Silibilin component for treating hepatitis

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 use of silibinin a component of a medicinal product for the treatment of viral hepatitis, preferably hepatitis b or C, in particular to reduce viral load. Preferably the drug is adapted for parenteral administration. Preferably silibinin component is a complex ester of silibinin.

Silibinin {3,5,7-trihydroxy-2-(3-(3-hydroxy-4-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydrobenzo[b][1,4]-dioxin-6-yl)chroman-4-one, or in 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-benzodioxin-6-yl]-2,3-dihydro-4H-1-benzopyran-4-one}, represents the main part of silymarin and main flavonoid extracted from milk Thistle (Silybum marianum Gaertneri).

Silibinin has the structure:

Diastereoisomer silibinin a and silibinin In present in the literature separately:

Silibinin is the main component part of oleum (a mixture of 50:50 silybin and silybin). Other constituent parts are isosilybin (isosilybin and isosilybin), silidianin, silikristin, isoliquiritin, Taxifolin and others. How the selection of silibinin known to the prior art (for example, US 4871763).

Silibinin and silymarin have been thoroughly studied and described. In this regard, we can refer to the work of N.-C. Kim and others, Org. Biomol. Chem. 1, 2003, SS-1689; D.Y.W. Lee and others, J. Nat. Prod. 66, 2003, SS-1174; D.J. Kroll and others, Integrative Cancer Therapies, 6, 2007, s-119; Z.Wen and others, DMD Fast Forward, doi:10.1124/dmd.107.017566; and US 4871763.

The history of medicinal plant Silybum marianum contains about 2000 years. Silymarin is an extract of milk Thistle, is an ancient remedy for the treatment of various disorders of the liver and gallbladder, including hepatitis, cirrhosis, and hepatoprotector, protecting the liver from poisoning of wild mushrooms, alcohol, chemicals and environmental toxins. The mechanism of action of silymarin diverse. The largest randomized controlled study conducted in the 1970-ies have shown that prolonged use of silymarin may reduce mortality in patients with chronic cirrhosis (P.Ferenci etc., J Hepatol 9, 1989, SS-113). However, the role of this drug for the treatment of liver disease remains controversial (S.Verma and others, Clinical Gastroenterology and Hepatology 5, 2007, s-416; F.Rainone, Am Fam Phys 72(7), 2005, cc.1285-1288). Partly this uncertainty caused by limited information on the pharmacokinetics and optimal dosing schedules. Silymarin is poorly soluble in water, and oral administration leads to limited bioavailability.

Pharmacist the ical application of silibinin also known. Silibinin has strong antioxidant properties (see A.Pietrangelo and others, Gastroenterology 109, 1995, SS-1949; .I.Lucena etc., Int J Clin Pharmacol Ther 40, 2002, cc.2-8; L.Mira and others, Biochem Pharmacol 48, 1994, cc.753-759) and protivovirusnymi properties (see G.Boigk and others, Hepatology 26, 1987, SS-649; .Dehmlow and others, Hepatology 23, 1996, s-754), so it is potentially applicable as a drug for the treatment of chronic liver diseases. Pure substance silibinin is injected, for example, by poisoning the liver pale grebe (toxins amanitin, phalloidin) to prevent liver damage (see .Hruby and others, Hum Toxicol 2, 1983, SS-195). The action of mushroom poisoning is partly explained by the stimulation of nucleolar polymerase a, which increases the synthesis of ribosomal protein and inhibits lipid peroxidation (J.Sonnenbichler and others, Prog Clin Biol Res. 213, 1986, cc.319-331). Clinical studies have also been successful in the prevention and treatment of certain types of cancer (L.Varghese and others, Clin Cancer Res 11(23), 2005, SS-8447; Letschert, K. and others, Toxicological Sciences, 91, 2006, SS-149).

Ester silibinin get 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 caused by viruses. Viral hepatitis is actively exploring throughout the world. Viral hepatitis not only causes high mortality, but also IP omaet medical resources and can cause severe economic consequences. Most of all viral hepatitis can be prevented.

The term "viral hepatitis" refers to five different diseases that are caused by at least five different viruses. Hepatitis a and hepatitis b (infectious hepatitis and serum hepatitis, respectively) represent different diseases and both are diagnosed by specific serological test. Hepatitis C and E represent the third category, differing in type, and hepatitis C is transmitted parenterally, and hepatitis E is transmitted enterline. Hepatitis D or Delta hepatitis is a disease caused by a virus of a different type-specific infection with hepatitis C. This form of hepatitis can be in the form of superinfection in the carrier of hepatitis b or in the form of joint infection in an individual with acute hepatitis C.

