneration (NAFLD) or non-alcoholic steatohepatitis (HASH) involves administering the therapeutically effective amount of the composition containing cysteamine or cystamine, or the pharmaceutically acceptable salt thereof. In both methods, the composition may be presented by a delayed or controlled release dosage form containing an enteric coating and providing the improved delivery of cysteamine or cystamine, or the pharmaceutically acceptable salt thereof.

EFFECT: improving the method of treating.

24 cl, 3 ex, 7 dwg

The technical field to which the invention relates

The invention relates to the substances and methods for the treatment of fatty degeneration of the liver using products.

The level of technology

Fatty degeneration (infiltration of the liver (or steatohepatitis) often associated with excessive alcohol consumption or obese, but there are also other reasons, such as metabolic deficiency, including insulin resistance and diabetes. Fatty degeneration of the liver is the result of accumulation of fat in the vacuoles of the liver cells, leading to decreased function of the liver and possibly leading to cirrhosis or liver cancer.

fatty liver disease (NAFLD) is the spectrum of the disease, which occurs in the absence of alcohol abuse. Satisfactory treatment of fatty degeneration of the liver, such as NAFLD and NASH is currently unavailable.

Disclosure of the invention

The invention relates to a method of treatment of the subject is suffering from fatty degeneration of the liver, including the introduction of a therapeutically efficient quantity of the composition . In one embodiment fatty degeneration of the liver is selected from the group consisting of nonalcoholic fatty degeneration of liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fatty degeneration of the liver, resulting from hepatitis, fatty degeneration of the liver, which is the result of obesity, fatty degeneration of the liver, which is the result of diabetes, fatty degeneration of the liver, which is the result of insulin resistance, fatty degeneration of the liver, which is the result of hypertriglyceridemia , , disease Weber-, disease , acute fatty degeneration of the liver of pregnancy and lipo dystrophy. In another embodiment, the total daily dose composition is around 0.5-1.0 g/m 2 . In another embodiment composition injected at a frequency of 4 or less times a day (for example, one, two or three times a day). In one embodiment, the implementation of the composition is a pharmaceutical form of continuing or adjustable release that provides improved delivery or derived into the small intestine. Dosage form of continuing or adjustable release can provide a C max or derived , or biologically active metabolite, which, at least, approximately 35%, 50%, 75% or more higher than a C max achieved dosage form with the immediate-release, containing the same number of or derived . In another embodiment dosage form of continuing or adjustable release contains coating that releases a song , when the song reaches the small intestine or a section of the gastrointestinal tract of the subject in which the pH is greater than approximately 4.5. For example, the coating can be selected from the group consisting of cured gelatin, shellac, methacrylic acid copolymer type With NF, butyrate-phthalate cellulose, cellulose propionate-phthalate cellulose, (PVAP), acetate phthalate cellulose (CAP), acetate- cellulose (CAT), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, succinate , (CMEC), acetate succinate hydroxypropyl methylcellulose (HPMCAS) and polymers and copolymers of acrylic acid, is usually formed of methyl acrylate, ethyl acrylate, methyl methacrylate and/or with copolymers of esters of acrylic and methacrylic acid. The song can be administered orally or parenterally. In another embodiment way may result in some improvement in fibrosis of the liver compared to the States before the introduction of the composition . In another embodiment way leads to the reduction of fat liver, reduce the incidence of cirrhosis or progressive development of cirrhosis or reduce morbidity carcinoma. In one embodiment method leads to a decrease in the levels of liver aminotransferase levels before the introduction of the composition . In the following variant of the implementation of the introduction leads to a decrease in levels of hepatic transaminases approximately 10%-40% compared to levels before treatment. In another embodiment introduction leads to a decrease in the levels of alanine or aspartate aminotransferase have been subjected to the treatment of the patient, approximately up to 30%, 20% or 10% above the normal ALT levels or to normal ALT levels. In another embodiment introduction leads to a decrease in levels of serum ferritin levels before treatment composition . Methods and composition according to the invention may also include the introduction of a second agent in combination with the composition for the treatment of fatty degeneration of the liver. The subject may be adult, adolescent or child.

The one aspect of the description refers to a method of treatment of a patient suffering fat infiltration liver, including NAFLD or NASH, including the introduction of a therapeutically efficient quantity composition containing product. Methods include the use of product upon receipt of the medicinal product for the treatment of fatty degeneration of the liver and application product upon receipt of the drug for the introduction in combination with a second agent for the treatment of fatty degeneration of the liver. Included also the application of the second agent for the treatment of fatty degeneration of the liver, with the receipt of the drug for the introduction in combination with product. The description below applies to sets, containing product for the treatment of fatty degeneration of the liver, not necessarily with a second agent for the treatment of fatty degeneration of the liver, and instructions for use in the treatment of fatty degeneration of the liver. The term "fatty liver" may include or exclude NASH.

Short description of the shapes

Figure 1 shows the effect of the treatment at a dose of 0, 75 and 250 mg/kg/day, delivered by intra-peritoneal levels of aspartate aminotransferase (AST) in animals that were given food with high fat content (HFD) within 8 days. Also shown are the levels of AST to control animals not fed HFD. The graph shows the average values AST of blood samples collected at the analysis in the day -1 ("before") and in the analysis in day 8 (SD8).

Figure 2 shows the effect of treatment at a dose of 0, 75 and 250 mg/kg/day, delivered by intra-peritoneal levels of cholesterol in animals fed HFD within 8 days. Also shown are the levels of cholesterol for control animals not fed HFD. The graph shows the average values for cholesterol, blood samples selected for analysis in the day -1 ("before") and in the analysis in day 8 (SD8).

Figure 3 shows the effect of treatment at a dose of 0, 75 and 250 mg/kg/day delivered by intra-peritoneal levels of low-density lipoprotein-cholesterol (LDL-cholesterol) in animals fed HFD within 8 days. Also shown are the levels of LDL-cholesterol control animals not fed HFD. The graph shows the average values of LDL-cholesterol for blood samples selected for analysis in the day -1 ("before") and in the analysis in day 8 (SD8).

Figure 4 shows the effect of the treatment at doses of 0, 75 and 250 mg/kg/day, delivered by intra-peritoneal, the levels of lactate dehydrogenase (LDH) in animals fed HFD within 8 days. Also shown are the levels of LDH for control animals not fed HFD. The graph shows the average values for LDH of blood samples collected at the analysis in the day -1 ("before") and in the analysis in day 8 (SD8).

Figure 5 shows the effect of the treatment at doses of 0, 25, 75 and 250 mg/kg/day, delivered through drinking water, on the levels of AST in animals fed HFD for 8 weeks. Also shown are the levels of AST to control animals not fed HFD. The graph shows the average values AST ± CKO (SEM) for blood samples selected for analysis in the day -1 ("week 0") and on the last day of the week (week 2, 4, 6 or 8).

Figure 6 shows the effect of the treatment at doses of 0, 25, 75 and 250 mg/kg/day, delivered through drinking water, on the levels of LDH in animals fed HFD for 8 weeks. Also shown are the levels of LDH for control animals not fed HFD. The graph shows the average values LDH ± CKO (SEM) for blood samples selected for analysis in the day -1 ("week 0") and on the last day of the week (week 2, 4, 6 or 8).

Figure 7 shows the impact of treatment at doses of 0, 25, 75 and 250 mg/kg/day, delivered through drinking water, on the levels of high density lipoprotein-cholesterol (HDL-cholesterol) in animals fed HFD for 8 weeks. Also shown are the levels of HDL-cholesterol control animals not fed HFD. The graph shows the average values of HDL-cholesterol ± CKO (SEM) for blood samples selected for analysis in the day -1 ("week 0") and on the last day of the week (week 2, 4, 6 or 8).

Realization of the invention

Used in the context of and in the accompanying formula of the invention, the singular shall include the plural, unless other means. For example, the reference to "derivative" includes many of such derivative and the reference to "principal" includes an indication of one or several subjects and so on.

In addition, the use of the word "or" means "and/or", unless otherwise stated. Similarly, the terms "include", "includes", "including", "include", "includes" and "including" are used interchangeably and not assume that they are restrictive.

Should be further it is clear that when in the descriptions of the different options for implementing used the term "contains", the specialist in this sphere should be clear that in some specific cases, the option may alternatively be described with the use of the term "consisting essentially of" or "consisting of".

Unless otherwise stated, all technical and scientific terms used in the context, have the same meaning as what usually knows specialist in the field to which the invention. Although the methods and substances similar or equivalent methods and substances described in context, you can apply in practice methods and compositions, in the context describes sample methods, devices and materials.

Publication discussed above and throughout the text, offered only to describe the publication before the date of filing of this application. Nothing in the context should be construed as the assumption that the authors of the invention shall not have the right to date this description retroactively due to the previous description.

The invention relates to new therapies, which can reduce the symptoms associated with the disease fatty degeneration of the liver, in patients suffering from this disease. The invention relates to compositions that provide effective therapy for patients in need of treatment.

