Silibilin component for treating hepatitis. RU patent 2482844.

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed are: application of silibinin component of general formula (I) for obtaining medication for parenteral introduction for trweatment of viral hepatitis, with medication optionally containing cyclodextrin and/or phospholipid, and set of similar purpose, which includes said silibinin component and other medication, representing one or several pharmaceutical agents from: arginine, glutamate, silymarin, citiolone, epodemiol, ornithine oxoglurate, tidiacic arginine, myoinosite, methionine and N-acetyl methionine, choline, ornithine aspartate, cyanidanol, thiopronin, betaine, cyanocobalamin, leucine, levolose, acyclovir, idoxuridine, vidarabine, ribavirin, ganciclovir, famciclovir, valaciclovir, cidofovir, penciclovir, valganciclovir, brivudin, interferon. Medication preferably does not contain silidianin, and/or silicristin, and/or isosilibinin.

EFFECT: reduction of viral strain and reactivation of patients after parenteral introduction of claimed silibinin component.

21 cl, 12 dwg, 5 ex

The present invention relates to the application of a component of a medicinal product for the treatment of viral hepatitis, preferably hepatitis b or C, in particular to reduce the viral load. Preferably drug adapted for parenteral administration. Preferably component of a complex air silibinina.

Silibinin {3,5,7-trihydroxy-2-(3-(3-hydroxy-4-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydrobenzo[b][1,4]-dioxin-6-yl)-4-one, or the nomenclature of the European Pharmacopoeia (2R,3R)-3,5,7-trihydroxy-2-[(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydro-1,4--6-yl]-2,3-dihydro-4H-1-benzopiran-4-he}, is the major component of silymarin and major flavonoid extracted from milk Thistle (Silybum marianum Gaertneri).

Silibinin has the structure:

silibinin And silibinin and In present in the literature separately:

Silibinin represents the main component of silymarin (in a mixture of 50:50 and In). To the other components of parts include ( and ), , , , Taxifolin and others. The methods of extraction of silibinina known in the prior art (for example, US 4871763).

Silibinin and silymarin thoroughly studied and described. In this regard, reference can be made to work N.-C. Kim and others, Org. Biomol. Chem. 1, 2003, .1684-1689; D.Y.W. Lee and others, J. Nat. Prod. 66, 2003, .1171-1174; D.J. Kroll and others, Integrative Cancer Therapies, 6, 2007, .110-119; Z.Wen and others, DMD Fast Forward, doi:10.1124/dmd.107.017566; and US 4871763.

History of medicinal plants Silybum marianum counts about 2000 years. Silymarin extract of milk Thistle, is an ancient remedy for the treatment of various disorders of the liver and gall bladder diseases, including hepatitis, cirrhosis, and hepatoprotector, protects the liver from poisoning wild mushrooms, alcohol, chemicals and toxins from the environment. The mechanism of action of silymarin diverse. The largest randomized, controlled trial conducted in the 1970s, showed that long-term use of silymarin can reduce the mortality rate of patients with chronic cirrhosis (P.Ferenci and others, J Hepatol 9, 1989, .105-113). However, the role of this drug for the treatment of liver diseases remains controversial (S.Verma and others, Clinical Gastroenterology and Hepatology 5, 2007, .408-416; F.Rainone, Am Fam Phys 72(7), 2005, cc.1285-1288). Partly this uncertainty is caused by limited information on the pharmacokinetics and in optimum performance of dosing. Silymarin is poorly soluble in water, and oral use leads to reduced bioavailability.

Pharmaceutical applications silibinina also known. Silibinin has strong properties (see A.Pietrangelo and others, Gastroenterology 109, 1995, .1941-1949; .I.Lucena and others, Int J Clin Pharmacol Ther 40, 2002, cc.2-8; L.Mira and others, Biochem Pharmacol 48, 1994, cc.753-759) and properties (see G.Boigk and others, Hepatology 26, 1987, .643-649; .Dehmlow and others, Hepatology 23, 1996, .749-754), so it is potentially applicable as a medicament for the treatment of chronic liver diseases. Pure substance silibinin injected, for example, in case of poisoning liver pale toadstool (toxins , phalloidin) to prevent liver damage (see .Hruby and other, Hum Toxicol 2, 1983, .138-195). Action mushroom poisoning partly due to the stimulation of nucleolar polymerase And, which increases the synthesis of ribosomal protein and ingibiruet the peroxide oxidation of lipids (J.Sonnenbichler and other Prog Clin Biol Res. 213, 1986, cc.319-331). Clinical studies also were successful in the prevention and treatment of certain types of cancer (L.Varghese and others, Clin Cancer Res 11(23), 2005, .8441-8447; K. Letschert, and others, Toxicological Sciences 91, 2006, .140-149).

Ester silibinina receive in the form of solution for infusion, for example, the product Legalon® SIL in the Federal Republic of Germany.

Viral hepatitis refers to infections that affect the liver and are viruses. Viral hepatitis are actively exploring all over the world. Viral hepatitis is not only causes high mortality but also depletes medical resources and can cause severe economic consequences. The majority of viral hepatitis be prevented.

The concept of «viral hepatitis» refers five different disease caused by at least five different viruses. Hepatitis A and hepatitis A (infectious hepatitis and serum hepatitis respectively) represent different diseases and both diagnosed with a specific serum test. Hepatitis C and E are the third category, a different type, and hepatitis C is transmitted parenterally and hepatitis E is passed enterally. Hepatitis D, or Delta hepatitis is a disease caused by a virus of a different type-dependent infection with hepatitis Century This form of hepatitis may be in the form of superinfection in media hepatitis b, or in the form of co-infection in individuals with acute hepatitis Century

Hepatitis C is an infectious human disease caused by the hepatitis C virus (HCV). Infection With the hepatitis C virus can lead to serious liver damage, such as inflammation of the liver parenchyma, fibrosis of the liver, liver cirrhosis and carcinoma of the liver. More than 80% of infected patients HCV infection becomes chronic. Transmission of HCV occurs usually parenteral way through the blood.

Found that an estimated 170 million people worldwide are infected With the hepatitis C virus (HCV). For decades the infected patients, symptoms are absent until not develop cirrhosis and/or hepatocellular carcinoma. About 40-50% of cases of liver transplantation in the United States caused by infections of the GHS. Identified six HCV genotypes (1-6), which differ in geographical distribution, and on their response to treatment.

Found that HCV proteins induce activation of STAT-3 through oxidative stress and CA 2+ signal transmission (.і and others, Hepatol Res 34, 2006, .65-73; G.Waris and others, J Virol 79, 2005, .1569-1580), and also products of lipid peroxidation and antioxidant gene expression (.Okuda and others, Gastroenterology 122, 2002, .366-375). Assume that the balance of oxidative and recovery potentials in the cell (cell redox potential) has pronounced effects on the metabolic pathways of signal transduction (Y.M.Janssen and others, Am J Physiol 273, 1997, .789-796), including a weakened IFN-alpha signal transmission (D.Di and other Bona, J Hepatol. 45, 2006, .271-279).

HCV infection is divided by the requirements of ICD10 (who, 2007) acute (17.1) and chronic hepatitis C (18.2).

HCV is one of the most important causes of acute or chronic hepatitis. However, the course of the disease can vary greatly and highly subject to variability. Therefore, one cannot speak of a typical course of the disease, because HCV infection manifests a wide spectrum of clinical manifestations, i.e. symptoms, different clinical pictures and various secondary liver diseases and lesions outside the liver.

Approximately 20% of patients with acute hepatitis liver inflammation is the result of infection by HCV. However, in the acute phase of hepatitis C is usually asymptomatic and therefore around 85% of cases are not diagnosed. In some cases, there are only nonspecific flu-like symptoms. Usually, the infection manifests itself during the acute phase.

Hepatitis C becomes chronic approximately 85% of patients with acute HCV infection. This high degree of transfer of the disease in the chronic phase is the result of the high variability in the GHS, i.e. gene that encodes shell HCV, mutates with a high frequency. Due to the high variability of the virus and, in particular, the high variability of antigenic epitope HCV mutant HCV avoids recognition by the human immune system. Approximately 25% of patients result of chronic inflammation of the liver is the formation of cirrhosis of the liver and increased risk of carcinoma of the liver (see, for example, J..Hoofnagle, Hepatology 1997, 26, Annex 1, .15S-20S; .І. Memon and others, Journal of Viral Hepatitis 9, 2002, .84-100; S.L.Tan and others, Nature Reviews, Drug Discovery 1, 2002, cc.867-881).

Patients infected with HCV is usually receive a standard combined treatment interferon-α2 or interferon α2b and ribavirin. When infection with HCV genotypes 2 or 3 (infection 2 or 3) the combined treatment for 24 weeks. When infection with HCV genotype 1 (1) for 1-positive patients, a combination therapies for 48 weeks. Many of HCV-infected patients, however, interrupt treatment because of side effects and/or rejection of injecting, and duration of application. In addition, only about 50% of patients with infection 1 reach a positive result in such a long treatment, i.e. the remaining not respond to this treatment, i.e. they are non- (see, for example, R.E.T.Smith, Nature Reviews, Drug Discovery, 5, 2006, .715). Treatment caused by hepatitis C virus disease interferon plus ribavirin therapy is ineffective in about half of patients with genotype 1. Treatment failure occurs either because of lack of response to treatment (minimum reduction in the titre of virus), or due to relapse (strong initial response to treatment is replaced by the recent rise in titer of virus during or after treatment). Such different effects of treatment may depend on various factors, including genetic status of the host immune response and genetic differences viruses (see M.W.Fried and other, New England Journal of Medicine 347, 2002, .975-982; H.S.Conjeevaram and others, Gastroenterology 131, 2006, .470-477; M.P.Manns and others, Lancet 358, 2001, .958-965; D.B.Strader and others, Hepatology 39, 2004, .114771; S.J.Hadziyannis and others, Ann Intern Med, 140, 2004, .346-355). Genetic differences viruses can enable or differences existing before the start of treatment, or the differences that arise during treatment due to the evolution of the virus in response to pressure applied treatment.

Develop new treatment options, including the optimization of existing standard treatment interferon plus ribavirin, especially targeted antiviral therapy against HCV, new immunomodulating agents and treatment aimed at reducing fibrosis (see R.E.Stauber and others, Drugs 68(10), 2008, .1347).

To date there is no vaccine against HCV. Standard treatment is very expensive, give an insignificant impact in terms of destruction of HCV infection and sometimes cause significant side effects (S.L.Tan and others, Nature Reviews, Drug Discovery 1, 2002, .867; R.Bartenschlager, ibid, .911).

There is a need for medicines for the treatment of viral hepatitis, especially hepatitis b and C.

Problem solved in the present invention consists in obtaining effective remedy for treatment of viral hepatitis, in particular hepatitis b or C, which offers advantages over drugs prior art. Drug shouldn't have any side effects or have bastions side effects, and to be effective, for example, for patients with hepatitis C, which essentially do not respond to traditional combined treatment with the peginterferon/ribavirin. In addition, the drug should have a pronounced antiviral properties and thus reliably reduce the burden of the virus.

The fulfillment of the tasks set out in the formula of the present invention.

Suddenly it was found that silibinin, its pharmaceutically acceptable salts or derivatives are applicable for the treatment of inflammation, viral liver diseases, especially hepatitis C. therefore, in patients with hepatitis C who do not respond to treatment immunomodulatory/ antiviral combined therapy (non-responders), for example with the peginterferon/ribavirin, which is currently the standard treatment for hepatitis C, a significant reduction of the burden of the virus can be achieved by the introduction, preferably parenteral component. It was also shown that pre-treatment component increases the response of patients to the later introduction of interferon and ribavirin.

Research related to the treatment of HCV infections, particularly relating to suppress HCV infections, through the introduction of silymarin, are described in the prior art (see, for example, R.Sailer and others, Drugs 61(14), 2001, .2035-2063; .. and others, Journal of Viral Hepatitis, 12, 2005, cc.559-67; US 2005/0123628; S.J.Polyak and others, Gastroenterology 132, 2007, cc.1925-1936).

R.Sailer and others report that, while not installed influence of silymarin on the replication of the virus, pharmacological estimates, we can expect that it inhibits inflammation and cytotoxic cascade of events triggered by a viral infection. Oral administration of complex silibinina-phosphatidylcholine (IdB1016, 240 mg silibinina twice daily) in the short-term, placebo-controlled pilot study of 20 patients with chronic hepatitis showed that the evolution of the levels of AST significantly reduced in the group silibinina in the absence of significant differences between the other studied in liver function tests (see A.Vailati and others, Fitoterapia, 64(3), 1993; G.Buzzelli and others, Int. J.Clin. Pharmacol. Ther. Toxicol. 31, 1993, cc.456-460).