The following links provide expert in this field many common definition of terms used in this description: Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLEKULAR BIOLOGY (2d ed. 1994); THE CAMBRIDGE DICTIONARY OF SCIENCE AND TECHNOLOGY (Walker, ed., 1988); THE GLOSSARY OF GENETICS, 5 TH ED., R. Rieger, et al. (eds.), Springer Verlag (1991); and Hale and Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGE (1991).

Cysteamine is the predecessor of (GSH) predecessor protein and is currently permitted by the Department for quality control of food, medicines and cosmetics (FDA) for use in the treatment of cystinosis, of cystinosis. When cysteamine operates by converting cystine into cysteine and mixed disulfide of cysteine-, both of which then are able to leave the by conveyors cysteine and lysine respectively (Gahl et al., N Engl J Med 2002; 347(2): 111-21). In the cytosol mixed disulfide can recover his reaction with glutathione and released cysteine can be used for further synthesis of GSH. Synthesis of GSH of cysteine is catalyzed by two enzymes, gamma and GSH-synthetase. This metabolic pathway occurs in almost all types of cells, and the liver is the main producer and exporter of GSH. Restored mixed disulfide of cysteine- can also release cysteamine, which theoretically can then reenter the , associate additional cystine and repeat this process (Dohil et al., J Pediatr 2006; 148 (6): 764-9). In the latter study, introduction children with caused increased levels of in plasma, which then caused an extended efficacy in reducing levels of leukocyte cystine (Dohil et al., J Pediatr 2006; 148 (6): 764-9). This may be due to "recycling" where adequate number of medicinal product reached . If cysteamine is acting this way, producing the GSH can also be considerably increased.

Cysteamine is a potent tool, amplifying secretion of gastric acid, which is used for inducing a duodenal ulcer in laboratory animals; research on humans and animals have shown that the induced hypersecretion of gastric acid is very likely mediated by gipergastrynemii. In previous studies on children with who suffered the symptoms of regular functions bottom of the gastrointestinal tract, it was shown that one oral dose (11-23 mg/kg) causes and in 2-3 times increase hypersecretion of gastric acid and 50% increases in serum gastrin. Symptoms that are observed in these individuals, include abdominal pain, heartburn, nausea, vomiting and anorexia. In the application at the U.S. patent # 11/990869 and WO 2007/089670, and both seek the priority of a provisional patent application, US no 60/762715, registered on January 26, 2006 (all of which are included in context as a reference in their entirety) show that the induced hypergastrinemia occurs partly as a local effect on gastric, mainly G-cells in susceptible individuals. These data also suggest that this is also a systemic action gastrina release . Depending on the route of administration, gastrin levels of plasma usually reaches a maximum after intragastric delivery for 30 minutes, while the levels peaking later.

Subjects with required to take oral cysteamine (®) every 6 hours, day and night. When administered regularly cysteamine can Deplete the contents of cell cystine up to 90% (measured in circulating leukocytes), and was shown that it reduces the speed of the progressive development to kidney failure/transplantation and also eliminates the need for thyroid replacement therapy. Because of the difficulty of receiving ® reduction of the required dosage weakens the attachment to the medical scheme. In WO 2007/089670 shown that the delivery to the small intestine reduces gastric distress and ulceration, increases C max and increases the AUC. Shipping into the small intestine is useful due to the increased speed of absorption from the small intestine and/or smaller excretion that undergoes hepatic first passage, upon absorption over the small intestine. Reduction of cystine level in leukocytes observed within hours of treatment.

The invention relates to products applicable in the treatment of diseases and disorders of fatty degeneration of the liver. The term product refers generally to the , or its biologically active metabolite, or a combination of or applied and includes salts, esters, amides, alkylated derivatives, prodrugs, analogues, phosphorylated derivatives, sulfated derivative or applied or other forms, chemically modified through methods such as the introduction of marks (for example, radionuclides or different enzymes) or covalent attachment to the polymer, such as (derivatization with polyethylene glycol).

product includes cysteamine, tsistamin, biologically active metabolites, forms of connection, chemically modified in such a way as etherification, alkylation (for example, C1, C2 or C3), the introduction of marks (for example, radionuclides or different enzymes), covalent attachment to the polymer, such as (derivatization with polyethylene glycol), or their mixture. In some cases, the implementation of products include, but are not limited to, salt, salt, phosphorylated derivatives and sulfated derivatives.

Examples of other products include 2--1,1--2,N - and S-substituted cysteamine, AET, , , amifostine (U.S. patent 4816482). In one embodiment product, in particular includes N-acetylcysteine. In one embodiment products include, but not limited to described below structure:

where n is 2 or 3, each of the R 1 and R 2 represents hydrogen atom or an alkyl group, optionally substituted hydroxy, amino, - or , or is a or aryl group and X 1 represents a partition selected from the group consisting of =N CN =N-NO 2 , =N-COR 3 , =N-NR-COOR 3 , =N-NR-CONH 2 , =N-SO 2 R 3 , -CH-NO 2 , -CH-SO 2 R 3 , =C(CN) 2, =(CN)COOR 3 and a =C(CN)CONH 2 , where R 3 represents an alkyl or aryl group. In another aspect of product may contain radical associated with any number of non-toxic groups listed below

where R 1 represents hydrogen atom or an alkyl group with an unbranched or branched-chain, having 1-10 of carbon atoms.

Pharmaceutically acceptable salt products are also included in the description and contain pharmaceutically acceptable anions and/or cations. Pharmaceutically acceptable cations include, among other cations, cations of alkaline metals (e.g., Li + , Na + , K + ), cations of alkaline-earth metals (for example, Ca2+ , Mg 2+ ), non-toxic cations of metals and ammonia (NH 4+ ) and substituted ammonium (N(R') to 4+ , where R' represents the hydrogen alkyl or substituted alkyl, i.e. which includes methyl -, ethyl or hydroxyethyl, specifically, cations trimethylammonium, and ). Pharmaceutically acceptable anions include, among other anions, halides (for example, Cl - , Br - ), sulfate, acetates (for example, acetate, ), , , , citrata and lactate.

products can be covered shell. Covered shell medicine or pill refers generally to the drug or pill, which is covered by a substance ("enteric coated"), which remains intact or essentially intact, so the drug or tablet passes through the stomach, but dissolves and releases the drug in the small intestine.

the product may include additional pharmaceutically acceptable carriers or excipients. Pharmaceutically acceptable carrier or filler refers generally to the materials (substances)that are suitable for the introduction of the subject, where media or filler is not biologically harmful, or otherwise, does not cause undesirable actions. Such media or fillers are usually inert ingredients of the medicinal product. Media or filler usually enter a subject, together with the active ingredient without inducing any unwanted biological action or interaction harmful way with any of the other ingredients in the pharmaceutical composition, in which it is contained.

product or another active ingredient may contain a pharmaceutically acceptable salt, ester, or other derivative. For example, salts, esters or other derivatives containing biologically active forms to have similar biological effect, comparable with the "parent" connection. Approximate salt include salt and salt.

The active ingredient, pharmaceutical or other description of composition may contain a stabilising agent. Stabilizing agents usually are compounds that reduce the speed with which the pharmaceutical agent is destroyed, especially oral pharmaceutical product, in the environmental conditions during storage.

Used in the context of the term "pharmaceutically effective" or "effective number" refers to the number of connections, sufficient to lead to a reduction of the intensity of the symptoms, for example, treatment, cure, prevention, or improve the relevant medical condition, or the increase of the speed of the treatment, cure, prevention or improvement of such States usually provides a statistically significant improvement in patients subjected to treatment patient population. With regard to separate active ingredient introduced separately, the term therapeutically effective dose refers to the dose of this particular ingredient. With regard to the combination, therapeutically effective dose refers to the total quantities of active ingredients that lead to therapeutic action, regardless of whether injected them in combination, including sequentially or simultaneously. In one embodiment therapeutically effective amount product reduces the intensity of the symptoms of diseases, including but not limited to listed, fibrosis of the liver, excess fat in the liver, the incidence of cirrhosis or progressive development of cirrhosis, the incidence of carcinoma, elevated hepatic transaminases, such as ALT and AST, elevated levels of serum ferritin, elevated levels of gamma-glutamyltransferase (gamma-GT) and elevated levels of insulin, cholesterol and triglycerides in plasma.

fatty liver disease (NAFLD) is the spectrum of the disease, which occurs in the absence of alcohol abuse. It is characterized by the presence of steatosis (fat in the liver) and can be a manifestation of the liver and the metabolic syndrome (including obesity, diabetes and medications known to exacerbate hypertriglyceridemia). NAFLD is connected with , it causes liver disease in adults and children and may eventually lead to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2); 373-9). NAFLD severity extends from the relatively benign separate predominantly steatosis (i.e. non-alcoholic fatty degeneration of the liver or NAFL) to nonalcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppi: S 186-90). NASH is characterized by histological presence of steatosis, cytological bloating, diffuse inflammation and fibrosis (Contos et al., Adv Anat Pathol 2002; 37-51). Fibrosis of the liver, which is the result of NASH, can progress to cirrhosis or liver failure, and in some cases can lead to carcinoma.