K.E.Mayer and others describe that oral treatment leads to a decrease in transaminaz in the serum compared with baseline in four studies and placebo in only one study. However, there is no evidence that silymarin affect the load of the virus or improves liver histology In hepatitis b or C (see M.L.Chavez, J.Herb. Pharmacother. 1(3), 2001, .79-90; L.B.Seeff and others, Hepatology, 34(3), 2001, .595-603). It was concluded that compounds probably reduce the level of serum transaminases in patients with chronic viral hepatitis, but presumably not affect the burden of the virus or liver histology.

US 2005/0123628 refers, inter alia, to receive and oral introduction of the compositions that incorporate glycyrrhizin, preparation of Schizandra fruit, ascorbic acid, L-glutathione, silymarin, lipoic acid and D-alpha-tocopherol. Report that the above compositions apply to reduce oxidative stress and lipid peroxidation, for the treatment of chronic liver disease, chronic infection of viral hepatitis C and nonalcoholic fatty hepatitis. Numerous studies report hepatoprotective properties that silymarin manifests against a large number of different toxins, including acetaminophen, ethanol, carbon tetrachloride and D-, as well as against ischemic injury, radiation and toxicity of iron. During the first twenty weeks of open clinical trial subjects were given for oral administration two times a day in total 1000 mg of glycyrrhizin; three times a day in the total number of 1500 mg extract of the herb infusion three times a day in total the amount of 6000 mg of ascorbic acid; two times a day in the total number of 300 mg of L-glutathione; three times a day in the total quantity 750 mg extract of milk Thistle; two times a day in the total number of lipoic acid 300 mg; once a day in the amount of 800 ME D-alpha-tocopherol. During the first ten weeks of the study subjects administered by intravenous infusion twice a week for four different parenteral song, none of them contains silymarin. After 10 weeks of 12.0% of the subjects, after 20 weeks of 24.0% of the subjects showed a 1 log reduction of the burden of the virus. In the US 2005/0123628 not even a hint that silymarin, or that only silibinin could be responsible for a relatively small reduction in viral load.

S.J.Polyak etc. compare in vitro standardized extract of silymarin (MC-001) with commercial preparations of silymarin. Report that both drugs are showing an antiviral effect when using a model based on cell culture, though the impact of commercial products is not so strong in comparison with the MC-001. MK-001 inhibits the expression factor alpha tumor necrosis in anti-CD3 peripheral blood mononuclear cells and contingent on the nuclear factor Kappa b transcription in human hepatoma cells Huh7. In addition, dose MC-001 suppresses the infection of cells Huh7 and Huh7.5.1 virus JFH-1 dose-dependent manner. MK-001 manifests action against HCV infection in selected cells and in combination with interferon-alpha ingibiruet replication of HCV in a greater degree compared to the inhibition of only one with interferon-alpha. For comparison anti-HCV actions MC-001 with commercial preparations of silymarin, testing product Ultrathistle® (firm Natural Wellness, Montgomery, new York and the product Silybinin® (firm Indena SpA, Milan). But the report that the MC-001 shows a more potent antiviral activity compared to products Ultrathistle® and Silybinin®. On the basis of the in vitro studies, it was concluded that, as is the action of anti-HCV, standardized extract of silymarin MC-001 exceeds two commercial products. S.J.Polyak nothing about the parenteral administration of the pure silibinina, not to mention the treatment of non-response. In addition, the findings Polyak and other contradict clinical research, which showed a lack of effect of silymarin on HCV in patients with chronic hepatitis C (M.D.Tanamly and others, Dig Liver Dis. 36, 2004, .752-759; .Gabbay and others, World J Gastroenterol. 13, 2007, .5317-5323).

Now suddenly it was found that the introduction of, especially parenteral introduction, preferably pure component silibinina reduces the in vivo load of virus in patients with viral hepatitis. Thus, the component silibinin is able to reduce the viral load. This circumstance allows to optimize dose silibinina in the absence of other components of silymarin, which can cause unwanted side effects.

A reduction in viral load through injecting component especially surprising as clinical studies show that silymarin no effect on HCV in patients with chronic hepatitis C (.Torres and others, P.R.Health Sci J 23(2), 2004, .69-74; M.D.Tanamly and others, Dig Liver Dis., 36, 2004, .752-759; (Gordon and others, J Gastroenterol Hepatol. 21, 2006, cc.275-280; E.Gabbay and others, World J Gastroenterol. 13, 2007, cc.5317-23; L.B.Seeff and others, Hepatology, 80(11), 2008, cc.1900-1906).

M.Torres and other reported clinical study in which invited to participate patients aged 21-65 years with chronic hepatitis C, not exposed to antiviral therapy. 34 patients for treatment S.marianum 160 mg orally three times per week for four weeks or treatment is not carried out (control). The study showed that S.marianum does not act as an antiviral agent.

M.D.Tanamly and other reported clinical study in which 177 patients with chronic hepatitis caused by the hepatitis C virus, were randomly divided to obtain or oral silymarin or multivitamin supplements. Research has shown that the recommended dose of silymarin has no effect on the hepatitis C.

A.Gordon, and other reported clinical study involving 24 subjects with chronic hepatitis C, namely in the randomized, double-blind, placebo-controlled study. Subjects received 12 weeks S.marianum (or 600 mg, or 1200 mg/day) and placebo. Sang biochemical, virological, psychological studies and analysis of the quality of life. Seventeen patients have completed the study. The study showed that the average changes of HCV RNA titers did not differ significantly from the subjects treated S.marianum, compared with those who received placebo.

.Gabbay and other reported clinical study, which involved 100 patients with chronic HCV infection, for whom treatment with interferon was unsuccessful, and were randomized to receive seven different antioxidants along with capsules of silymarin, 250 mg three times a day. The primary endpoints of the study were liver enzymes levels of HCV RNA and histology. The study showed that therapy no effect on viral load.

L.B.Seeff and other report about the study prolonged antiviral treatment for HCV cirrhosis cirrhosis (HALT-C), involving subjects with the formed With chronic hepatitis C who are non- in primary antiviral therapy, but are ready to participate in the long-term treatment of interferon. Not found beneficial effects of silymarin on RNA levels of hepatitis C virus (HCV). Thus, from receiving silymarin had similar levels of HCV compared with the levels of those who did not receive such treatment.

Figure 2. Example 1 study 1: HCV RNA (log IU/ml; average ± standard deviation) to (1 day) and after (7 days) intravenous administration of 10 mg/kg component/day.

Figure 3. Example 1 study 1: changes HCV RNA after intravenous administration of 10 mg/kg/day component within 7 days with the subsequent combination therapy with the peginterferon Alfa-2A/ribavirin and 140 mg silimarina three times a day.

Figure 4. Example 1, study 2: changes in HCV-RNA during introduction component in different doses for 14 days, followed combined therapy with the peginterferon Alfa-2A/ribavirin launched on the 8th day.

Figure 5. Example 1, study 2: average ± standard deviation reduction of HCV RNA within 7 days of monotherapy in the form of intravenous component silibinina and 7-day intravenous component silibinina with with the peginterferon Alfa-2A/ribavirin in different doses.

6. Example 1, study 2: changes in HCV RNA after completion of intravenous silibinina (2 weeks) in 14 patients treated silibinin in the amount of 15 or 20 mg/kg/day. Combination therapy with the peginterferon Alfa-2A/ribavirin begin on the 8th day and 280 mg three times a day by day 15.

Fig.7. Example 2, a specific patient, changes HCV RNA after intravenous administration of 20 mg/kg/day component during the introduction of two intervals, including 14 days in a row, the first interval during the intravenous administration begins on 24 day, and the second interval in the introduction, starting from 35 weeks, during continuous combined therapy with 180 mcg Alfa-2A/ribavirin for 60 weeks.

Fig.8. Example 2, a specific the patient, changes in HCV RNA after intravenous administration of 20 mg/kg/day component during the interval of introduction, including 14 consecutive days, and since its 32nd weeks of continuous combined therapy with 180 mcg Alfa-2A/ribavirin in for 60 weeks.

Fig.9. Example 2, a specific patient, changes in HCV RNA after intravenous administration of 20 mg/kg/day component during the interval of introduction, including 14 consecutive days and starting from 72 weeks during combination therapy with continuous application of 180 mcg Alfa-2A/ribavirin for 80 weeks.

10. Schematically shows the different ways of joint use of ribavirin and/or of interferon Alfa and of a medicinal product containing component.

11. Data obtained in a study of suppression in vitro NS5B for six purified components of silymarin.

Fig.12. Data obtained in a study of suppression in vitro NS5B for silibinin-bis().

The present invention relates to the application of a component of medicinal product, preferably or antiviral, it is more preferable to reduce the viral load to treat viral hepatitis, in particular hepatitis b or C, preferably infections chronic or acute viral hepatitis C, preferably parenteral the introduction.

In the context of the present invention concept of a «medicine» preferably a synonym of «drug treatment».

In a preferred embodiment, the invention relates to the application of a component of a medicinal product which contains almost no , and/or , and/or , for the treatment of viral hepatitis, preferably hepatitis b or C.

In a preferred embodiment of the present invention treatment of viral hepatitis, in particular hepatitis b or C, carried out by reducing the viral load. It is established that components can reduce the viral load in patients with hepatitis b or C. This is especially surprising as in the prior art no evidence that silymarin, a mixture which contains a certain number of silibinina, the effect on viral load and improves liver histology In hepatitis b or C (see .. and others, Journal of Viral Hepatitis, 2005, 12, 559-567).

In another preferred embodiment of the present invention treatment of viral hepatitis, in particular hepatitis b or C, conducted in patients who have or who underwent liver transplantation. Patients undergoing liver transplantation for viral hepatitis, are at risk of resumption of viral hepatitis in the transplanted liver. Typically, the virus has been removed completely from the body, when the infected liver is removed surgically, and the remaining in the body viruses re-infect liver. In chronic hepatitis C infected patients are re-infected after liver transplantation in 100% of cases. Suddenly it was found that silibinin can reduce your viral load, the risk of re-infection after liver transplantation can be significantly reduced by the introduction, preferably parenteral component silibinina.

Forms of viral hepatitis are known to specialists in the field.

At the present time is at least six different forms: hepatitis A, b, C, D, E, and G. the Organisms that cause these infections are hepatotropic viruses. They belong to different families of viruses in each case and are the genome of DNA or RNA. Transmission occurs or food, or through tissue fluids such as semen and blood. Also there are differences in different forms, about the course of the disease and its severity. Although hepatitis A and E are usually in acute form, hepatitis b, C and D can lead to chronic course of the disease, and in some cases to severe complications.

In this description of the concept of «viral hepatitis» preferably includes hepatitis b and C.

In a preferred embodiment of the present invention treatment by reducing the viral load one or more viruses, selected from the group consisting of genotypes 1, 2, 3, 4, 5 and 6, preferably 1, but not only them.

If the genotype is the genotype of the virus 1 preferable subtypes 1a, 1b, 1c, 1d, 1e, 1f 1g, 1h, 1i, 1j 1k and 1l. If the genotype is the genotype of the virus 2 preferable subtypes 2A, 2b, 2C, 2d, 2E, 2f 2g 2h 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p and 2q. If the genotype is the genotype of the virus 3 preferable subtypes 3A, 3b, 3C, 3d, 3E, 3f 3g 3h 3i 3j and 3k. If the genotype is the genotype of the virus 4 preferable subtypes 4A, 4b, 4C, 4d, 4E, 4f, 4g 4h 4i, 4j, and 4k, 4l, 4m, 4n, 4o, 4p, 4q 4r and 4t. If the genotype is the genotype of the virus 5 is preferable subtype 5A. If the genotype is the genotype of the virus 6 preferable subtypes 6A, 6b, 6C, 6d, 6E 6f 6g 6h 6i, 6j, 6k, 6l, 6m, 6n, 6o, 6p and 6q. On the nomenclature of genotypes and subtypes of hepatitis C virus (see, for example, P.Simmonds and others, Hepatology, 42, 2005, 962-973.

In a preferred embodiment, the invention relates to the application component silibinina to obtain a medicinal product which preferably adapted for parenteral injection for the treatment of viral hepatitis, preferably hepatitis C patients who do not respond to usual immunomodulatory/antiviral combination therapy, such as therapy with ribavirin/interferon («non-responders»), and/or patients who are partly responsible for traditional immunomodulatory/antiviral combination therapy for example, therapy with ribavirin/interferon («partial responders»), and/or patients who exhibit a clear initial response renewable viral titers during or after therapy («relapse»).

The present invention also relates to the treatment of viral hepatitis C with component, and this treatment follows the traditional combination therapy with ribavirin/interferon. Preferably treatment introduction component begins after unsuccessful treatment with ribavirin/interferon (or first, or after a period of treatment).

In connection with the traditional treatment of hepatitis C through the introduction of ribavirin/interferon notion of «non-responders», «partial responders» and «patients with relapse» known to the specialists in this field. Currently, treatment of viral hepatitis C interferon together with ribavirin unsuccessfully for about half of patients in genotype 1. Resistance and treatment failure manifests itself either in the form of lack of response to treatment (minimum reduction titles virus), or in the development of relapse (original clear response to treatment is replaced by the restoration of the titles of the virus during or after treatment).

With the purpose of specification of non- preferably called patients in whom there is no reduction in viral load to <2 log 10 IU/ml (i.e. 100 times) for the introduction of ribavirin/interferon (usually a), preferably within 12 weeks. In a preferred embodiment of the present invention of non-response virus titres reduced by an amount ≤2,1 log10 IU/ml and absolute titles & GE 4,62 log 10 copies/ml with the minimum value.

With the purpose of specification partial preferably called patients in whom there is no reduction in viral load at & GE 2 log10 IU/ml at week 12 with detectable HCV RNA at week 24.

With the purpose of specification of patients with relapse, preferably called patients in whom a reduction titles viruses is & GE 2,8 log 10 and absolute titles temporarily fall below the limit of detection (2,78 log 10 IU/ml).

In the present invention of the concept of « component preferably refers to , including all of its stereoisomers, for example silibinin And silibinin and In its pharmaceutically acceptable salts or derivatives, in particular esters. Preferred esters are derived inorganic acids, such as phosphoric acid or sulfuric acid; or organic acids such as formic acid, acetic acid, propionic acid, citric acid, malic acid, mandelic acid and other

Among dicarboxylic acids, particularly preferred , for example, malic acid, glutaric acid, succinic acid, adipic acid, acid, azelaic acid, sebacic acid, fumaric acid, maleic acid, itaconic acid, acid, terephthalic acid, isophthalic acid and other Preferred are that may be in the form of free acids or their salts, such as sodium, potassium or ammonium. One or more hydroxyl groups silibinina can be . Preferably, 1, 2, 3, 4, or all the hydroxyl group silibinina .

In a preferred embodiment of the present invention component is silibinin-With-2',3-bis() or pharmaceutically acceptable salt such as sodium salt, potassium salt, ammonium salts and other, as well as their mixtures. Especially preferable disodium salt.

Relevant esters are also esters of gluconic acid.

Preferably component represents a connection with the General formula (I)

in which

R 1 , R 2 , R 3 , R 4 and R 5 independently selected from the group consisting of MR., -SO 3 H, -PO 3 H 2-WITH-1-8 --IT-WITH-1-8--CO 2 H-1-8--SO 3 H, -CO-1-8--OPO 3 H 2-WITH-1-8--PO 3 H 2 -(2-3--O) n-N, where n= 1 to 20-WITH-1-8 --N(1-3-alkyl) 3 + X , where X represents a pharmaceutically acceptable anion,

or their pharmaceutically acceptable salt. Preferably, R 1 , R 2 and R 5 represent Mr..

Preferably, component of General formula (I) has General formula (I-A) or (I-B)

In a preferred embodiment of the present invention connection with the General formula (I-A) mixed with the connection of the General formula (I-B) any relative ratio of the mass, for example 50±5:50 ą5. In a preferred embodiment of the present invention, however, excess (di) compounds of General formula (I-A) is at least 50% CI, more preferably at least 75% CI, even more preferably at least 90% CI, even more preferably at least 95% CI, most preferably at least 98% CI, and especially preferably at least 99% CI. In another preferred embodiment of the present the invention excess (di) compounds of General formula (1-B) is at least 50% CI, more preferably at least 75% CI, even more preferably at least 90% CI, even more preferably at least 95% CI, most preferably at least 98% CI and especially preferably at least 99% CI.

Other preferred components are described in the patent WO 03/090741, the essence of which in the present description a link is provided.

Preferably component in pure water at room temperature has a better solubility compared with as such.

In a preferred embodiment, the invention relates to the application of ester silibinina to obtain a medicinal product which preferably processed for parenteral or oral administration, for the treatment of viral hepatitis, in particular hepatitis b or C. Preferably medicinal product contains almost no , and/or , and/or .

In a preferred embodiment of the present invention drug process for parenteral administration. Parenteral may be conducted, for example, subcutaneously, intravenously, intramuscularly, vnutriarterialno, intraperitoneally, intradermally, vnutrisustavno, , , in the vitreous body of the eye retrobulbarno and .

Especially preferably drug processed for injections or infusions, in particular for intravenous or intraarterial administration.

Appropriate drugs, applicable for injections or infusions, known to the specialists in this field. See, for example, kN.: .. and other «Lehrbuch der Pharmazeutischen Technologie [Textbook of Pharmaceutical Technology]», 1999, 6th ed., WVG Stuttgart.

Medicines, applicable for injection represent the usual sterile solutions, emulsions and suspensions, which receive dissolution, or active substance and not necessarily well as excipients in the water, in the respective liquid other than water, which should not be sterilized, if this is the justification, or a mixture of these solvents.

Medicines for infusion are the usual sterile aqueous solutions or emulsions with water as the permanent phase.

Drugs for injection or infusion may optionally contain additional . this type preferably are solvents, such as lecithin and 188, substances for giving to isotonicity, such as sodium chloride, glucose, and mannitol, buffers, for example, acetate, phosphate and , antioxidants such as ascorbic acid, sodium , sodium sulfite and sodium , chelating agents, such as , preservatives, such as esters of hydroxybenzoic acid, benzyl alcohol and cholesterol, as well as emulsifiers, such as lecithin, fatty alcohols, sterols, esters sorbitol and fatty acids, esters sorbitol and fatty acids, glycerides of the fatty acids ethers of fat acids, esters of fatty alcohols, esters of glycerol and fatty acids, and .

Especially preferred drug is powder for solution for infusion, including silibinin-With-2',3-bis() preferably as disodium salt, and optional inulin as . Containers containing 598,5 mg powder silibinina-With-2',3-bis() disodium salt and inulin, adapted for solution for infusion and manufactured in Germany under the trade mark Legalon® SIL. In a preferred embodiment of the present invention medicine according to the present invention to this composition.

In another preferred embodiment of the present invention drug refined for oral administration. Preferably medicine is a form for oral administration, selected from the group consisting of tablets, capsules, tablets, sugar-coated, pills and Sasha.

With the introduction of component by oral ensure that the bioavailability of component silibinina oral dosage form of a rather high. So the limiting factor is expressed lipophilicity silibinina.

In particularly preferred embodiment the present invention relates to the application of a component of a medicinal product which has been redone for oral administration and contains almost no and/or , and/or , for the treatment of viral hepatitis, preferably hepatitis b or C.

It appears that these additional components of silymarin also have a physiological effect (for example, can cause side effects), but for the treatment of viral hepatitis silibinin (or its analogues) the most effective, especially for reduction of viral load. Thus, with the introduction of silymarin, i.e. a mixture of silibinina, , , and other components, the total dose of silymarin should be relatively high to guarantee a certain number of silibinina. For example, if silymarin contains, for example, 42 wt.% silibinina, introduction 125 mg silimarina provides only about 52 mg silibinina and approximately 73 mg other compounds also possess physiological effect (but not the desired effect). The risk of unwanted side effects increases with the dose of physiologically active substances. Thus, since complication is the profile of unwanted side effects, the introduction of 52 mg highly pure silibinina exceeds the introduction 125 mg silimarina with the content silibinina 42 wt.% (see .Ding and others, J.Pharm. Biomed. Anal. 26(1), 2001, .155-161).

Patterns silibinina (), , and (), described below, are the works D.Y.-W. Lee and others, J. Nat. Prod. 66, 2003, .1171-1174; N.-C. Kim and others, Org. Biomol. Chem., 1, 2003, .1684-1689):

For the forms of introduction, which are applicable for oral administration (oral drugs)are known to specialists in the field. See, for example, kN.: .. and other «Lehrbuch der Pharmazeutischen Technologie [Textbook of Pharmaceutical Technology]», 1999, 6th ed., WVG Stuttgart.

The form of oral administration preferably selected from the group consisting of tablets, powders, pills, granules, tablets, coated in sugar syrups, juices, solutions, effervescent powder, effervescent granules, effervescent tablets, and capsules. Especially preferred form of oral administration of a tablet, tablet coated in sugar granules, pills or powders, especially preferably tablets.

Relevant for compositions in the forms of oral dosing known to specialists in this field. See, for example, .P.Fiedler, Lexikon der Hilfstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete [Encyclopedia of excipients for pharmacy, cosmetics and related areas], Editio Cantor Aulendorf, 2001.

Tablets can be obtained, for example, by mixing component with known , for example inert solvent, such as calcium carbonate, calcium phosphate and lactose, separator, such as corn starch, and alginic acid, binders, such as starch, gelatin, lubricating agents such as magnesium or talcum powder, and/or agents to achieve the effect depot, for example, , pulp or . The pill may also consist of a number of layers. In addition to these solvents pills may also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate, along with various additional substances such as starch, preferably potato starch, gelatin and other In addition, for tablets can be applied slip agents such as magnesium stearate, sodium lauryl sulfate and talc.

Coated tablets of sugar can be obtained, for example, applying the coating to the core, who receive a manner close to a method for tablets with agents normally used to obtain coatings of sugar tablets, for example, or shellac, gum Arabic, talc, titanium dioxide or sugar. To avoid the effect of depot or incompatibility, the core can also consist of a number of layers. Coated tablets of sugar can also consist of a number of layers for the effect of the depot, and you can get them using the above for the tablets.

Juices, syrups, emulsions, suspensions and solutions for oral administration of can optionally contain sweetener, such as saccharin, cyclamate, glycerin and sugar, as well as a flavoring agent, such as flavor, such as vanilla or orange extract. In addition, they may contain additional agents to obtain suspension or thickening agents, such as sodium salt of carboxymethylcellulose, moisturizing agents, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives, such as ethers p-hydroxybenzoic acid.

Capsules can be obtained, for example, stirring component with inert media such as lactose or sorbitol, and a location in gelatinous capsules. that can be used are, for example, water, pharmaceutically acceptable organic solvents, for example paraffins (for example, oil fractions), vegetable oils (such as peanut or sesame), mono - or multi-effect alcohols such as ethanol or glycerol), solvents, such as natural minerals (e.g. kaolin, clay, talc, chalk), crushed synthetic materials (for example, highly dispersed silica and silicates), sugar (such as sucrose, lactose, and dextrose), emulsifying agents (for example, lignin, sulfitno-spirit Barda, methyl cellulose, starch, polivinilpirrolidon) and lubricating agents (e.g., magnesium stearate, talc, stearic acid and sodium sulfate).

The medicine may allocate component immediately or of controlled form. If there is a release of controlled form, preferably a form is . Delayed allocation of the present invention preferably implies profile release, which component is released over a relatively long with a reduced speed for prolonged therapeutic effect. This can be, in particular, achieved with a dose. The expression «with at least partially a slow release» according to the present invention includes any drug that ensures modified release contained in the dosage form component silibinina. Medicines preferably in the forms of introduction of coated or uncoated that get using special , certain processes or by a combination of both forms, for selectively modified speed of release or the designated release. Due to the length of the release if the medicines according to the present invention includes the following types: delayed release (extended-release), the release of repetition, prolonged release and sustained release. See, for example, kN.: .. and other «Lehrbuch der Pharmazeutischen Technologie [Textbook of Pharmaceutical Technology]», 1999, 6th ed., WVG Stuttgart.

Appropriate measurement of a controlled release of the active compound known to specialists in this field. If the medicinal product in the form for oral administration, for example in the form of tablets, delayed release can be achieved, for example, immersion component in a polymer matrix and/or film coating forms of oral dosing with a membrane.

Drugs with controlled release of the active substance may contain component soluble and/or solid, amorphous or crystalline form.

For obtaining of medicinal forms with a controlled release of the current connection according to the present invention controlled release of the active compound, component can be used in the form of particles of the different size, such as producing, crushed particles or .

The drugs with controlled release of active connection, component, preferably appears in the form of particles containing the active substance, for example, pills, granules, microcapsules, tablets, extrudates or crystals, which are covered with a membrane that controls diffusion.

Such drugs with controlled by diffusion preferably consist of many particles, i.e. they preferably consist of multiple cores coated, for example, neutral pills, which put a mix component with the usual binder and a thickener, optional with ordinary emollients and solvents, and then their glaze for diffusion, and other . Drugs with controlled by diffusion of the present invention, in addition, may consist of homogeneous marrows, including component, which receive, for example, by pelleting, rotary granulating, agglomeration in the fluidized bed, tableting, wet extrusion extrusion or melting, without necessarily giving a spherical shape, and glaze for diffusion, which may contain softeners and other .