Insulin resistance (and hyperinsulinemia) correlates with the severity of NAFLD, and is more pronounced in patients with NASH, than with a simple fatty degeneration of the liver (Sanyal et al, Gastroenterology 2001; 120(5); 1183-92). As a result of this takes place mediated by insulin suppression of lipolysis and circulating levels of fatty acids increase. Two factors associated with NASH include insulin resistance and increased delivery of free fatty acids to the liver. Insulin blocks oxidation of fatty acids. Increased formation of free fatty acids in the liver and interesterification oxidation leads to the accumulation of intrahepatic fat and increases susceptibility of the liver secondary damage.

Glutathione (gamma-; GSH) is the main endogenous antioxidants and the decrease of its content has an impact on the development of damage (Wu et al., J Nutr 2004; 134(3): 489-92). One such damage is acetaminophen poisoning, when the levels of the restored GSH become depleted when you try to and inactivate gepatotoksichesky metabolite drug. After the appearance of toxic doses of acetaminophen excess metabolite (N-) covalently associated with hepatic proteins and enzymes, which leads to damage to the liver. (Wu et al., J Nutr 2004; 134(3); 489-92; Prescott et al., Annu Rev Pharmacol Toxicol 1983; 23: 87-101). It turns out that elevated levels of glutathione therefore have some protective actions by reducing the ROS. Himself glutathione cannot easily enter cells, even when it is given in large quantities. However, the precursors glutathione really enter cells, and found that some of the predecessors of GSH, such as N-acetylcysteine, is effective in treating conditions such as toxicity caused by acetaminophen, slowing or preventing the depletion level of GSH (Prescott et al., Annu Rev Pharmacol Toxicol 1983; 23: 87-101). Examples predecessors GSH include cysteine, N-acetyl cysteine, methionine and other compounds such as cysteamine (Prescott et al., J hit Med Res 1976; 4 (4 Suppi): 112-7).

Cysteine is the main limiting factor for the synthesis of GSH, and such factors (e.g. insulin and growth factors), which stimulate the absorption of cysteine cells, which usually leads to higher levels of intracellular GSH (Lyons et al., Proc Nati Acad Sci USA 2000; 97(10): 5071-6; Lu SC. Curr Top Cell Regul 2000; 36: 95-11).

N-Acetylcysteine was administered to patients with NASH. In messages of Turkey shows that the obese individuals with NASH, subjected to treatment with N-acetylcysteine for 4-12 weeks, found improvement in levels of aminotransferase, gamma-GT, even if it was not specified change in index of body mass of the subject (Pamuk et al., J Gastroenterol Hepatol 2003; 18(10): 1220-1).

Cysteamine (HS CH 2 CH 2 NH 2 ) can easily cross cell membranes due to its small size. Currently cysteamine is enabled PDA (Food and Drug Administration) for the treatment of cystinosis, violations zistinoz. When cysteamine operates by converting cystine into cysteine and mixed disulfide of cysteine-, both of which then are able to leave the by conveyors cysteine and lysine, respectively (Gahl et al., N Engi J Med 2002; 347(2): 111-21). It was shown that treatment leads to a decrease in intracellular levels of cystine in circulating leukocytes (Dohil et al., J Pediatr 2006; 148(6): 764-9).

Studies in mice and with the participation of the people showed that cysteamine is effective in the prevention of induced acetaminophen damage (Prescott et al.. Lancet 1972; 2(7778): 652; Prescott et al., Br Med J 1978; 1(6116): 856-7; Mitchell et al., din Pharmacol Ther 1974; 16(4): 676-84). Describes what tsistamin and cysteine reduces liver cell necrosis induced by several (Toxicol Appi Pharmacol. 1979 Apr; 48(2): 221-8). Found that tsistamin reduces the intensity of the symptoms of liver fibrosis induced carbon through inhibition of tissue (Qiu et al., World J Gastroenterol. 13: 4328-32, 2007).

The prevalence of NAFLD in children is unknown as to confirm the diagnosis, a histological examination of the liver (Schwimmer et al., Pediatrics 2006; 118(4): 1388-93). However, prevalence estimates can be obtained from the data of child obesity with hepatic ultrasound echography and elevated levels of serum transaminase and information that 85% of children with NAFLD are obese. Survey data of the national survey of health and nutrition showed a threefold increase in the prevalence of obesity in childhood and adolescence during the last 35 years; the data for 2000 suggest that 14-16% of children aged 6-19 years obese with a BMI of>95% (Fishbein et al., J Pediatr Gastroenterol Nutr 2003; 36(1): 54-61), as well as the fact that 85% of children with NAFLD are obese.

In patients with histologically proven NAFLD levels of hepatic transaminases, especially alanine aminotransferase (ALT), are elevated from the upper limit of the normal up to 10 times a Schwimmer et al., J. Pediatr 2003; 143(4): 500-5; Rashid et al., J. Pediatr Gastroenterol Nutr 2000; 30(1): 48-53). The ratio of ALT/AST (aspartate aminotransferase), which >1 (range 1.5-1.7)and different from such a relationship alcoholic steatohepatitis, which is usually <1. Other serological tests abnormal, which may be abnormally enlarged with NASH include the level of gamma-glutamyltransferase (gamma-GT) and the levels of insulin, cholesterol and triglycerides in the plasma in starvation.

The exact mechanism by which development of NAFLD in NASH remains unclear. Because insulin resistance are associated with NAFLD and NASH, postulated that for the NASH require other additional factors. This postulate is called the hypothesis of the "two tremors Day CF. Best Pract Res Clin Gastroenterol 2002; 16(5): 663-78) and it includes, first, the accumulation of fat in the liver and, secondly, the presence of large quantities of free radicals with increased oxidative stress. steatosis is a hepatic accumulation of triglycerides and this, in turn, is a result of the imbalance between delivery of free fatty acids to the liver and the utilization of their liver. During periods of food intake with high calorie triglycerides will be accumulated and act as a backup source of energy. When calories in food are insufficient stored triglycerides (fat) are lipolysis and fatty acids are released into the bloodstream and is consumed by the liver. Oxidation of fatty acids will produce energy for recycling. Treatment of NASH currently revolves around reducing the two main pathogenetic factors, namely, the accumulation of fat in the liver and excessive accumulation of free radicals that cause oxidative stress. Accumulation of fat decreases reduced intake of fat, and increase calorie consumption. One therapeutic approach is to steadfastly supported and even weight loss. Although it is certainly not proven, it is shown that the >10% body weight loss in some cases, reduces the accumulation of hepatic fat, normalizes levels transaminaz liver and improves the condition when liver inflammation and fibrosis (Ueno et al, J. Hepatol 1997; 27(1): 103-7; Vajro et al., J Pediatr 1994; 125(2): 239-41; Franzese et al., Dig Dis Sci 1997; 42(7): 1428-32).

Some studies have shown that the reduction of oxidative stress by treatment with antioxidants is effective. For example, obese children who had steatosis, treated with vitamin E (400-1000 IU/day) for 4-10 months (Lavine J Pediatr 2000; 136(6): 734-8). Despite any significant changes in BMI, the average levels of ALT decreased from 175±106 IU/l up to 40±26 IU/l (P<0,01) and average levels of AST decreased from 104±61 IU/l to 33±11 IU/l (P 0,002). Levels of hepatic transaminases increased in patients who have chosen to continue therapy with vitamin E. Study involving adults and using vitamin E within one year showed a similar decrease levels of liver transaminases and the levels of markers of fibrosis TGFβ (Hasegawa et al., Aliment Pharmacol Ther 2001; 15(10): 1667-72).

Steatosis may also develop in steatohepatitis through oxidative stress by reactive oxygen compounds (ROS) and reduced antioxidant protection Sanyal et al., Gastroenterology 2001; 120(5): 1183-92). ROS can be formed in the liver by means of several metabolic pathways, including the mitochondria, in peroxisomes, cytochrome P450, NADPH-oxidase and (Sanyal et al., Nat Clin Pract Gastroenterol Hepatol 2005; 2(1): 46-53). It was shown that insulin resistance and increased hepatic oxidative stress and lipid through increased activity of hepatic CYP2EI (Robertson et al., Am J Physiol Gastrointest Liver Physiol 2001; 281(5): Gl 135-9; Leclercq et al., J Clin Invest 2000; 105(8): 1067-75).