Particles containing component may contain , e.g. acids or buffering agents that modify pH and, through this, impact on reducing dependence release component of pH environment of the release.

Controlling the diffusion membrane may also include additional , which due to the pH-dependent solubility affect the permeability of the membrane at different pH and thus influence minimizing dependence release component of pH.

Binders and thickeners, applied to obtain neutral pills coated, preferably are hydroxypropylmethylcellulose (HPMC) and polivinilpirrolidon (PVP). In a similar manner may be used by other natural, synthetic or semi synthetic polymers such as methyl cellulose (MC), hydroxypropylcellulose (GOC), other and , carboxymethylcellulose and their salts, polyacrylic acid, , gelatin, starch and starch derivatives.

To obtain the pills, particles and (mini)tablets containing component, preferably applied cellulose, cellulose, derivative cellulose, for example , the GOC and with a low degree of substitution (GOC-Nha), phosphate, lactose, PVP and sucrose, as binders and fillers, methods of granulation agglomeration in psevdoozhizhennom, layer, wet extrusion and tableting.

To obtain the pills extrusion melting component immersed in thermoplastic . Preferably relevant thermoplastic preferably are GOC, HPMC, , hydroxypropyl methylcellulose, PVP, co-vinylpyrrolidone/vinyl acetate, polyethylene glycol, polietilenoksid, , polyvinyl chloride alcohols, partially hydrolyzed polyvinylacetate, polysaccharides, for example, alginic acid, alginates, galactomannan, waxes, fats and derivatives of fatty acids.

In the particles that contain component can also be included pH-modifying substances, such as acids, bases, and buffering agents. The addition of such substances can significantly reduce the dependence release component and its salts, hydrates, solvate pH.

, which are used for modification of pH in the hearts containing component, are, for example, adipic acid, malic acid L-arginine, ascorbic acid, aspartic acid, acid, benzoic acid, succinic acid, citric acid, acid, 2- acid, fumaric acid, gluconic acid, acid, glutamic acid, potassium, maleic acid, malonic acid, acid, acid, trometamol, tartaric acid. Preferably use citric acid, succinic acid, tartaric acid and potassium.

In addition to controlling the diffusion of polymer, sprayed glaze may also contain additional with a pH-dependent solubility, e.g. polymers gastrointestinal dissolution, such as phthalate pulp, in particular pulp and phthalate hydroxypropyl methylcellulose, pulp, in particular pulp and hydroxypropyl methylcellulose or (for example, a product Eudragit " L). By adding these substances can reduce the dependence release component of pH.

Used in emollients are, for example, derived citric acid, derived acid, benzoic acid and esters of benzoic acid, other aromatic esters of carboxylic acids, esters of aliphatic dicarboxylic acids, -, diacetate and glycerol triacetate, polyols, fatty acids and their derivatives, glycerides fatty acids, castor oil and other natural oils fatty acids and alcohols.

To prevent clumping particles coated during the process and the final product, to glaze can be added agents lowering the viscosity, for example, talc, magnesium stearate, glycerol monostearate and aeroforces.

The rate of release control the composition of the glaze and the thickness of a layer of glaze. Additives that increase the permeability of cover, the agents are the formation of pores that can be added to the glaze or to particles that are coated and which contain component. Agents of the formation of the dispute - soluble polymers, such as polyethylene glycols, PVP, PVA, HPMC, MPC, hydroxyethyl cellulose (SCE), MC, carboxymethylcellulose and their salts, dextrins, , cyclodextrins, dekstrana or other soluble substances such as urea, sodium chloride, potassium chloride, ammonium chloride, saccharose, lactose, glucose, fructose, maltose, mannitol, sorbitol, xylitol and .

with a pH-dependent solubility, which can be the components of diffusing coating, are, for example, intestinal-soluble polymers, such as phthalates pulp, in particular pulp and hydroxypropyl methylcellulose phthalate, pulp, in particular pulp and hydroxypropyl methylcellulose and (for example, a product Eudragit " L).

In addition, the drug controlled release component can be a form for the introduction of coated, containing one or more of the swelling excipients, which greatly increases the penetration of a liquid through a membrane and cause rupture of membranes as a result of swelling and increase the volume. As a result of rupture release of pharmaceutical agent of the medicinal product becomes possible (pulsating release). Such medicines as swelling excipients preferably contain , , cross-linked sodium carboxymethyl cellulose, cross-linked carboxymethyl amylum sodium salt, polyethylene oxides, , with a low degree of substitution (GOC-Nha). Relevant coating materials are preferably cellulose acetate, and .

Medicines coated controlled by diffusion and pulsating release may be applied directly as a finished pharmaceutical forms. They, however, can also be additionally , not necessarily with the addition of excipients, to obtain the final form of administration (for example, capsules, tablets, sachets). To achieve the desired profile for the release, the particles coated also can be combined with other particles in the pharmaceutical form and the initial dose may be given, for example, combination of particles quick release, for example pills without coating, granules or powders.

Drugs with controlled release that may apply also are compounds that contain component in a matrix. Such matrix formulations release component diffusion and/or erosion. Preferably, these medicines are in the form of tablets or number of tablets, which can be encapsulated. The pill can have coverage (film-pills) or varnishing. Such medicines receive, for example, mixing of components and direct tabletting, or wet or dry granulirovaniem followed by tabletting.

Agents that form the matrix, can be water soluble, swellable in water or water insoluble substances. Preferably medicines contain one or more swellable in water polymers.

Used water-soluble and swellable polymers in water, forming a matrix, preferably are hydroxypropylmethylcellulose (HPMC), , (GOC), hydroxyethyl cellulose, methyl cellulose (MC), ethyl cellulose, other , and , natrievaja salt karboksimetiltselljulozy, alginates, galactomannan, for example gum and flour carob beans, , polyethylene oxides, polyacrylic acid, acid derivative acid, polyvinyl chloride alcohol (PVA), partially hydrolyzed polyvinylacetate, polivinilpirrolidon, agar, pectin, gum Arabic, tragacanth, gelatin, starch or starch derivatives, and mixtures of these substances. Application HPMC especially preferable.

In addition, water-insoluble particulates substances may used as agents, forming the structure, for example, or unsaturated-saturated () fatty acids and their salts, esters or amides, mono-, di - and triglycerides, fatty acids, waxes, ceramide derivatives of cholesterol and mixtures of these substances.

Medicines may also contain regular for tabletirovanija, preferably with highly dispersed silicon (product Aerosil), magnesium stearate, talc, PVP, lactose or cellulose.

In addition, the substances can be embedded in a matrix that control pH in the matrix. The addition of such modifying the pH of the excipients and/or the addition of substances that increase the pH or washed away by the dissolution of the matrix and thus increase the porosity or permeability of the matrix and/or induce the erosion of the matrix, it is possible for such preferred options of the present invention to achieve the greatest degree of pH-independent release.

A matrix containing component can also be in special shapes, with the release of the matrix depends on the special geometry and surface matrix. Matrix surface and surface can be controlled, such as compression for special formats (for example, a ring-shaped tablets), and/or the application of sub-areas, or the application of barrier layers using a multilayer press.

Compositions with different properties release may preferably be combined to obtain pharmaceutical form in the form of multilayered tablets or pills with -core. For example, with the help of multilayered tablets, including layer quick release, or tablets with -core with shell quick release, achieved a controlled release of the present invention with high initial release component, although it can be achieved with the help of pills -core with quickly released the core and the high the release at the end.

Other drugs with controlled release component is a drug, in which component add a matrix consisting of one or more physiologically acceptable excipients process of melting. Release component of such «sintered extrudates» occur due to diffusion and/or erosion. Preferably such compositions with controlled-release component are in the form of pellets, of pills or tablets. The forms received by extrusion melting include, in particular, pills, granules, which can be for other pharmaceutical forms, for example, by encapsulating or tabletirovanija, not necessarily with the addition of other conventional pharmaceutical excipients. In addition, fused extrudates according to the present invention can be pulverized and subsequently applied in such a powdered form for other drugs, such as matrix tablets. Additional processing also includes a combination of compounds with different pharmaceutical release, for example, retard-particle and particle quick release, to obtain the drug.

Used thermoplastic native speakers, which preferably swell and become dissolved in physiological environments, preferably are: polivinilpirrolidon (PVP), copolymers of N-vinylpyrrolidone (N) and vinyl esters, in particular vinyl acetate, vinyl acetate copolymers and krotonovoj acid, partially hydrolyzed polyvinyl acetate, polyvinyl alcohol, cellulose esters, in particular methylcellulose and , , in particular hydroxypropylcellulose, , in particular, hydroxypropyl methylcellulose, and , karboksimetiltselljulozy, phthalates pulp, in particular pulp and hydroxypropyl methylcellulose phthalate, succinate pulp, in particular pulp and hydroxypropyl methylcellulose, , , and (class products Eudragit®), methyl-methacrylate copolymers and acrylic acid, , polyethylene glycols, polyethylene oxides and polysaccharides, such as galactomannan and alginic acid and its salts of alkaline metals and ammonium.

Preferred thermoplastic to obtain drugs with controlled release component are , polivinilpirrolidon, copolymers vinylpyrrolidone/vinyl acetate, , in particular product Eudragit " L, hydroxypropyl methylcellulose, polyethylene glycols, polyethylene oxides and their compounds. Softening that can be used to reduce the temperature of vitrification mixtures are, for example, propylene glycol, glycerin, triethylene glycol, , , for example, pentaerythritol, , long-chain alcohols, polyethylene glycols, , polyethylene/, silicones, derivative acids (e.g. dimethyl phthalate, , dibutyl), benzoic acid and esters of benzoic acid, other aromatic ethers carboxylic acids (e.g. esters acid), citric acid derivative (for example, agent foaming, , ), esters aliphatic dicarboxylic acids (for example, , sebacic acid esters, in particular , esters of tartaric acid), glycerin, diacetate glycerol glycerol triacetate, fatty acids, and derivatives (for example, glycerin, acetylated glycerides of the fatty acids, castor oil and other natural oils ), alcohols, fatty acids (for example, cetyl alcohol, Cetearyl alcohol, sugar, polyatomic alcohols and derivatives sugars (such as , , , mannitol, ▫ maltitol,, , xylitol).

In addition component holder (s) and do not necessarily softener (softeners), mixture may also contain other pharmaceutical traditional additional substances, such as slip agents and agents release lubrication, slip agents and agents of fluidity, fillers and adsorbents, stabilizers, trap free radicals, complexing agents, anti-oxidants, , , surface-active ingredients, preservatives, dyes and sweeteners and flavors.

Agents of sliding and greasing for forms may include, for example, stearic acid, and stearaty, in particular stearates of aluminium, calcium and magnesium, calcium , sodium stearyl fumarate, talc, silicones, waxes, and mono-, di - and triglycerides, such as glycerol monostearate, glycerin, glycerin, glycerin, glycerin.

Applied agents fluidity preferably are animal and vegetable oils, preferably in form with a melting point of at least 50 C, waxes (for example, Carnauba wax), mono-, di - and triglycerides (for example, glycerol monostearate, glycerin, glycerin, glycerin, ), fosfatida, in particular lecithin.

Used chemicals, fillers, for example, are titanium dioxide, aluminium oxide, magnesium oxide, silica and silicates, stearic acid, and stearaty, derivative cellulose (for example, methylcellulose), starch and starch derivatives, sugar, polyatomic alcohols and derivatives sugars.

Drugs with controlled release component can also be that contain with pH-modifying properties and/or pH-dependent solubility. Using these excipients (for example, acids, bases, buffer substances intestinal-soluble polymers, already described above), you can minimize dependence release component of pH.

When obtaining sintered extrudates may be forming a «solid solutions», in which component is contained in the matrix in molecular dispersed form.

Osmotic system preferably consists of a core that contains component optional hydrophilic agent swelling and optional water soluble substance for the induction of osmosis and not necessarily also pharmaceutically acceptable , and shell, which consists of material that is impervious to core components and has at least one output, which can be released core components.

The material of which the formed coating of medicines according to the present invention with controlled release component will consist of a semipermeable, i.e. permeable to water, aquatic environments and biological liquids, and impervious or very limited permeable for core components, and is suitable for the formation of film coverings. Selectively a material of the shell nerastvorim in tissue fluids, not corroded not destroyed in the gastrointestinal tract and is excreted unchanged, or it undergoes only by the end of the period release.

Typical materials for the production of coatings for osmosis systems are preferably derived cellulose esters of cellulose, which are from mono to trisubstituted groups or from mono to disubstituted groups and additionally radical instead of acetyl, for example acetate cellulose triacetate cellulose, cellulose acetate/, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, cellulose, -R- cellulose, cellulose and other derivatives of cellulose acetate, and acetate agar and acetate amylose.

Suitable material osmotic membrane systems are also , copolymers and ether , polymeric epoxy, polyglycols and derivatives of polylactic acid. In addition, a mixture of water-insoluble acrylates per se, for example, can be applied copolymer of ethyl acrylate and methyl methacrylate.

If necessary, the shell osmotic systems can also contain softeners, such as mitigating the substances mentioned above, and other additional substances, such as pore agents. If necessary glaze can be used for a semi-permeable membrane, which may consist, for example, of HPMC and MPC, and the corresponding softener (for example, polyethylene glycol) and pigments (for example, titanium oxide, iron oxides).

To monitor the initial dose component, osmotic system can also be provided with a coating that contains component from which component preferably quickly released when in contact with releasing environment before osmotically controlled release component of the core.

Relevant swelling in water polymers that can be contained in the core of the osmotic systems, preferably are (for example, product Polyox®), gum and xanthan gum, copolymers vinylpyrrolidone and vinyl acetate, , , cross-linked sodium salt of carboxymethylcellulose, cross-linked carboxymethyl amylum sodium salt, with a low degree of substitution (GOC-Nha), poly(), alginates and and other hydrophilic polymer swelling agents and their mixtures.

Relevant osmotically active substances that may be added to the core for the induction of osmosis, are water-soluble salts of organic and inorganic acids or non-ionic organic compounds with high solubility in water, such as carbohydrates, in particular sugar, or amino acids. As an example, several substances that may be included in the core of osmotic systems separately or in mixture for induction osmosis: inorganic salts such as chlorides, sulphates, sulphites, carbonates, bicarbonates, phosphates, phosphates, phosphates-alkali metals and alkaline earth metals, such as sodium, lithium, potassium, calcium, or magnesium, organic acids, for example adipic acid, ascorbic acid, succinic acid, citric acid, fumaric acid, maleic acid, tartaric acid, benzoic acid and their salts of alkaline or alkaline earth metals, acetates, pentose, for example arabinose, ribose or xylose, , such as glucose, fructose, galactose or mannose, and sugars, such as glucose, maltose and lactose, , for example raphinose, polyols, such as mannitol, sorbitol, ▫ maltitol,, xylitol or Inositol, and urea. Preferably use sodium chloride and sodium carbonate.

In addition, osmotic system may include other common additional pharmaceutical substances, for example, greasing and separation agents, agents slip, resins, dyes, thickeners, protective colloids, stabilizers and surface-active substances.

Osmotic system release preferably receive standard methods, such as wet or dry granulirovaniem pressing, tabletting and followed by the application of organic coatings.

Coverage osmotic system has at least one public output, which is released optional component together with other components of the core. Output can be made in the membranes of different ways, such as punching, machining, laser drilling. The term «open» also includes material that acts from the shell with the introduction of a medicinal product according to the present invention, resulting in the formation of open outputs in situ.

In another embodiment of the present invention for controlled release component, component can also be kept as an ion-exchange complex (adsorbate).

Preferably drug process for the introduction once a day, twice a day, three times a day or four times a day.

In a preferred embodiment of the present invention from 0,5 up to 75% by weight initially contained component released from the medicine in 1 h in vitro. Relevant conditions to determine the release of active substances in vitro known to specialists in this field. In this regard, the information can be obtained, for example, in the European Pharmacopoeia. Preferably definition of the release is carried out with the help of the device with vane agitator artificial gastric juice (buffer with pH 1,2) or in the artificial intestinal fluids (with the size of the buffer pH 7.6). The number of the released component can be tested, for example, by HPLC and UV-scopy.

Preferred release profiles from A 1 to A 8 are summarized in the table below

Over time [h]

A 1

And 2

3

And 4

And 5

And 6

7

And 8

wt.%

wt.%

wt.%

wt.%

wt.%

wt.%

wt.%

wt.%

0,5

5.0-34

6.0-33

7.0-32

9.0-31

11-30

13-30

15-29

17-28

1

12-53

15-52

18-50

20-48

22-46

24-44

27-42

30-40

2

25-74

27-71

29-68

31-65

33-62

36-60

39-58

42-56

3

33-85

36-82

39-79

42-76

45-73

48-71

50-69

52-67

4

41-92

44-89

47-86

50-83

53-81

55-79

58-77

60-75

6

52-98

55-97

58-96

60-94

63-92

66-90

69-88

72-86

8

>62

>65

>68

71-99

74-98

76-98

78-97

80-97

12

>70

>73

>76

>79

>82

>84

>86

>88

In a preferred embodiment of the present invention medicine contains cyclodextrin and/or phospholipids.

Pharmaceutical compositions containing silibinin and cyclodextrins, known from the prior art (see, for example, the EP 422497). Preferably, silibinin forms included complex with cyclodextrine. Preferred are α-, b - and g-cyclodextrins, their O-1-C4-alkyl and hydroxy-1-4-alkyl derivatives.

Pharmaceutical compositions that contain silibinin and phospholipids, are also known from the prior art (see US 4764508). Preferably silibinin forms a complex with . Preferred phospholipids are phosphatidylcholine, and . Preferred phospholipid complexes are tertiary complexes, optionally containing vitamin E (tocopherol). Complexes of this type are known from the prior art and marked «complexes SPV» (see A.Federico, Gut. 55(6), 2006, .901-902).

In addition component of the medicinal product may contain one or more of terpenes. Due to the action of and necessary conditions for adsorption and adsorption processes in General could be improved. Terpenes can be natural or synthetic essential oils and/or their terpenoid components in the form of pure substances or mixtures, or derivative of such pure substances. Among the essential oils can be noted, in particular, oil thyme, eucalyptus oil, oil of pine needles, tea tree oil, oil tree, cardamom oil, peppermint oil, sage oil and oil of rosemary, preferably oil of thyme. Of terpenes - substances, is also intended to the inclusion, in particular, you can use , which include, for example, isoprene, acid, common valeric acid; , including acyclic , for example, 2,6-, a-, (E)-(p-, , , geraniol, (S)-(+)and citronellol monocyclic , for example and , for example acid or , , for example or or (-)- and (-)-oleuropein, cyclohexane, for example, , CIS - or TRANS-R-, (R)-(+)-limonene, , (-)-menthol, (+)-, (-)-Menton or (+)-, bicyclic , for example, terpenes with oxygen bridges 1,4-cineole, 1,8-cineole or ; Karana and , , and and ; sesquiterpenes, for example, , , , elements and . Especially preferred terpenes are thymol, menthol, cineole, borneol, , and pinene, it is usually preferable thymol.

Medicine contains component. Silibinin is an integral part of silymarin. Preferably, in addition to silibinina or components, medicinal product contains none of the other component parts of silymarin. If component is the silibinin, drug and contains none of the other component of silymarin. If component is the silibinin, as, for example, ether, drug and contains none of the other components of silymarin, i.e. contains silibinina.

Preferably one or more substances, selected from the group consisting of , , , Taxifolin, , , , and are not in the medicinal product, i.e. drug preferably practically does not contain at least one of the above-mentioned pollutants. In this regard, the concept of «contained practically no» means that the residual content of substances preferably less than 2.0 wt.%, more preferably less than 1.0% even more preferably less than 0.5% it is most preferable to less than 0.1 wt.% and especially less than 0.05 wt.% of the total mass of the medicinal the funds. Analytical methods for determination of residual quantities of these substances are known to specialists in the field, such as HPLC.

It is established that certain parts of silymarin differ in chemical and physical properties and influence on the pharmacological effects of silymarin in different degree, so it is useful to assign silibinin, or its derivatives, and/or salt as the only component of silymarin, i.e. exclusively. Obviously, in such manner, and effectiveness of, and compliance of the patient can be improved.

In addition, unexpectedly it was found that tolerance of different component parts of silymarin is different, and that silybin better things, especially less toxic in comparison with (i.e. compared with a mixture containing other components in addition to silibinina).

The preferred variant the implementation of the present invention relates to the application of a component of a medicinal product which preferably processed for parenteral or oral administration and that in addition to component does not contain any of the components of silymarin, for the treatment of viral hepatitis, in particular, hepatitis b or C.

Below are especially preferred drugs, which are adjusted for oral administration component. All these oral dosage forms in the aggregate contain preferably component in substantially pure form, i.e. preferably in the absence of other components of silymarin, especially in the absence of , and/or , and/or .

Wt.%

B 1

B 2

3

B 4

B 5

B 6

component

1,0-50

2,5-20

8,0±5,0

8,0±4,0

8,0±3,0

8,0±2,0

PVP

1,0-97

10-80

64±15

64±12

64 ą10

64 ħ 7.0

Dextrin

1,0-70

5,0-50

22,8 of + 20

22,8±15

22,8 ą10

22,8 ħ 7.0

Aeroforces

0-10

0-7,5

4,0±3,0

4,0 within (2.5

of 4.0 + or-2,0

4,0 ą1.5

Talc

0-5,0

0-2,5

1,2 ą1.0

1,2±0,7

1,2 approximately 0.5

1,2±0,3

The composition can be provided, for example, in the hard gelatin capsule.

In another preferred embodiment of the present invention provides a medicinal remedy in the form of microemulsions. lipid systems can be used as carriers and can lead to high bioavailability is contained in them medicinal agent. Lipid system has colloidal nature and allows sucked micro-particles, especially colloidal size, also through the lymphatic system in the gastrointestinal tract. Usually the dissolved drug saturate, but recrystallization is not happening. The oral introduction of lipophilic drugs, such as component, micro emulsion is mainly used optimized vector, which increases the degree of solubility of dissolved or highly dispersed medicines in place suction. In other words, lipid system acts as an amplifier of adsorption.

An example of such a lipid system is component corresponding to the first emulsifier (for example, , for example, the product Gelucire® 44/14), and not necessarily corresponding to the second emulsifier (for example, , for example, the product Labrasol OS). Composition may additionally include , for example Polysorbate.

Preferred options of solid solution from C 1 to 6 are presented in the table below.

Wt.%

C 1

C 2

3

C 4

C 5

C 6

component

0,1-50

0,5-20

4,0±3,5

4,0±3,0

4,0 within (2.5

4,0±2,0

First emulsifier

1,0-99

5-97

54±15

54±12

54 ą10

54 ħ 7.0

The second emulsifier

0-70

0-70

41 to + 20

41±15

41 ą10

41 ħ 7.0

Polysorbate

0-10

0-7,5

1,5 ą1.0

1,5±0,7

1,5 approximately 0.5

1,5±0,3

Composition that may be hard or preferably , may be provided, for example, in the hard gelatin capsule or soft gelatin capsule.

In another preferred embodiment of the present invention provides a medicinal remedy in the form of nanotechnology composition. The average particle size, and preferably less than 1 micron. Nanoparticles can penetrate biological cellular structures. component preferably adsorbed on the surface of these nanoparticles. Nanoparticles preferably selected from the group consisting of inorganic nanoparticles and organic nanoparticles.

Inorganic nanoparticles include crystalline silicates, for example, mineral origin or artificial silicates, for example , for example aluminium silicates (for example, zeolites). Inorganic nanoparticles preferably chemically modified so that they are electrostatic charges. Silicates are the basis of ultrathin for nanoparticles and component is connected (adsorbed) with the porous surface of the nanoparticles.

Organic nanoparticles include clusters or agglomerates molecular proteins, or oligopeptides, or lipids. The corresponding media protein is, for example, Protamine.

Methods of obtaining nanoparticles known to specialists in this field. For example, colloidal nanoparticles as carriers for oral liberation of medicinal products, can be obtained by sputtering of a medicinal product, i.e. component, together with the relevant materials-bearers under pressure at a temperature of, for example, 60, The injector is equipped with perforated sieves (matrices) in a very chilled towers. Spontaneous cooling forms the amorphous phase, consisting of nanoparticles.

Solid lipid nanoparticles can be obtained, for example, high pressure and subsequent cooling spray. Preferably medicinal product, i.e. component, used as a solution in the solvent or nominally in the form of . component can be sprayed and homogenized pressure, respectively, when mixed with a lipid solvent and surface-active substance at a temperature of, for example, 60°n After an optional add finely divided fillers as an external phase, and slip agents and other surface-active substances received in result of the composition can be used for filling hard gelatin capsules.

Examples of these solid lipid nanoparticles refers kernel component corresponding to the first emulsifier (for example, , for example, a product Gelucire® 50/13), and not necessarily appropriate neine surface-active substance (for example, ). Composition preferably also contains external phase (coating), including the first surface-active substance (for example, Tween 20), Aerosil and the second surface-active substance (for example, , for example, a product Percirol OS).