In addition, containing (SH) compounds such as cysteamine, tsistamin and glutathione, are among the most important and active intracellular ants. Cysteamine protects the animals from the syndromes of exposure of bone marrow and gastric part-intestinal tract. The importance of SH connections further confirmed by the study of mitotic cells. These cells are the most susceptible to radiation damage in the sense of reproductive cell death, and noted that they have the lowest level of SH-connections. On the contrary, S-phase cells, which are the most resistant to radiation damage applying the same criterion to detect the highest levels own SH connections. In addition, when mitotic) cells treated , they become very resistant to radiation. It was also noted that cysteamine may directly protect the cells from induced mutations. It is considered that the protection is the result of the disposal of free radicals, either directly or through the release of protein coupled GSH. Enzyme, which allocates cysteamine of coenzyme A, found in the bird liver and kidney pigs. Recently conducted studies to demonstrate a protective effect from hepatotoxic agents acetaminophen, bromine benzol and .

Found to cysteamine in addition to his role as funds weakens tremors and prolong the life of mice with a gene mutation causing Huntington's disease (HD). This medicine may act by increasing the activity of proteins that protect nerve cells or neurons from degeneration. Cysteamine, apparently, inactivates the enzyme, named , and thus causes the decrease of protein Huntington (Nature Medicine 8, 143-149, 2002). Moreover it was found that tsistamin increases the levels of certain proteins. However, due to modern methods and preparation for shipping applied, destruction and weak absorption need excessive dosing .

Currently cysteamine is allowed only FDA for the treatment of cystinosis. Patients with usually required to take cysteamine every 6 hours. Ideally effective drug with adjustable release when possible introduction of twice a day can improve the quality of life of these patients.

The invention is not confined to a particular salt or complex air or derivative or applied; the composition of the invention can contain any connection from or applied derived or applied, or a combination or . The active agent in composition, i.e., cysteamine or tsistamin, you can enter in the form of a pharmaceutically acceptable salt, ester, Amida, prodrugs or analogue, or as a combination of them. Salts, esters, amides, prodrugs and analogs of active agents can be obtained by using standard methods, well-known specialists in the field of synthetic organic chemistry, they are described, for example, J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th ed. (New York: Wiley-Interscience, 1992). For example basic-additive salts obtained from neutral medicinal product with the use of conventional methods, including the reaction of one or more of free hydroxyl groups of the active agent with a suitable base. Usually a neutral form of the medicinal product dissolved in polar organic solvents such as methanol or ethanol, and it added base. The resulting salt is either deposited or it can be the highlight of the solution by adding less polar solvent. Suitable bases for education basic-additive salts include, but are not limited to, inorganic bases, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, or the like. Obtaining esters includes functionalization of hydroxyl groups, which may be present in the molecular structure of the medicinal product. Esters are usually derivative of free alcohol groups, i.e. parts, which are formed of the carboxylic acid formula R-COOH, where R represents an alkyl, usually lower alkyl. Esters, if you wish, you can again turn to the free acid, using the common methods hydrogenolysis or hydrolysis. Getting amides and Prokopenko can be performed in the same way. Other derivatives and analogues of active agents can be obtained using standard methods, well-known specialist in the field of synthetic organic chemistry, or you can learn the appeal to the appropriate literature.

Ways of manufacture of compositions in this description further provide the obtaining of compositions with enteric coated, which allow you to enter dose (2X/day compared with 4X/day), allow the patient to accurately observe the therapeutic recommendations and fewer gastrointestinal side effects, such as pain, heartburn, acid producing, vomiting, and other side effects (e.g., patients have a smell similar to that of rotten eggs - especially this problem appears when the patient reaches sexual maturity). Description refers to having coating compositions (/®) and compositions applied.

The invention relates to methods of treatment of rebirth liver fatty acids, including, but not limited to, non-alcoholic rebirth liver fatty acids (NAFLD), non-alcoholic steatohepatitis (NASH), fatty degeneration of the liver, resulting from hepatitis, fatty degeneration of the liver, which is the result of obesity, fatty degeneration of the liver, which is the result of diabetes, fatty degeneration of the liver, which is the result of insulin resistance, fatty degeneration of the liver, which is the result of hypertriglyceridemia , glycogenoses, disease Weber-, disease , acute fatty liver of pregnancy and lipodystrophy.

Efficiency is described in the context of the process or the composition can be estimated, for example, measurement of concentrations of leukocyte cystine. Additional evaluation of the effectiveness of different descriptions include measurement of attenuation of symptoms associated with fatty degeneration of the liver, including, but not limited to listed, liver fibrosis, content of fat in the liver, the appearance or progressive development of cirrhosis, the emergence of hepatocellular carcinoma occurrence, elevated hepatic transaminases, elevated levels of alanine aminotransferase (ALT), elevated aspartate aminotransferase (AST), and elevated levels of serum ferritin. The choice of dose therapy and may make doctor-specialist, depending on, for example, the gravity of the fatty degeneration of the liver and/or concentration of cystine. For example, the treatment of fatty degeneration of the liver can lead to reduced levels of hepatic transaminases approximately 10%-40% compared to before treatment. In a related embodiment treatment leads to a reduction in levels of alanine aminotransferase subjected to treatment of the patient to levels approximately 30%, 20% or 10% above the normal ALT levels or until the normal levels of ALT (&GE; 40 IU/l). In another embodiment processing product leads to lower levels of aspartate aminotransferase the patient to levels approximately 30%, 20% or 10% above the normal levels of AST or back to normal levels of AST.

In one embodiment description relates to a method of treatment NAFL using products by reducing oxidative stress caused by reactive oxygen connection (ROS) when steatohepatitis. This can be achieved with the use of through its direct or indirect ability to raise levels of glutathione in the liver. Glutathione has a protective effect against oxidative damage, but it could not easy to enter the cells, even when it is given in large quantities in the treatment. However, the precursors glutathione really enter cells, such predecessors include cysteine, N-acetylcysteine, S- (SAMe) and other compounds such as cysteamine.

The composition of the invention can be used in combination with a second agent, or other therapies, applicable for the treatment of NAFLD or NASH or other breaches of the type of rebirth liver fatty acids. For example, a song product can be entered with such drugs as /thiazolidinediones, which is used for the treatment of insulin resistance, including mesylate ( (®)), that the antidiabetic drug rosiglitazone (®), pioglitazone (®), as well as other agents, including, but not limited to listed, Metformin, sulfonylureas, alpha-glucosidase inhibitors, , vitamin E, (xenical™), protein Thistle sea (®) and antiviral agents.

In combination with the techniques and the compositions of the present invention for the treatment of diseases and disorders that is credited with NAFLD or NASH or are the result of NAFLD or NASH, you can apply other therapies that reduce side effects products. For example, the loss of urinary phosphorus leads to the appearance of rickets, and it may be necessary to recharge phosphorus. Carnitine is lost in the urine and levels in the blood become low. Carnitine allows the muscles to use body fat for providing energy. Sometimes it is necessary replenishment of hormones. Sometimes the thyroid gland cannot produce enough thyroid hormones. Therefore produce thyroxine (drops or tablets). Sometimes you need to be treated with insulin, if you receive diabetes when the pancreas does not produce enough insulin. Such treatment becomes very necessary for children who are treated product because treatment blocks the thyroid gland and pancreas. Some teenage boys require treatment with testosterone, if puberty is delayed. Growth hormone therapy can be shown, if the increase is insufficient, despite the good balance . Accordingly, such therapy can be combined with compositions product and the ways to describe. Additional therapy, including the use of omeprazole (®)can reduce adverse symptoms affecting the digestive tract.

The invention relates to products applicable in the treatment of diseases and disorders of fatty degeneration of the liver. For the introduction of products describe a person or animal subjects products preferably produce in the composition, containing one or more pharmaceutically acceptable carriers. As stated above, pharmaceutically or pharmaceutically acceptable carriers or excipients relate to molecular compounds and compositions that do not cause allergic or other adverse reactions with the introduction of the application of ways, well-known in this field, as described below, or admitted control over the quality of food, medicines and cosmetics USA or similar governing foreign authority as acceptable supplements to the oral or parenteral introduced pharmaceuticals. Pharmaceutically acceptable carriers include any and all clinically applicable solvents, dispersive environment, coatings, anti-bacterial and anti-fungal agents, isotonic and delaying the absorption agents and the like.

Pharmaceutical carriers include pharmaceutically acceptable salt, especially when the connection is present basic or acidic group. For example, when there is acid Deputy, such as-COOH, for the introduction intended to apply ammonium salt, sodium, potassium, calcium, and so forth. In addition, when there is an acid group, pharmaceutically acceptable ethers compounds (e.g., methyl tert-butyl, , and the like) are considered as forms of connections, and such esters are known in this area for the modification of the characteristics of the solubility and/or hydrolysis when applying the preparations of Prokopenko with steadfastly supported release.

When there is a core group (such as amino or main radical, such as pyridyl), salt, acid, such as hydrochloride, hydrobromide, acetate, maleate, , phosphate, methanesulfonate, p- and the like, is regarded as a form for the introduction.

In addition, the compounds can form with water or conventional organic solvents. Such considered as appropriate.