Preferred options exercised D 1 to D 6 solid solution are presented in the table below.

wt.%

D 1

D 2

D 3

D 4

D 5

D 6

component

0,1-30

0,5-20

4,5±3,0

4,5 within (2.5

4,5±2,0

4,5 ą1.5

First emulsifier

10-99

20-95

75 to + 20

75±15

75 ą10

75±7,5

neine surfactant

0-50

0-40

15 ą10

15±7,5

15 ą5

15 within (2.5

The first surfactant

0-10

0,1-7,5

1,5±0,7

1,5 approximately 0.5

1,5±0,3

1,5±0,2

Aerosol

0-10

0,1-7,5

3,0±2,0

3,0 ą1.5

3,0 ą1.0

3,0±0,7

The second surfactant

0-10

0,1-7,5

1,5±0,7

1,5 approximately 0.5

1,5±0,3

1,5±0,2

Loaded nanoparticles reach substantially more rapid the beginning of the receipt of the medicine.

Medicine contains component preferably at a dose of at least 10 mg, at least 15 mg, at least 20 mg at least 25 mg of at least 50 mg of at least 75 mg at least 100 mg at least 125 mg, at least 150 mg, at least 175 mg or at least 200 mg; more preferably at least 225 mg, at least 250 mg, at least 275 mg at least 300 mg at least 325 mg of at least 350 mg at least 375 mg or at least 400 mg; even more preferably at least 425 mg, at least 450 mg, at least 475 mg of at least 500 mg, at least 525 mg at least 550 mg of at least 575 mg or at least 600 mg; most preferably at least 625 mg, at least 650 mg of at least 675 mg at least 700 mg, at least 725 mg at least 750 mg of at least 775 mg or at least 800 mg; and particularly at least 825 mg, at least 850 mg at least 875 mg of at least 900 mg at least 925 mg at least 950 mg, at least 975 mg, or at least 1000 mg; in each case as of the equivalent dose based on .

Medicinal the tool contains component preferably at a dose of at least 1.0 mg/kg, more preferably at least 2.5 mg/kg, even more preferably at least 5.0 mg/kg, it is most preferable to at least 7.5 mg/kg and, particularly at least 10 mg/kg, at least 12.5 mg/kg, at least 15 mg/kg, at least by 17.5 mg/kg, at least 20 mg/kg, at least 22.5 mg/kg, at least 25 mg/kg, at least to 27.5 mg/kg or at least 30 mg/kg based on body weight of a patient and in each case in the form of equivalent dose silibinina. Preferably specified dose is daily dose. Thus, if the medicinal product is adapted, e.g. twice a day, corresponding to a daily dose is divided into two parts of equal number. Similarly, e.g. if the medicinal product is adapted to the introduction of three times per day, corresponding to the daily dose divided into three parts of equal number.

In a preferred embodiment of the present invention daily dose component is at least 5 more preferably at least 10, even more preferably at least 15, and most preferably at least 20 mg / kg of body weight, based on an equal mass silibinina.

In a preferred embodiment of the present invention daily dose component is 20 mg per kg of body weight, based on an equal mass silibinina. Thus, if the medicinal product is adapted for the introduction of times a day, it is preferable contains all the number component, for example 1400 mg silibinina for a patient with a body weight of 70 kg If the medicinal product is adapted for the introduction of twice a day, it is preferable contains half the number of component, for example 700 mg silibinina for a patient with a body weight of 70 kg If the medicinal product is adapted to the introduction of three times per day, it is preferable contains a third of the number of component, for example 467 mg silibinina for a patient with a body weight of 70 kg If the medicinal product is adapted for the introduction of four times a day, it is preferable contains a quarter of the number of component, such as a 350 mg silibinina for a patient with a body weight of 70 kg

If the medicinal product is adapted for parenteral injection, preferably for infusion, the preferred treatment regimen is 4 equal infusion lasting 2 hours each. Preferably within 4 hours the same infuziu repeat so that for 24 hours in total spend 4 infusion. Such a regime can schematically be abbreviated by «

»where each number indicates the number of hours and the underlined numbers mean duration of infusion and numbers mean lag-phase between the two periods infusion. Preferably treatment heterogeneous, i.e. for 24 hours all infusion is equal to the measured for equal periods of time, and lag-phase between consecutive third limited is also identical.

Based on the foregoing, the preferred modes of injecting summarized in the table below.

Once a day

Twice a day

Three times a day

Four times a day

In a preferred embodiment of the present invention drug adapted for the introduction of a one, two, three or four times a day so that the total daily dose injected in the established way, contains at least 300 mg at least 325 mg of at least 350 mg at least 375 mg or at least 400 mg; more preferably at least 425 mg, at least 450 mg, at least 475 mg of at least 500 mg, at least 525 mg at least 550 mg of at least 575 mg or at least 600 mg; even more preferably at least 625 mg, at least 650 mg of at least 675 mg at least 700 mg, at least 725 mg at least 750 mg of at least 775 mg or at least 800 mg; more preferably at least 825 mg, at least 850 mg, at least 875 mg of at least 900 mg at least 925 mg at least 950 mg, at least 975 mg, or at least 1000 mg; most preferably at least 1050 mg at least 1100 mg at least 1150 mg at least 1200 mg or at least 1250 mg; and particularly at least 1300 mg at least 1350 mg at least 1400 mg at least 1450 mg or at least 1500 mg; in each case, the equivalent dose is based on .

Preferred pharmacokinetic parameters AUC 0-t , AUC t-OO , AUC 0-OO AUC 0-C (corrected) (preferably after several infusions, for example after 11 infusion; one dose of 12.5 mg/kg daily dose: 4 infusion; total dose: 11 infusion) are summarized as options for the implementation of E-1 to E 8 in the table below.

E 1

E 2

E 3

E 4

E 5

E 6

E 7

E 8

mcg h/ml

mcg HR/ml

mcg HR/ml

mcg HR/ml

mcg HR/ml

mcg HR/ml

mcg HR/ml

mcg HR/ml

AUC 0-t

333±200

333 about 150

333±125

333 approx.100

333±80

333±60

333±40

333 of + 20

AUC t-OO

322±200

322 about 150

322±125

322 approx.100

322±80

322±60

322±40

322 of + 20

AUC 0-OO

655±200

655 about 150

655±125

655 approx.100

655±80

655±60

655±40

655 of + 20

AUC 0-OO

(fixed)

414±200

414 about 150

414±125

414 approx.100

414±80

414±60

414±40

414 of + 20

In a preferred embodiment of the present invention a medicine containing component, adapted for adjuvant therapy, preferably by immunomodulatory/antiviral combination therapy, such as interferon/.

In a preferred embodiment of the present invention addition component medicine contains additional pharmaceutical agent, which preferably is applicable for treatment of inflammatory diseases of the liver, especially preferably viral liver diseases, especially for the treatment of hepatitis b or C.

Preferably, additional pharmaceutical agent is selected from the group consisting of means of treating liver, lipotropic agents [05]; nucleosides, nucleotides, selective inhibitors of reverse transcriptase inhibitor [J05AB]; interferons [L03AB] and monoclonal antibodies against HBV (hepatitis b virus). Designations in brackets refer to the index PBX, preferably in the German version of 2007.

Especially preferably, if other pharmaceutical agent is selected from the group consisting of arginine glutamate, , , ornithine , , , methionine and N-, choline, ornithine aspartate, , , betaine, cyanocobalamin, leucine, , acyclovir, , , ribavirin, ganciclovir, famciclovir, valacyclovir, cidofovir, penciclovir, valgancyclovir, brivudin, interferon Alfa, interferon, interferon gamma, interferon Alfa-2A, interferon Alfa-2b, interferon Alfa-n1, interferon beta-1A interferon beta-1b interferon -1, Peginterferon Alfa-2b, pegylated interferon Alfa-2A and interferon gamma-1b.

In a preferred embodiment of the present invention treatment of the patient component is designed to maintain and/or treatment of viral hepatitis, especially hepatitis b or C, with the subsequent treatment of pharmaceutical means, which preferably selected from the group consisting of arginine glutamate, silymarin, , , ornithine , , , methionine and N-, choline, ornithine aspartate, , , betaine, cyanocobalamin, leucine, , acyclovir, , , ribavirin, ganciclovir, , valaciclovir, cidofovir, , , , interferon Alfa, interferon beta, interferon gamma interferon Alfa-2A, interferon Alfa-2b, interferon Alfa-n1, interferon beta-1A interferon beta-1b interferon -1, Alfa-2b, Alfa-2A and interferon gamma-1b.

Thus, preferably after the treatment of viral hepatitis, especially hepatitis b or C, a medicinal agent, which contains component, the treatment of viral hepatitis, especially hepatitis b or C or other medical agent.

In a preferred embodiment of the present invention drug processed as part of the further treatment, with drug first introduced during the first period of preferably dropped, and then another the drug is administered during the second period. Preferably the first period includes at least 2 days, more preferably at least 3 days, even more preferably at least 4 days, most preferably at least 5 days and especially preferably at least 6 nights. Preferably, the second period includes more days than the first period. Preferably, the second period includes at least two days, more preferably at least 3 days, even more preferably at least 4 days, most preferably at least 5 days and particularly at least 6 nights. In particularly preferred embodiment of the present invention second medication contains a combination of ribavirin and interferon alpha, and the second period lasts for 24 to 48 weeks.

Preferably, another medication contains one or more pharmaceutical agents, selected from the group consisting of arginine glutamate, silymarin, , , ornithine , , , methionine and N-, choline, ornithine aspartate, , , betaine, cyanocobalamin, leucine, , acyclovir, , , ribavirin, ganciclovir, famciclovir, valacyclovir, cidofovir, penciclovir, valgancyclovir, brivudin, interferon Alfa, interferon, interferon gamma interferon Alfa-2A, interferon Alfa-2b, interferon Alfa-n1, interferon beta-1a interferon beta-1b interferon -1, Peginterferon Alfa-2b, pegylated interferon Alfa-2A and interferon gamma-1b and monoclonal antibodies to HBV, especially preferably interferon and/or ribavirin and/or silymarin. If your medicine contains interferon, it is preferable interferon Alfa (pegylated interferon Alfa-2A or Peginterferon Alfa-2b).

In particularly preferred embodiment of the present invention medicine contains one or more pharmaceutical agents, selected from the group consisting , , , Taxifolin, , , , and , more preferably only one pharmaceutical agent, chosen from the above list. Preferably, other the drug includes component, characterized in connection with the above-described as a medicinal agent that is administered during the first period, and preferably practically does not contain at least one, preferably all of the above-mentioned pollutants. In this regard, the concept of «contains almost no» means that the residual content of substances preferably less than 2.0 wt.%, more preferably less than 1.0% even more preferably less than 0.5% it is most preferable to less than 0.1 wt.% and especially less than 0.05 wt.% of the total mass medicinal product.

Another medication may in principle be processed for parenteral or oral administration. According to the present invention is preferable processed for another way of introduction unlike a drug which is administered during the first period. Especially preferably another medication refined for oral administration. In particularly preferred embodiment of the present invention a medicine that is injected during the first period, adapted for parenteral, preferably intravenous injection and other drug that is administered during the second period next after the first period, adapted for oral administration.

In a preferred embodiment of the present invention treatment according to the present invention comprises two phases, following one after another, which is called the first period and the second period. Preferably, during the first period of injected drug containing component, preferably parenterally, but other means of treatment of liver simultaneously is not administered. During the second period impose another drug that preferably contains ribavirin and/or interferon Alfa. In a preferred embodiment of the present invention a medicine containing component, also introduced during the second period, preferably parenterally. In another preferred embodiment of the present invention a medicine containing component, do not enter in the second period, i.e. impose only the specified another medication.

Preferred embodiments of the F-1 to F 15 two-phase mode of introduction summarized in the table below.

In another preferred embodiment of the present invention treatment according to the present invention includes three phases, following one after the other, called the first period second period third period. Preferably, during the first period of injected drug containing component, preferably parenterally, but other means of treatment of liver simultaneously is not administered. During the second period also introduce another drug that preferably contains ribavirin and/or interferon alpha, and a medicine containing component, preferably parenterally. Preferably, during the third period impose specified medicine, which preferably contains ribavirin and/or interferon alpha, but a medicine containing component, do not enter into the third period of time, i.e. impose only the specified another medication.

Preferred options for implementation from 1 G to 15 G three-phase mode of treatment are summarized in the table below.

Day

G 1

G 2

G 3

G 4

G 5

G 6

G 7

G 8

G 9

G 10

G 11

G 12

G 13

G 14

G 15

First period

& GE 1

& GE 1

& GE 2

& GE 1

& GE 1

& GE 2

& GE 2

& GE 2

O3

& GE 4

& GE 5

& GE 6

& GE 7

& GE 14

& GE 14

The second period

& GE 1

& GE 2

& GE 1

& GE 1

& GE 2

& GE 2

& GE 1

& GE 2

O3

& GE 4

& GE 5

& GE 6

& GE 7

& GE 7

& GE 14

The third period

& GE 1

& GE 1

& GE 1

& GE 2

& GE 2

& GE 1

& GE 2

& GE 2

O3

& GE 4

& GE 5

& GE 6

& GE 7

& GE 7

& GE 7

In another preferred embodiment of the present invention treatment according to the present invention includes three phases that follow sequentially, namely the first period second period third period. Preferably, during the first period impose another drug that preferably contains ribavirin and/or interferon Alfa injected drug containing component, in the first period. During the second period still enter the specified second drug that preferably contains ribavirin and/or interferon alpha, and also introduce (jointly) is a medicine containing the component during the second period, preferably parenterally. Preferably, during the third period impose specified medicine, which preferably contains ribavirin and/or interferon alpha, but do not impose a medicine containing component during the third period, i.e. impose only the specified another drug the tool. In other words, according to their preferred option for the implementation of the present invention constantly injected specified medicine, which preferably contains ribavirin and/or interferon alpha, and during the interim period (= the second period) together enter a medicine containing component, preferably parenterally.

Preferred options exercised H-1 to H 15 three-phase treatment period are summarized in the table below.

Day

H 1

N 2

N 3

H 4

N 5

N 6

N 7

N 8

N 9

N 10

N 11

N 12

N 13

N 14

N 15

First period

& GE 1

& GE 1

& GE 2

& GE 1

& GE 1

& GE 2

& GE 2

& GE 2

O3

& GE 4

& GE 5

& GE 6

& GE 7

& GE 14

& GE 14

The second period of

& GE 1

& GE 2

& GE 1

& GE 1

& GE 2

& GE 2

& GE 1

& GE 2

O3

& GE 4

& GE 5

& GE 6

& GE 7

& GE 7

& GE 14

The third period

& GE 1

& GE 1

& GE 1

& GE 2

& GE 2

& GE 1

& GE 2

& GE 2

O3

& GE 4

& GE 5

& GE 6

& GE 7

& GE 7

& GE 7

Figure 10 visualizes the different ways of sharing the the introduction of ribavirin and/or of interferon Alfa and of a medicinal product containing component (options and from 1 ) to m 2 )). Each band belongs to the period of time of administration. For example, according to option f 1 , introduction begins with ribavirin/ interferon alpha and continues. During an interim period at the same time introducing component.

Another object of the present invention refers to the medicinal product, as described above, preferably tailored for injecting, for the treatment of viral hepatitis, as outlined above.

Another object of the present invention refers to the set, which includes at least one medicinal product according to the present invention, which includes component and at least one other drug. Both medicinal products according to the present invention, which contain component, and medicine are described above in such a way that all similar preferred options for the implementation of the present invention also applied to a subset of the present invention.

In a preferred embodiment of the present invention set contains as many drugs (individual metered units)as necessary for the fulfillment of continuous therapy, with a medicine that contains component first introduced in the first period, and then a second drug administered for the second period. Preferably, the first period includes at least 2 days, more preferably at least 3 days, even more preferably at least 4 days, most preferably at least 5 days and especially preferably at least 6 nights. Preferably, the second period includes more than a day compared with the first period. Preferably, the second period includes at least 2 days, more preferably at least 3 days, even more preferably at least 4 days, most preferably at least 5 days and especially preferably at least 6 nights.

In particularly preferred variant the implementation of the present invention relates to the application of component, preferably ester silibinina, for obtaining of medicinal product to be processed for parenteral injection for the treatment of viral hepatitis C in non-response in the treatment of ribavirin/interferon, i.e. in patients who do not respond to the immunomodulatory/antiviral combination therapy, such as therapy with ribavirin/interferon.

Another object of the present invention relates to component, preferably a complex ether silibinina, preferably for parenteral injection for the treatment of viral hepatitis, preferably hepatitis C. Preferred embodiments of the present invention are obvious from the above description of the preferred options other objects of the present invention, and therefore not repeated.

Another object of the present invention refers to the treatment of viral hepatitis, preferably hepatitis C, which includes introduction, preferably parenteral introduction, pharmaceutically effective number of component, preferably ester silibinina, subject to the needy. Preferred embodiments of the objects of the present invention is becoming apparent from the above description of the preferred options for the implementation of other objects of the present invention, and therefore not repeated.

In the examples below additionally illustrate the present invention, but they do not limit the coverage area.

Example 1

component administered parenterally in the form of silibinin-With-2',3-bis() (product Legalon Sil®, Madaus, Cologne) (referred to below ).

Patients and methods

Patients

Protocol 1

Protocol 2

N (male/female)

16 (14/2)

20 (17/3)

Average age (years ± standard deviation)

49,9±9,7

52,7±12,8

Genotype (1/2/4)

15/-/1

17/1/2

Fibrosis stages:

0-2

3

10

3-4

13

7

No

-

3

Previous treatment*

PEGinterferon-2/ribavirin

14

18

PEG-interferon-2b/ribavirin

2

4

Log drop at week 12 of previous therapy:

>2**

3

4

1-2

4

1

<1

5

12

No

2

3

14

18

2

4

* some patients are more than one cycle of treatment ** all were positive after 24 week

For these studies are selected patients who have shown themselves as non-response to combination therapy of full doses of /ribavirin. The lack of response to treatment manifests itself in the form of no reduction in >2 log viral load after 12 weeks of treatment, and/or by the absence of a response by the end of treatment. Patients had done liver biopsy for the 2 years prior to inclusion in this study. Apply standard inclusion/exclusion criteria for treatment with the peginterferon/ ribavirin.

The study Protocol

During the screening phase for 35 days prior to the first dose study medicinal product assess the acceptability of patients for inclusion/exclusion criteria. All patients must be at least one quantitative study of HCV RNA within 6 months prior to screening phase.

Protocol 1

First, patients receive daily 10 mg/kg silibinina (product Legalon Sil®, Madaus, Cologne), which is administered by infusion over 4 hours for 7 consecutive days. In the first day of taking blood for analysis to determine a baseline of oxidative stress, and every 30 minutes during the infusion, and after 2 h after completion of the infusion. On the 8th day treatment is replaced by 140 mg of silymarin (product Legalon, firm Madaus, Cologne) three times a day orally in combination with 180 ug/week Alfa-2A (product PEGASYS®, firm Roche, Basel) and 1-1,2 g/day of ribavirin (product COPEGUS®, firm Roche, Basel).

Protocol 2

In both protocols, in case of intolerance interferon Alfa-2A or ribavirin use standard recommendations for the selection of dosage. Antiviral combination therapy receive for a total of 24 weeks (when stopping the treatment of patients with >2 log decrease on 12 week); on antiviral therapy at week 24 offer to continue treatment for an additional 48 weeks. After the end of infusion patients assessed in 2, 4 weeks, and then monthly up to the end of therapy at week 24.

The Protocol was approved by the ethics Committee of the Medical University of Vienna. Details of research explain to patients, and they all give to sign the consent form to participate in the study.

Methods

The level of HCV RNA in serum is determined by TaqMan PCR (Cobas Ampliprep/ Cobas TaqMan VHC Test; detection limit of 15 IU/ml, the firm Roche Diagnostics).

Reactive oxidizing metabolites in the blood is measured by the method derived compounds of reactive oxygen metabolites (p-REC; firm Diacron, Grosseto, Italy), and the number of antioxidants by biological antioxidant potential (BAP; firm Diacron, Grosseto, Italy), using a portable detection system free radicals (FRAS 4, SEAC, Calenzano, Italy), to infusion silibinina, every 30 minutes during the infusion (1 day) and after 2 h after infusions. Method of p-REC measure reactive oxidative metabolites (mainly )emitted from the plasma proteins under the influence of acid buffer, which in the presence gland produces and radicals, in accordance with the Fenton reaction. Such radicals in turn are able to oxidize alkyl-substituted aromatic amine (N,N-), thus getting painted in pink derivative, which calculate quantitatively at 505 nm. Results reactive oxidative expressed in units ( norm: 250-300, 1 =0.08 mg /DL). Method BAP measure the intensity of bleaching solution of ferric chloride, mixed with a derivative of thiocyanate by plasma samples added photometrically at 505 nm, which is proportional to the ability to restore the iron ions available in plasma quantities of antioxidants (norm >2200 PM). In the description of the methods of the manufacturer does not specify a particular substances define.

Statistics

Initially, the resulting variable is viral response, expressed as a percentage of the patients who are PCR-negative at the end of treatment (24 weeks). Secondary efficient variables are the degree of viral response after 12 weeks, safety and tolerability of treatment with the peginterferon/ribavirin/, quality of life relative to the baseline, week 24 48 weeks, 72 weeks (SF-36, digital scale of pain), and oxidative status after infusion silibinina. Due to the unexpectedly strong viral response after 7 days of infusion silibinina, infusion pause and study based on the parameters of viral response and using longer periods infusion and high doses of silibinina. For the initial study sample size set based on the two-stage plan Double. Based on previous studies, the degree of response >10% seems to be the rationale for further study regimen. 29 patients gained at the first stage, respectively (probability of error & beta=5%).

Results

Protocol 1

Include sixteen characterized non-response (see table above). All patients received a full dose treatment interferon (12 Alfa-2A, 2 alpha 2b and ribavirin (1000-1200 mg/day) for at least 12 weeks. Parameters of oxidative stress does not change during the infusion silibinina (figure 1).

The content of serum HCV RNA falls in all patients in the intravenous monotherapy (figure 2), (baseline: 6,59±0,53, day 8: 5,26±0,81 log IU/ml, [average ± standard deviation], p<0.001) with a mean log reduction of 1.32±0,55 within one week. In parallel ALT decreases with 162±133 to 118±107 U/l (p=0.004). All patients HCV RNA remains identified during initiation of treatment with the peginterferon/ribavirin. Three of the patients refused combination therapy with the peginterferon/ribavirin. In 11 of the remaining 13 patients HCV-RNA rises again after completion of the infusion silibinina despite the beginning of treatment with the peginterferon/ribavirin. Week 12 of all patients remain HCV-RNA-positive, but 5 the fall of >2 log and they continue treatment (figure 3). None of them became HCV-RNA negative to week 24, one patient was 5,5 log drop, and he continued treatment on their own.

Protocol 2

Include twenty non-response to certain characteristics (see table above). All patients receive a full dose of treatment interferon (18 Peginterferon Alfa-2A, 4 Peginterferon Alfa-2b; 2 patients received 2 courses of treatment) and ribavirin (1000-1200 mg/day) for at least 12 weeks.

After 1 week combination therapy and with the peginterferon/ ribavirin load virus additionally decreases (log drop: 5 mg/kg: 1,63±0.78, and 10 mg/kg: 4,16±1,28; 15 mg/kg 3,69±1,29; 20 mg/kg 4,8±0,89; all values of p<0.0001 from baseline) (Fig.5). Two of the five patients in the group taking a dose of 15 mg/kg and four of the nine patients in the group taking a dose of 20 mg/kg have the magnitude of HCV-RNA<15 ME by day 15. HCV-RNA is <15 IU/ml in 8 and 7 patients for 4 weeks (Protocol 5-week study) and at 12 weeks (Protocol 13-week study) after the beginning of the /ribavirin respectively. Antiviral combination therapy continues for all patients (6).

Security

Usually silibinin tolerate well. Five patients had moderate symptoms of gastrointestinal disorders (pain in the abdomen: 5, diarrhea: 2, nausea 1), two complain of headache and one of pain in joints. Patients are they assessed as moderate to fall after the completion of the infusion; changes in dosage is not required. All patients in groups of 15 and 20 mg/kg note a feeling of heat in the beginning of infusion, which decreases for 30 min without treatment. No serious side effects. When alone cannot detect changes in hemoglobin, white blood cells, platelets and creatinine. Note the typical side effects of antiviral combination therapy (including one patient increased shortness of breath due to induced Hemophilus influenzae pneumonia requiring cessation of treatment with the peginterferon/ribavirin for 8 weeks).

This example shows that injecting silibinina-(2',3-bis()) has a pronounced antiviral effect against the virus of hepatitis C. This observation shows that this medicine may be used for the treatment of chronic hepatitis C, especially for non-response.

Suddenly it was found that intravenous silibinin-(2',3-bis()) is a powerful antiviral agent in patients with chronic hepatitis C who do not respond to the standard antiviral combination therapy. Intravenous silibinin well tolerated, but manifest side effects. Reported that the most frequent side effect is temporary feeling of warmth. The antiviral effect is dose-dependent, but is not retained after the end of the infusion oral administration of silymarin.

When comparing found that the relatives of the number of silymarin entered oral, do not affect the load of HCV (A.Gordon and others, J Gastroenterol Hepatol. 21, 2006, .275-80), reflecting differences in bioavailability and metabolism silibinina and leading to much lower levels in the plasma. After oral dosing silymarin quickly and quickly eliminate with short half-lives (Z.Wen and others, Drug Metab Dispos. 36(1), 2008, .65-72).