Song product can be administered orally, parenteral , intranasal, transdermally, through the mucous membrane of, inhalation of spray, vaginally, rectally or intracranial injection. The term parenteral used in context, includes methods for subcutaneous injection, intravenous, intramuscular, of intracavitary injections or infusions. The introduction of intravenous, intradermal, intramuscular, , , , , injection and/or surgical implantation in a certain place is considered as appropriate. Song for the introduction of any of the methods above, usually on the merits does not contain pyrogens and other impurities that may be harmful to the recipient. In addition, compositions for parenteral introduction, are sterile.

Various water carriers, for example, water water, 0,4% salt solution 0.3% solution of glycine or aqueous suspensions may contain active connection in the mixture with , suitable for the manufacture of aqueous suspensions. Such are agents, such as sodium salt of carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polivinilpirrolidon, gum and Arabian gum; dispersing or agents may be present in nature , for example, lecithin, or condensation products with fatty acids, for example, , or condensation products of ethylene oxide with aliphatic alcohols long-chain, for example, , or condensation products of ethylene oxide with incomplete esters derived from fatty acids and , such as , or condensation products of ethylene oxide with incomplete esters derived from fatty acids and anhydrides , for example, .

Water suspensions may contain one or more preservatives, for example, ethyl - or n-propyl p-hydroxybenzoate, one or more of coloring agents, one or more corrigentov and one or more sweetening agents, such as sucrose or saccharin.

In some cases, the implementation of product of this invention can be for storage and recreate in a suitable medium before using. You may use any suitable methods freeze-drying and re-create. Specialists in this field it is clear that lyophilization and rekeying can lead to different levels of loss of activity and that activity levels to compensate for the loss can be adjusted.

Dispersable powders and pellets, suitable for receiving water suspension addition of water and provide an active link in the mixture with a toothed or a wetting agent, agent and one or more preservatives. Examples of suitable dispersant or wetting agents and agents are agents that are already specified above. May also be additional , for example, sweetener agents, and colouring agents.

In one embodiment, the invention relates to the application of the composition product enteric coated. coverage is prolonged release until it reaches the intestines, usually small intestine. Due coatings delivery to the small intestine increases, resulting in increased absorption of the active ingredient with a decrease gastric side effects.

In some cases, the implementation of a substance to cover chosen to therapeutically active agent , when the dosage form reaches the small intestine or the area in which the pH of greater than 4.5. Coverage can be pH-sensitive substance that remains intact at the lower the pH value of the environment of the stomach, but that disintegrates or dissolves at pH, usually detectable in the small intestine of the patient. For example, substance coating begins to dissolve in aqueous solution at pH between approximately 4.5 and approximately 5.5. For example, the pH-sensitive substances will not be significant dissolution until dosage form is not out of the stomach. the pH of the small intestine gradually increased from approximately 4.5 to approximately 6.5 in the duodenum to approximately 7.2 in the distal parts of the small intestine. To ensure the expected dissolution corresponding to the time of passage through the small intestine approximately 3 hours (for example, 2-3 hours), and to make possible reproducible release it, the coating should start dissolving when the pH range in the small intestine. Therefore, the number of polymeric coating should be enough for the dissolution essentially for about three hours time passing within the small intestine, such as proximal and middle part of the colon.

coating used for many years to delay the release of the medicinal product of orally taken inside medicinal forms. Depending on the composition and/or thickness coating is resistant to stomach acid for the required periods of time before they start and allow released a medicinal product in the lower abdomen or the upper part of the small intestine. Examples of some of the coverings are described in U.S. patent №5225202, which is included fully in context as a reference. As described in U.S. patent №5225202, some examples of previously used coatings are beeswax and ; beeswax, Lac and pulp and cetyl alcohol, resin tree and shellac, and shellac and stearic acid (US patent # 2809918); polyvinylacetate and (US patent # 3835221) and neutral copolymer of poly (methacrylic esters, acids ( L30D) (F.W. Goodhart et al., Pharm. Tech., pp 64-71, April 1984); co-methacrylic acid and methyl ester of methacrylic acid () or neutral copolymer of poly (methacrylic esters of acid containing metal stearates (Mehta et al., USA patent №4728512 and 4794001). These coatings contain a mixture of fats and fatty acids, shellac and derivatives of shellac and sour phthalates cellulose, for example, sour phthalates cellulose, containing available . Cm. publication Remington on .1590 and Zeitova et al. (US patent # 4432966) for descriptions of suitable songs coatings. According to this, increased absorption in the small intestine due to coating compositions products could lead to increased efficiency.

cover is usually contains polymeric material which prevents the release of product in the environment of a stomach with low pH value, but which is ionized with slightly higher levels of pH, usually pH 4 or 5, and thus significantly dissolves in the small intestines with the gradual release of the active agent. According to this, among the materials for the most effective coatings are polyacrylic acid with RCA in the range of approximately 3-5. Suitable materials for coatings include, but are not limited to, the cured gelatin, shellac, methacrylic acid copolymer type With NF, butyrate-phthalate cellulose, cellulose propionate- cellulose, (PVAP), acetate phthalate cellulose (CAP), acetate- cellulose (CAT), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, succinate , (CMEC), acetate succinate, hydroxypropyl methylcellulose (HPMCAS) and polymers and copolymers of acrylic acid, is usually formed of methyl acrylate, ethyl acrylate, methyl methacrylate and/or with copolymers of esters of acrylic and methacrylic acid ( NE, RL, RS). For example, coverage may contain L30D, agent foaming and ((NRMS), where coverage is 10-13% of the final product.

In one embodiment composition product is administered in tablet form. Tablet manufactures of first enrolment product coverage. Manner education tablets context is the use of direct pressing of powders containing covered shell product, not necessarily in combination with thinners, binders, lubricating substances, means, painting substances, stabilizers or the like. As an alternative to direct to pressing pressed tablets can be obtained by means of wet granulation or dry granulation. Tablets can be molded and not compressed, and get them out of the wet substance containing a suitable water-soluble lubricating substance.

In some cases, the implementation of the composition product is a pharmaceutical form of the detainee or adjustable release, which provides a C max product, at least approximately 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 100% more than C max , provided dosage form with the immediate-release, containing the same number of product. In some variants of implementation of the C max of up to approximately 75%, 100%, 125% or 150% greater than C max dosage form with the immediate-release. C max refers to the maximum dose of product in the blood after taking a dose, and is an indicator that the drug is absorbed systemically.

Obtaining forms of pharmaceutical compositions with detainees (continued)regulated or steadfastly supported/prolonged release and with the required pharmacokinetic characteristics known in this region and can be done in various ways. For example, oral system with adjustable delivery include adjustable dissolution of the release (for example, regulation of dissolution or regulation dissolution matrix)with adjustable diffusion release (device with a reservoir or device with the matrix), ion exchange resin, osmotically modified release or system. Adjustable dissolution of the release can be achieved, for example, a slowdown in the rate of dissolution of the medicinal product in the gastrointestinal tract, the inclusion of a medicinal product in soluble polymer coated particles or granules of a medicinal product polymeric materials of different thickness. Adjustable diffusion release can be achieved, for example, regulation of diffusion through a polymer membrane or polymer matrix. Osmotically modified release can be achieved, for example, regulation influx of solvent through a semipermeable membrane, solvent, in turn, transfers the drug out through the laser-drilled holes. The difference in osmotic and hydrostatic pressure on any side of the membrane regulates the transfer of liquid. Prolonged preservation in the stomach can be achieved, for example, a change in the density of drugs, to the lining of the stomach or increased time swimming in the stomach. For more details, see the publication of the Handbook of Pharmaceutical Controlled Release Technology, Wise, ed., Marcel Dekker, Inc., New York, NY (2002), included in context as a reference in its entirety, for example. Chapter 22 ("An Overview of Controlled Release Systems").