Example 2

Patients always treat 180 mcg Alfa-2A and dependent on the weight of the number of ribavirin. Despite such treatment, five patients were HCV-RNA positive at week 24 of treatment: three men and two women; four patients with HCV genotype 1 and one patient with HCV genotype 3A; three patients with cirrhosis.

Four patients can be estimated as not subjected to any influence, but one patient can be estimated resident at the stage of recurrence relative to the previous two therapies (24 and 48 weeks).

During the course of treatment 180 mcg Alfa-2A and dependent on the weight of the number of ribavirin, all patients administered at least once during the period of 14 consecutive days 20 mg/kg/day silibinina intravenously. During this period, the combined therapy with the peginterferon/ribavirin continue.

All 5 patients become negative for HCV RNA.

Fig.7 shows the results in one specific patient (male, 55 years). You can see that the treatment with the peginterferon/ribavirin causes a decrease in viral load only about 7 log IU/ml to approximately log of 4.5 IU/ml after 24 weeks. Joint treatment of 20 mg/kg/day intravenously silibinin-bis() within 14 days, however, leads to a sharp decrease in viral load from about log of 4.5 IU/ml to values below the detection limit. After the first interval the introduction of parenteral silibinin-bis(), the viral load increases again until about 2 IU/ml, which nevertheless constantly suppressed below the limit of detection the second joint intravenous administration of 20 mg/kg/day silibinin BMS() for 14 days.

Fig.8 shows the results of another individual patient (woman, 44 years). From the figures should be that pegylated interferon/ribavirin rarely causes a decrease in viral load from about 7 log IU/ml to approximately 5 log IU/ml after 30 weeks. Joint intravenous treatment with 20 mg/kg/day silibinin-bis() within 14 days after 30 weeks, however, leads to a sharp and continuous reduction in viral load of approximately 4 log IU/ml to values below the detection limit.

These clinical studies show that the parenteral treatment component over a relatively short period of time supports and improves significantly the traditional treatment with the peginterferon/ribavirin. It is shown that injecting component activates (reactivating a) sensitivity of patients to the traditional treatment with the peginterferon/ribavirin (Fig.7 and 8) and/or increases the antiviral effects of traditional treatment with the peginterferon/ribavirin (Fig.9).

Example 3

Study of in vivo spend to describe the plasma concentration/time profiles of silibinin in 8 patients with chronic hepatitis C, who 7 day intravenous infusion impose 20 mg silibinin/kg body weight (product Legalon® SIL). For multiple doses of 20 mg/kg body weight analyze profiles plasma concentration/time and RK parameters of free and total silibinin for 1 day (= terms and conditions of a single dose) and compared with the indicators on the 7th day (= the expected requirements of the established mode).

Analytical method

Examine samples of using a known method HPLC-UV. During the study the analytic method to confirm the two calibration curves for each analytical run. Analysis of chromatograms data represented in the calibration curves and quality control samples shows that the result of the determination of concentrations of total and free silibinina and silibinina in such a study is reliable.

Pharmacokinetic parameters are summarized in the table below.

Total silibinin

1st day

the 7th day

Silibinin And

Silibinin In

Silibinin And

Silibinin In

AUC(0-OO) [h ng/ml]

61733±27489

13745±76040

-

-

Total silibinin

1st day

the 7th day

Silibinin And

Silibinin In

Silibinin And

Silibinin In

AUC(0-t z ) [h ng/ml]

50019±20048

109038±51342

-

AUCss [h ng/ml]

-

-

84299±25111

150780±47780

C min [h ng/ml]

-

-

1967±831

3311±1426

C max [ng/ml]

4550±928

9539±2843

5791±977

11083±2269

C av [ng/ml]

-

-

3512±1046

6282±1991

t 1/2 [ng/ml]

8,30±2,26

8,29 of + 2,98

13,32±3,66

12,02±2,91

HVD [h]

9,28±3,36

9,47±3,29

15,20±4,09

13,17±3,62

MRT [h]

13,17±3,74

13,44±4,39

19, 22 the±5,28

17,34±4,20

CL [ml/(h kg)]

0,435±0,336

0,233±0,237

0,269±of 0.128

0,156±0,091

Vz [ml/kg]

4,7 ą 1.3

2,4 about 1.1

4,67±0,73

2,43±0,55

t max [h]

4,14±0,18

4,17±0,18

-

-

% PTF [%]

-

-

121,89±54,43

137,59±52,51

Free silibinin

1st day

the 7th day

Silibinin And

Silibinin In

Silibinin And

Silibinin In

AUC(0-OO) [h ng/ml]

3614±1648

753±397

-

-

AUC(0-t z ) [h ng/ml]

3302±1551

559±339

-

-

AUCss [h ng/ml]

-

-

4095±1942

104U627

C min [h ng/ml]

-

-

59±40

3,3±8,7

C max [ng/ml]

316±108

is 90 + 44

315±119

120±54

C av [ng/ml]

-

-

171±81

43±26

t 1/2 [ng/ml]

4,58±1,35

5,16±4,96

6,85±1,29

4,35±1,66

HVD [h]

10,12±4,29

6,09±2,14

11,87±2,64

7,17±1,63

MRT [h]

8,49±2,64

8,81±6,12

9,88±1,86

6,27±2,39

CL [ml/(h kg)]

7,0±4,2

44,8±42,5

5,9±2,9

26,8±16,7

Vz [ml/kg]

51,4±12,7

285,8±KZT 163.9

55,3±18,5

140,4±49,0

t max [h]

3,73±1,22

4,03±0,04

-

-

% PTF [%]

-

-

164,00±45,33

305,24±80,46

Example 4

In vitro study carried out for the assessment of the cytotoxic effect of silymarin, silibinina, silibinina-bis() disodium salt and succinic acid with the help of this test XTT using cell line L929 mouse (see D.A.Scudiero and others, Cancer Res. 48, .4827-4833; O.S.Weislow and others, J.Natl. Cancer Inst., 81, 577-586; N.W.Roehirm other, J. Immunol. Methods, 142).

Explore the following concentration in the studied positions: 9,77, 19,53, 39,06, 78,13, 156,25, 312,5, 625, 1250 mcg/ml Complete environment (RPMI 1640 containing 10% FTS) is used as a negative control. Control solvent for the position is the environment RPMI 1640 containing 10% The Federal tariff service and 1% DMSO. Control solvent for positive control environment is also RPMI 1640 containing 10% FTS and 10.0% deionized water. Sodium used as a positive control. Apply the following concentration: 3,125, 6,25, 12,5, 25, 50, 100, 125, 250 mcg/ml incubation Time is 24 hours at 37 ą1.5°N

Negative control and control of the solvent does not show decreased viability of cells. Positive control (SDS) induces a special dose-dependent decrease in cell viability.

Toxic effects observed after incubation with with 39,06 mcg/ml and up to the highest tested concentration (1250 mg/ml). The calculated value XTT 50 is a 35.2 mkg/ml

Toxic effects observed after incubation with with 78,13 mcg/ml and up to the highest tested concentration (1250 mg/ml). The calculated value XTT is 50 67,5 mcg/ml.

Not observed significant cytotoxic effects after incubation with sodium salt of silibinin-bis() until most of the analyzed concentration (1250 mg/ml). Because of the loss of cytotoxicity value 50 cannot be calculated.

Not observed significant cytotoxic effects after incubation with amber acid tested to the highest concentration (1250 mg/ml). Because of the loss of cytotoxicity value 50 cannot be calculated.

Studies show that in these conditions cytotoxic potential of silymarin approximately 100% higher cytotoxic potential silibinina. Therefore, we can expect that silibinin can be relatively high doses of silymarin without induction of serious side effects.

Example 5

NS5B RNA-dependent RNA polymerase (RNA-dependent RNA polymerase - RdRp) is an important enzyme for viral replication (see S.B.Hwang and others, Virology 227, 1997, .439-446). Then purified compounds tested in cell-free analysis to identify HCV RdRp action: silibinin And, silibinin, And, In, , and salt ester silibinina silibinin-With-2',3-bis() (active ingredient product Legalon® SIL).

The concentration of DMSO all reactions remain constant of 5%. Prepare the source solutions (100 mm) connections in 100% DMSO. Target enzyme in the study is HCV NS5BΔ21 polymerase genotype J4 (1b).

Figure 11 shows the data obtained for six treated component parts of silymarin (i.e. silibinina And, silibinina, And, In, ). Fig.12 respectively shows the data on the complex ether silibinina. Ester silibinina shows the greatest efficiency.

The value of the IC 50 of ester silibinina determined by the curve of the dose-response along two dimensions. The particular value of IC 50 is 47±14 microns. Curves agree on the data points and the value of the IC 50 interpolate the curves obtained using the software SigmaPlot 8.0.

1. Application component with the General formula (I)

where R 1 , R 2 , R 3 , R 4 and R 5 independently selected from the group consisting of Mr., -SO 3 H, -RO 3 N-2-WITH-1-8--IT-WITH-1-8--CO 2 H-1-8--SO 3 H, -CO-1-8- ORO 3 N-2-WITH-1-8--RO 3 N 2 , -(2-3--O) n -N, where n = 1 to 20, -CO-1-8--N(C 1-C 3-alkyl) 3 + X , where X is pharmaceutically acceptable anion, or pharmaceutically acceptable salts, to receive the medicinal product created for parenteral injection in the treatment of viral hepatitis, and drug does not necessarily contain cyclodextrin and/or phospholipids.

2. Use according to claim 1, and component represents ester silibinina.

3. Use according to claim 2, and ester silibinina is silibinin-With-2',3-bis() or physiologically acceptable salt.

4. Use according to claim 1, and medicine, essentially contains no , and/or , and/or .

5. Use according to claim 1, and viral hepatitis a hepatitis b or hepatitis C.

6. Use according to claim 1, and drug refined for injection or infusion.

7. Use according to claim 1, and drug processed for intravenous administration.

8. Use according to claim 1, and the medicinal product does not contain any one of the component parts of silymarin in addition component.

9. Use according to claim 1, and medicine contains component at a dose of at least 50 mg .

10. Use according to claim 1, and medicine contains additional pharmaceutical agents in addition to component.

11. The application of paragraph 10, and additional drug selected from the group consisting of arginine glutamate, , , ornithine , , , methionine and N-acetyl-methionine, choline, ornithine aspartate, , , betaine, cyanocobalamin, leucine, , acyclovir, , , ribavirin, ganciclovir, , valaciclovir, cidofovir, , , , interferon Alfa, interferon beta, interferon gamma interferon Alfa-2A, interferon Alfa-2b, interferon Alfa-n1, interferon beta-1A interferon beta-1b interferon -1, Alfa-2b, Alfa-2A and interferon gamma-1b.

12. Use according to claim 1 for reduction of viral load in patients with hepatitis.

13. Use according to claim 1 for the treatment of viral hepatitis in a patient who will or who had a liver transplant.

14. Use according to claim 1 for the treatment of viral hepatitis in a patient who is not responding to treatment with ribavirin/interferon.

15. Use according to claim 1 for support and/or preventive treatment of viral hepatitis pharmaceutical agent, selected from the group consisting of arginine glutamate, silymarin, , , ornithine , , , methionine and N-, choline, ornithine aspartate, , , betaine, cyanocobalamin, leucine, , acyclovir, , , ribavirin, ganciclovir, , valaciclovir, cidofovir, , , , interferon Alfa, interferon beta, interferon gamma interferon Alfa-2A, interferon Alfa-2b, interferon Alfa-n1, interferon beta-1A interferon beta-1b interferon -1, Alfa-2b, Alfa-2A and interferon gamma-1b.

16. Use according to claim 1, and after treatment of viral hepatitis specified medicine treat viral hepatitis another drug.

17. Use according to claim 1, and the drug was established in the form of component parts for subsequent treatment, first, the drug is administered during the first period and subsequently injected medicine during the second period.

19. Application for P16, with another medication that contains one or more of pharmaceutical agents, selected from the group consisting of arginine glutamate, silymarin, , , ornithine , , , methionine and N-, choline, ornithine aspartate, , , betaine, cyanocobalamin, leucine, , acyclovir, , , ribavirin, ganciclovir, , valaciclovir, cidofovir, , , , interferon Alfa, interferon beta, interferon gamma interferon Alfa-2A, interferon Alfa-2b, interferon Alfa-n1, interferon beta-1A interferon beta-1b interferon -1, Alfa-2b, Alfa-2A and interferon gamma-1b.

20. Application for P16, and medicine created for oral administration.

21. Set for treatment of viral hepatitis, including at least one drug, one of claims 1 to 11 and at least one medicinal product on .19 or 20.