Concentration product in these drugs can vary widely, for example, from less than approximately 0.5 wt.% usually approximately 1 wt.% or at least from 1 wt.% up to 15 or 20 wt.% and its mainly choose on the basis of the volume of liquid characteristics of manufacturing, viscosity, etc. specific to the selected route of administration. Existing methods of obtaining input compositions are known, or are obvious specialist in this field and are described in more detail, for example, in Remington's Pharmaceutical Science, 15 th ed.. Mack Publishing Company, Easton, Pa. (1980).

product is present in the composition of a therapeutically efficient quantity; composition is usually in the form of a dosed out medicinal form. The number of input product can, of course, depend on the age, body mass and the General condition of the subject, gravity exposed to treatment condition and assessment of medicine doctor. Appropriate therapeutic number will be known specialist in the field and/or described in the texts of relevant links and literature. Modern dose of the drug without cover approximately 1.35 g/m 2 body surface area and administered 4-5 times a day. One aspect of the dose administered either once daily or several times a day. product, you can enter one, two or three or four or five times a day. In some cases, the implementation of effective dose product can be in the range from 0.01 to 1000 mg / kg (mg/kg) of body weight per day. In addition, the effective dose can be 0.5 mg/kg 1 mg/kg and 5 mg/kg, 10 mg/kg 15 mg/kg to 20 mg/kg 25 mg/kg, 30 mg/kg 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 70 mg/kg, 75 mg/kg and 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, and it can be increased in increments of 25 mg/kg up to 1000 mg/kg, or dose can be between any two of the above quantities. In some cases, the implementation of product is administered to a total daily dose of approximately 0.25 g/m 2 up to 4.0 g/m 2 body surface area, for example, at least approximately 0,5, 0,6, 0,7, 0,8, 0,9, 1,0, 1,1, 1,2, 1,3, 1,4, 1,5, 1,7, 1,8, 1,9 or 2 g/m 2, or up to approximately 0,8, 0,9, 1,0, 1,1, 1,2, 1,3, 1,4, 1,5, 1,7, 1,8, 1,9, 2,0, 2,2, 2,5, 2,7, 3,0 or 3.5 g/m 2 . In some cases, the implementation of product can be entered at a total daily dose of about 1-1,5 g/m 2 body surface area or 0.5-1 g/m 2 body surface area, or about 0.7-0.8 g/m 2 body surface area, or approximately 1.35 g/m 2 body surface area. Molecular mass of salts or esters same active ingredient may vary depending on the type and weight of the balance of salt or ester. For the introduction of dosage forms such as tablets or capsules, or other oral dosage form containing product covered shell, applied dosage form with a total weight in the range of approximately 100 mg to 1000 mg Dosage form of the orally administered to a patient suffering from a disease fatty liver, including, but not limited to specified, NAFLD and NASH, which can be shown product. Introduction can continue for at least 3 months, 6 months, 9 months, 1 year, 2 years or more.

product covered shell can contain various , which are well-known in the pharmaceutical field, provided that such not have a destabilizing effect on any of the components in the composition. So, for example, such as binders, fillers to increase volume, and thinners, disintegrator, greasing substances, excipients, media and the like, can be combined with product. For solid compositions thinners are usually necessary to increase the amount of the pill to provide a practical size for pressing. Suitable diluents include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Connecting substances used for giving to a bonding properties of a tablet drug and thereby ensure that the tablet remain intact after pressing. Suitable connecting substances include, but are not limited to, starch (including corn starch and starch, swelling in cold water), gelatin, sugar (including sucrose, glucose, dextrose and lactose), polyethylene glycol, waxes, and natural and synthetic gums, for example, Arabian gum, sodium alginate, polivinilpirrolidon, cellulose polymers (including , , methylcellulose, hydroxyethyl cellulose, etc.) and . Greasing substances used to facilitate the manufacture of tablets; examples of suitable lubricants include, for example, calcium magnesium, calcium stearate and stearic acid, they are usually present in quantities of not more than approximately 1% of mass the weight of tablets. Disintegrator used to facilitate disintegration or "destruction" tablets after injection, they are usually starch, clay, cellulose, , gums or crosslinked polymers. If necessary, pharmaceutical composition, which is injected, and may also contain small amounts of non-toxic substances, auxiliary substances, such as wetting or emulsifying agents, buffer agents pH regulation and the like, for example, sodium acetate, , triethanolamine, sodium acetate, oleate and the like. Optionally, you can also add , colouring and/or sweetener agents. Other optional components for inclusion in the oral context include, but are not limited to, preservatives, agents, agents and the like. Fillers include, for example, insoluble substances such as silicon dioxide, titanium oxide, aluminium oxide, talc, kaolin, powder pulp, pulp and so on, but also soluble substances, such as mannitol, urea, saccharose, lactose, glucose, sodium chloride, sorbitol, and the like.

Pharmaceutical composition may also contain a stabilising agent, such as hydroxypropylmethylcellulose or polivinilpirrolidon, as described in U.S. patent №4301146. Other stabilizing agents include, but are not limited to, cellulose polymers such as hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, , acetate of cellulose acetate phthalate cellulose acetate- cellulose, hydroxypropyl methylcellulose phthalate, microcrystalline cellulose and sodium salt of carboxymethylcellulose, and vinyl polymers and co-polymers, such as polyvinyl acetate, , copolymer of vinyl acetate and krotonovoj acid and copolymers of ethylene and vinyl acetate. Stabilising agent is present in a quantity effective to ensure the required stabilizing action; usually this means that the attitude product to stabilizing agent is at least approximately 1:500 mass./mass, more typically around 1:99 mass./the masses.

Tablets can be produced first coating product shell. Way to make tablets context is the direct pressing of powders containing covered shell product, not necessarily in combination with thinners, binders, lubricating substances, , coloring tools, stabilizers or the like. As an alternative to direct to pressing, pressed tablets can receive by means of wet granulation or dry granulation. Tablets can be molded and not pressed for their use moistened substance containing a suitable water-soluble lubricating substance.

The composition of the invention can be used in combination with other therapies, applicable for the treatment of NAFLD and NASH. For example, in the combination (or simultaneously in a single composition, or in different compositions), you can enter antioxidants such as glycyrrhizin, Schizandra extract, ascorbic acid, glutathione, silymarin, lipoic acid and d-alpha tocopherol, and parenteral introduced to the subject of glycyrrhizin, ascorbic acid, glutathione and vitamins Century Alternatively, a combination of therapeutic agents can be administered consistently.

Efficiency of a method or composition according to the invention, you can estimate the dimension of the content and fatty acid metabolism in the liver. The establishment of the dose and the choice of therapy may make doctor-specialist subject, for example, from the severity of the NAFL.

In addition, various prodrugs you can "activate" use enteric coated. Prodrugs are pharmacologically inert, they do not act in the body, but after a prodrug absorbed, it splits it. approach was successfully used in a number of therapeutic areas, including antibiotics, and the treatment of ulcers. The advantage of using Prokopenko is that the active agent chemically protected and no active agent is not freed until the medicinal product does not pass the intestine and enters into the body cells. For example, a number of Prokopenko has connections S-S. Weak rejuvenating agents, such as cysteamine, restore these ties and release the drug.

According to this, the composition of the invention are applicable in combination with for regulated by the time of the release of the medicinal product. In this aspect prodrug you can enter with the subsequent introduction of a covered shell songs description (in the time required for activation of Prodrugs.

It should be clear that although the invention was described in combination with its concrete variants of implementation, it is assumed that the previous discussion, and examples, which are listed below are illustrative and do not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be evident for the specialists in the field to which it relates.

EXAMPLES

Example 1

Drug enteric coated

In WO 2007/089670 described introduction patients with using probe to determine the effectiveness of intestinal introduction for the improvement of patients with . In WO 2007/089670 shown that the introduction of in the small intestine improves the speed of absorption and increases the levels of in the plasma. Introduction into the small intestine also reduces the levels of cystine in leukocytes. These results showed that the introduction of in the small intestine was more effective than oral administration of .

Developed a drug enteric coated (-EU) for more efficient and easier administration. Capsules ® (Mylan Laboratories Inc., PA, USA) were covered shell using the device to cover Model 600 Wurster with camera coverage 4/6". Substance to cover is L30 (D-55, Rohm GmbH & Co KG, Darmstadt, Germany) and EU-connection (The Place Coating Inc, Verona, WI, Federal facilities establishment number 2126906). Capsules received with the use of approved PDA devices and substances.

coating experienced in vitro to confirm capsules in stomach acid. Testing was carried out by the placing of capsules in 100 ml of 0.1 n HCl solution for 2 hours at 37 deg C. Capsules considered acceptable, if less than 10% is released. After 2 hours of pH raised to the buffer pH 6.8 NaHCO 3 . Capsules considered acceptable if at least 80% released 2 hours.

Six adult subjects as of the controls and 6 patients with were studied by means of -EU. Levels in plasma were higher when patients took -EU than when they were regularly the drug ( OS). In addition, when patients with took -EU within 12 hours of levels of cystine in leukocytes remained approximately at the level of <0.2 and usually below 1 nmol /mg protein, it is suggested that this new drug is effective with the introduction of twice daily.

Example 2

Introduction patients suffering from fatty liver

It was shown that the introduction of reduces symptoms of cystinosis by reducing the damaging levels of cystine. To define the action on fibrosis, which causes liver damage in patients with NASPI, conduct , a preliminary study with an open label with the participation of 12 children and adolescents with non-alcoholic fatty degeneration of the liver, which subjected to treatment enteric coated.

For research using patients with a diagnosis NASH, who pledged to observe the lifestyle changes such as diet and physical load) for at least three months. Get a complete medical history and carry out an objective examination. Use evaluation symptoms developed for acid-peptic disease and previously applied for children treated with cysteamine. Take away the blood to determine the functions of the liver, including levels of transaminases, alkaline phosphatase, bilirubin, gamma-GT. Blood take for clinical analysis of blood, ESP, CRP, definition of the content of insulin in fasting and in fasting lipids and cholesterol, markers of oxidative stress and liver fibrosis (15 ml). Record the body weight of the patients.

The initial level for ALT in the study of set as & GE 60 IU/l and successful response to therapy is the normalization of a level or a decrease of 35% or more levels of hepatic transaminases. Normal levels of ALT take 40 IU/L. The subjects are introduced cysteamine enteric coated twice daily with total daily dose of 1 g/m 2 body surface area with a maximum dose of 1000 mg twice daily. Patients with usually take 1-1,5 g/m 2 body surface area/day.

Any person with a complaint significant gastrointestinal symptoms can have daily dose reduced by 10%. If GI symptoms are stable for 3 days, despite a 10% reduction in dose, you will be allowed an additional 10% reduction of the dose (up to a maximum of 50% of the original dose). If the symptoms are persistent, despite the maximum dose reduction of the EU-, subject excluded from the study.

If the symptoms are severe, the subject may leave the study at any point. If patients were subjected to suppression therapy acid secretion, such as proton pump inhibitors, they are asked to stop therapy one week before the beginning of treatment the EU-. Patients treated during the first 3 months and for a maximum of 6 months EU-. If detected 10-25% decrease in the levels of hepatic transaminases, the treatment is prolonged for a further 3 months. If, however, there is <10% reduction ALT after 3 months of therapy, the subject will continue to take part in the study. If there is an improvement in the levels of liver serum transaminases (>35%) after six months of therapy, monitor patients for an additional six months of medical examination and blood test, conducted every two months. Menstruating women will be subjected to the test of pregnancy blood in the beginning of the study and every month during the study. If required, patients are advised to take contraceptive precautions, using the method of double barrier.

Patients are asked to keep a diary of symptoms, they will also examine the GCRC/clinic for information, and patients almost not known the identity of the medicinal product research. Apply the developed assessment of the symptoms for acid-peptic disease and previously applied for children receiving cysteamine. Every 4 weeks, patients will repeat blood tests, including liver function tests, clinical analysis of blood, determination of the levels of plasma (10 ml). At the end of the study patients re-perform all the basic laboratory tests.

Example 3

Action product was evaluated on the "stern" animal models of disease non-alcoholic fatty infiltration of the liver (NAFLD), and the evaluation was performed in General, as described in Otogawa et al., Am. J. Pathol., 170(3): 976-980 (2007). Male New Zealand white rabbits were given food with high fat content (HED)containing 20% of corn oil and 1.25% of cholesterol in order to induce clinical and histological signs of NAFLD and nonalcoholic steatohepatitis (NASH). A preliminary study of the duration of 7 days was conducted with the application of intraperitoneal (IP) injection dose bitartrata on the scheme receive every 8 hours (Q8H) at dose levels: 75 and 250 mg/day. In the longer study for 8 weeks rabbits bitartrate taken to drinking water in quantities of 25, 75 and 250 mg/kg/day.

A preliminary study. In the preliminary study of two different doses of brought intra-peritoneal (IP) by every 8 hours (Q8H) for 7 days the white rabbit to New Zealand, which gave food with high fat content (HFD). Male rabbits weighing between 2.5 and 3.5 kg is divided into the following groups: 1) control group with standard food, 2 cats, 2) the control group with food HFD, 2 cats, 3) the group of low-dose bitartrata , 75 mg/kg/day, HFD, 4 animals, and 4) the group with high dose bitartrata , 250 mg/kg/day, HFD, 4 animals. Outcomes include data daily standard clinical surveys, quantitative daily feed intake, body weight in days of study (SD) -1, 2, 5 and 8 (day autopsy) and blood specimens collected in the days of SD-1 and SD8 for assessment of selected clinical biochemical parameters ( (ALT), aspartate aminotransferase (AST), amylase, lipase, total cholesterol, triglycerides, lactate dehydrogenase (LHD), high density lipoprotein-cholesterol (HDL-cholesterol) and low-density lipoprotein-cholesterol (LDL-cholesterol)and just hematological list. Animals put to death in the day SD8.

Were not found pharmacologically important differences regarding the clinical observations, the masses of the body or the values of Hematology received from the baseline in the days of SD-1 and SD8. The values observed for ALT, amylase, lipase, triglycerides, and HDL-cholesterol, did not differ between groups within 7 days of study. However, the increase observed in the values of total cholesterol, LDL-cholesterol and LHD in animals fed HFD.

It is important that in comparison with HFD-control group, group treated , found improvements in terms of four biochemical indices of blood serum: AST, total cholesterol, LDL-cholesterol and LDH.

AST revealed as the best marker of inflammation of the liver when NASH, and it is believed that he is the token, superior ALT. Compared with HFD-control group observed a decrease in the average value AST day SD8 in the high-dose group (250 mg/kg/day), as shown in figure 1. Average AST control HFD-group was 19,0 u/l, while the rabbits who received 250 mg/kg/day , found a 1.9-fold reduction in this amount to the 10,0 u/l or only 47% of the value of the control HFD-group. Since there were only 2 of animals in the control HFD-group, it was impossible to conduct a statistical comparison. However, the comparison of the results of the AST group with a dose of 75 mg/kg/day in day SD8 with the results of animal group of 250 mg/kg/day showed that a group of high-dose was statistically different from the group with a low dose of U-test Mann-Whitney, p=0.03. These data show that the treatment at 250 mg/kg/day when the medical scheme has a positive influence on the magnitude of the AST.

Average values of total serum cholesterol from baseline (SD-1) varied from 42,5 to 55,25 mg/DL for all groups that are historically established laboratory range for normal rabbits 20-78 mg/DL. The day SD8 it was found that the rabbits who received cysteamine in the amount or 75, or 250 mg/kg/day had less of an increase in the contents of the average total cholesterol compared with the control HFD-group, as shown in figure 2. Control rabbits in group 2 with HFD had average total cholesterol 842 mg/DL per day SD8, i.e. approximately 20-fold increase compared with their baseline values. Group 3 rabbits who received 75 mg/kg/day , had average 652 mg/DL, i.e. only approximately 12-fold increase compared with their base value, or 23% smaller increase than HFD-controls. Rabbits in group 4, who received 250 mg/kg/day , had average 347 mg/DL per day SD8, i.e. only about 7.5-fold increase compared with their base value, or 59% smaller increase than HFD-control values. These data show that the treatment leads to a clear dose-dependent reduction in the increase in total cholesterol caused by HFD-food.

The magnitude of LDH showed a similar tendency: rabbits who received cysteamine dose or 75, or 250 mg/kg/day had a lower content increased LDH, than control rabbits with HFD, as shown in figure 4. Control rabbits with HFD in group 2 had average LDH 190 E/l per day SD8, i.e. a 1.7-fold increase compared with their baseline values. Rabbits in group 3 (75 mg/kg/day) had the average size of 128 E/l per day SD8, which were 1,2-fold decrease compared to their baseline values, or 33% of control values with HFD in the day SD8. Rabbits in group 4 (250 mg/kg/day) had a mean values of 77.5 E/l per day SD8, which were a 3.1-fold decrease compared to their baseline values, or 59% of control values with HFD in the day SD8. These data show that the treatment resulted in a dose-dependent reduction of these values LDH compared to control rabbits fed HFD.

These data show that (IP) processing rabbits fed HFD, dose or 75, or 250 mg/kg/day according to the scheme Q8H resulted in marked improvement in levels of liver transaminases (AST), an important marker of inflammation and liver damage when NAFLD. Processing was also connected with favorable changes in biochemical markers serum total cholesterol, LDL-cholesterol and LDH. Taken together, these data support the conclusion that the treatment of can bring clinical benefits in patients-people with the disease NAFLH, such as NASH.

an 8-Week study. The aim of this study was to evaluate the actions processing on animal model NAFLH and NASH, in this study, male New Zealand white rabbits were given food with high fat content (HFD), containing 20% of corn oil and 1.25% of cholesterol in order to induce clinical and histological signs of NAFLD and NASH.

The scheme of the study consisted of five groups of eight rabbits. The control group did not receive cysteamine in their drinking water: a control group, fed with generally accepted feed rabbits, and other control group, fed HFD. In the three groups of rabbits fed HFD, bitartrate were introduced into the food-water at concentrations calculated for the delivery or, 25, 75, or 250 mg/kg/day. Drinking water was obtained fresh daily on the basis of information about stability at room temperature for bitartrata in this concentration range.

Survey during the study included the definition of body weight twice a week, daily data feed and water intake and daily clinical examination. Blood samples were taken before the start of the study and in weeks 2 4 6 and 8 for a complete set of haematological parameters and a selected set of serum biochemical parameters, including ALT, AST, lipase, total cholesterol, triglycerides, LDH, HDL-cholesterol and LDL-cholesterol.

In all groups, who received HFD, approximately in the middle of 8 weeks started to conduct clinical examinations such as coarse fur and calm behavior, while the signs of jaundice started to appear earlier, in the middle of 6 weeks. Some animals released urine dark or red at the same time intervals, allowing to confirm possible violations of the patency of bile (cholestasis). During the study animals that were given food HFD, much more frequently compared to animals with standard food, discovered, padded chair. Animals with HFD found the histological criteria, which include NAFLD. Three animals in group 4, group, with an average dose of died during the study or were killed in the state of agony in the days of study (SD) 51, 55 and 56. One animal in group 5, group high doses has been murdered by the state of agony 55 SD. These death during the study, apparently, were associated with complicated NAFLD.

Data body weight showed that animals with standard food and HFD increased mass of approximately the same extent during the first 6 weeks of the study. However, from 7 weeks dogs with HFD began to lose weight in comparison with the animals with standard food. It turned out that the body mass processed animals correspond to the masses of control animals with HFD. Data feed intake showed that the animals fed HFD, consume less feed than animals with standard food after the first week of the study, which could be the result of more high-calorie content HFD. Feed consumption-treated groups and control group with HFD was the same. Approximately 6 week animals with HFD consumed only about 15-30% of the amount of feed consumed by the animals with a standard feed that shows the area under the curve (AUC).

Data Hematology not shown pharmacologically important changes throughout the research. There was a trend for slightly increased number of white blood cells (WBC) control rabbits fed HFD, compared with controls with standard food, mainly because of lymphocytes. Processed groups were similar with HFD-control groups.

The data of biochemical analysis of serum reflect the differences between the control group of animals fed HFD, and a control group of animals that are fed a standard food. In the end of the study (week 8) the HFD-control animals in group 2 has increased percentage of AST (1,6 times), lipase (a 6.6-fold), cholesterol (64-fold), triglycerides (3,8 times), LDH (3-fold), HDL-cholesterol (2,3-fold) and LDL-cholesterol (55-fold) compared to the values of the control animals with standard food (group 1). The magnitude of amylase and ALT have not changed.

It is believed that the AST is the best marker of liver inflammation than ALT. When studying for 8 weeks control animals fed HFD, had average AST 117,1 u/l, i.e., a 2.6-fold increase compared to the control group of animals that were given the standard feed, as shown in figure 5. However, the median AST group processing with a low dose (25 mg/kg/day)and in the high-dose group (250 mg/kg/day) were lower compared with HFD-control group of animals. Animals in group 3 (25 mg/kg/day) had average AST only 62,5 u/l, i.e., a 1.9-fold reduction in relatively HFD-control group, a decrease of 47%. Similarly, animals group 5 (250 mg/kg/day) had average AST only 75,7 u/l, i.e. a 1.6-fold reduction in relatively HFD-control group, a decrease of 35%. If you have difficulty in determining the delivery of medicinal product feed in drinking water, it is noteworthy that these reduction in AST values were associated with two of the three treatment groups . Similar decrease AST were also found in the preliminary study.

Observed in the preliminary study decrease in the values of LDH in this study were observed in the animals treated . As shown in figure 6, in the week of 8 average LDH was 375 u/l in group 2 HFD-control animals. Processing led to a decrease in the values of LHD at all three dose levels of treated animals compared with HFD-controls group 2. In group 5 high dose (250 mg/kg/day) average of LDH in week 8 was 140 u/l, almost identical to the average of LDH 125,6 u/l 1-group, the control group with standard food. This difference between the value of LDH HFD-control and the size of the group of high-dose (250 mg/kg/day) was statistically significant U-test Mann-Whitney, p=0.03. These data show that the treatment significantly mitigated the decline in LDH caused by HFD.

It is quite clear that the levels of HDL cholesterol are a positive indication of normal lipid profiles. It is known that rabbits are a particularly good model for lipid profiles rights as they relate base lines, similar to the relationship of the basic lines detected in people, and they are considered a good model of the cardiovascular disease rights. Therefore deserve consideration the fact that in this study the animals treated with high-dose (250 mg/kg/day), showed favorable raised level of HDL-cholesterol compared with the control group with standard food and HFD-control group, as shown in figure 7. On week 8 average HDL-cholesterol in a group of 250 mg/kg/day was 58,3 mg/DL, i.e. a 1.6-fold increase compared with the average value of HPD-control group 36,9 mg/DL and 3.7-fold increase compared with the value of the control group with standard food for 15.7 mg/DL.

Taken together, the data collected in this 8-week study showed that rabbits fed HFD, showed clinical and serological characteristics associated with liver disease, relevant NAFLD and NASH. Dosing bottled water may lead to the variable delivery of the medicinal product processed animals. However, it was found that two of the same biochemical serum markers that have been improved in the preliminary study, were improved in this 8-week study, in the presence of : AST and LHD. They are considered important indicators, provided that, as it is considered AST is the best marker of inflammation in NASH, and that the reduction in the content of LDH probably also reflect less inflammation and possible protection from toxicity in these animals.

Another important aspect of this long-term study was that the treatment was associated with favorable increased levels of HDL-cholesterol in serum.

It is assumed that a specialist in this field can find numerous modifications and variants of the invention described in the above illustrative examples, and therefore, the invention may be subject only to such limitations, which are shown in the appended claims.

3. The method according to claim 1 or 2, in which the fatty degeneration of the liver is selected from the group consisting of nonalcoholic fatty degeneration of liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), fatty degeneration of the liver, resulting from hepatitis, fatty degeneration of the liver, which is the result of obesity, fatty degeneration of the liver, which is the result of diabetes, fatty degeneration of the liver, which is the result of insulin resistance, fatty degeneration of the liver, which is the result of hypertriglyceridemia , , disease Weber-, disease , acute fatty degeneration of the liver of pregnancy and lipodystrophy.

4. Way to treat a patient suffering from a disease nonalcoholic fatty degeneration of liver disease (NAFLD) or non-alcoholic (NASH), comprising an introduction therapeutically efficient quantity composition containing cysteamine, or tsistamin, or pharmaceutically acceptable salt.

5. The method according to claim 1 or 4 where the total daily dose , or applied, or pharmaceutically acceptable salts is 0,5-2,0 g/m 2 .

6. The method according to claim 1 or 4 where the total daily dose , or applied, or pharmaceutically acceptable salts is 0.5-1.0 g/m 2 .

7. The method according to any one of claims 1 to 6, where cysteamine, or tsistamin, or pharmaceutically acceptable salt, or composition injected at a frequency of 4 or less once a day.

8. The method according to claim 7, in which the introduction is carried out two times a day.

9. A method according to claim 2-8, in which the composition is the dosage form or adjustable release that provides improved delivery , or applied, or pharmaceutically acceptable salts into the small intestine.

10. The method of claim 9, in which the dosage form or adjustable release contains coating that releases cysteamine, or tsistamin, or pharmaceutically acceptable salt, when the song reaches the small intestine or a section of the gastrointestinal tract of the subject in which the pH of greater than 4.5.

11. Way in paragraph 10, in which the medicinal form contains a coverage, selected from the group consisting of cured gelatin, shellac, methacrylic acid copolymer type CNF, cellulose, cellulose, cellulose, (PVAP), cellulose (CAP), cellulose (CAT), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, succinate , (CMEC), hydroxypropyl methylcellulose (HPMCAS) and polymers and copolymers of acrylic acid usually formed of methyl acrylate, ethyl acrylate, methyl methacrylate and/or with copolymers of esters of acrylic and methacrylic acids.

12. The method according to claim 1-11, in which the introduction is carried out orally.

13. The method according to claim 1 or 4, in which the introduction is carried out parenterally.

14. The method according to claim 1 or 4 where the introduction may result in some improvement in fibrosis of the liver as compared to the condition before the introduction of , or applied, or pharmaceutically acceptable salts.

15. The method according to claim 1 or 4 where the introduction leads to the reduction of fat liver.

16. The method according to claim 1 or 4 where the introduction leads to a reduction in morbidity or progressive development of cirrhosis.

17. The method according to claim 1 or 4 where the introduction leads to a reduction in morbidity carcinoma.

18. The method according to claim 1 or 4 where the introduction leads to a decrease in levels of liver aminotransferase levels before the introduction of , or applied, or pharmaceutically acceptable salts.

19. The method according to claim 1 or 4 where the introduction leads to a decrease in levels of hepatic transaminases by 10-40% compared to levels before treatment.

20. The method according to claim 1 or 4 where the introduction leads to a decrease in the levels of alanine aminotransferase subjected to treatment of the patient up to 30, 20 or 10% above the normal ALT levels or to normal ALT levels (<40 IU/l).

21. The method according to claim 1 or 4 where the introduction leads to a decrease in levels of aspartate aminotransferase subjected to treatment of the patient up to 30, 20 or 10% above the normal levels of AST or until the normal levels of AST.

22. The method according to claim 1, wherein the introduction leads to a decrease in levels of serum ferritin levels before treatment , or , or pharmaceutically acceptable salt.

23. The method according to claim 1-22, in which cysteamine, or tsistamin, or pharmaceutically acceptable salt is introduced with a second agent, applicable for the treatment of fatty degeneration of the liver.

24. The method according to claim 1-23, in which the patient is a child or teenager.