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

It is established that approximately 170 million people worldwide are infected with hepatitis C virus (HCV). For decades the infected patients, symptoms are absent until until you develop cirrhosis and/or hepatocellular carcinoma. Approximately 40-50% of cases in the United States transplantation of the liver caused by HCV infections. Identified six genotypes of HCV (VGS-VGS), which differ in geographical distribution and their response to treatment.

It is established that HCV proteins induce the activation of STAT-3 via oxidative stress and CA2+signal transmission (Ccoke and others, Hepatol Res 34, 2006, SS-73; G.Waris etc., J Virol 79, 2005, SS-1580), and products of lipid peroxidation and antioxidant gene expression (.Okuda and others, Gastroenterology 122, 2002, SS-375). Assume that the balance of oxidative and reductive potentials in the cell (cellular redox potential) has pronounced effects on the metabolic pathways of signal transduction (Y.M.Janssen and others, Am J Physiol 273, 1997, SS-796), including attenuated IFN-alpha signal transmission (D.Di Bona and others, J Hepatol. 45, 2006, SS-279).

Infection with HCV is divided according to the requirements ICD10 (who, 2007) acute (V) and chronic hepatitis C (V).

HCV is one of the most important reasons for the development of acute or chronic hepatitis. However, the disease can vary greatly and are highly prone to variability. Therefore it is impossible to talk about the typical course of the disease, because HCV infection is manifested a wide spectrum of the ω clinical manifestations, i.e. variable symptoms, different clinical pictures and various secondary diseases of the liver and lesions outside the liver.

Approximately 20% of patients with acute hepatitis inflammation of the liver is a consequence of HCV infection. However, in the acute phase of hepatitis C is usually asymptomatic and therefore approximately 85% of cases are not diagnosed. In some cases, there are only nonspecific symptoms that resemble the flu. Usually the infection does not manifest itself during the acute phase.

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

Patients infected with HCV typically receive standard combined treatment pagesyou the major interferon-α2 or interferon-α2b and ribavirin. When infection with HCV genotypes 2 or 3 (infection VHS or VHS) such combined treatment should be performed within 24 weeks. When infection with HCV genotype 1 (VGS) for VGS-positive patients receive combination therapy for 48 weeks. Many of HCV-infected patients, however, discontinue treatment because of side effects and/or because of rejection parenteral administration and duration of application. In addition, only about 50% of patients with infection VGS achieve positive result of such long-term treatment, i.e. the remaining do not respond to such treatment, i.e. they are non-responders (see, for example, R.E.T.Smith, Nature Reviews, Drug Discovery, 5, 2006, s). The treatment caused by hepatitis C virus disease paglinawan interferon plus ribavirin is ineffective in approximately half of patients with genotype 1. Treatment failure occurs or due to the lack of response to therapy (minimal reduction of the titer of the virus), or relapse (strong initial response to treatment is replaced by new growth titer of the 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 between viruses (see M.W.Fried and others, New England Journal of Medicine 347, 2002, SS-982; H.S.Conjeevaram and others, Gastroenterology 131, 206, SS-477; M.P.Manns and others, Lancet 358, 2001, SS-965; D.B.Strader and others, Hepatology 39, 2004, s; S.J.Hadziyannis and others, Ann Intern Med, 140, 2004, s-355). Genetic differences between viruses can enable or differences existing before the start of treatment, or differences that arise during treatment due to virus evolution in response to pressure applied treatment.

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

To date there is no vaccine against HCV. Standard treatment methods are very expensive, give a negligible effect in terms of the destruction of HCV infection and sometimes cause significant side effects (S.L.Tan and other, Nature Reviews, Drug Discovery 1, 2002, s; R.Bartenschlager, ibid, s).

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

The problem to be solved in the present invention is to obtain effective drugs for the treatment of viral hepatitis, in particular hepatitis b or C, which possesses advantages in comparison with other drugs of the prior art. Drug for opportunities who should not have side effects or may have mild side effects, and to be effective, for example, for patients with hepatitis C, which essentially do not respond to traditional combined treatment with peginterferon/ribavirin. In addition, the drug should have a pronounced antiviral properties and, thus, reliably reduce the load of the virus.

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

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

Studies on the treatment of HCV infections, especially related to the suppression of HCV infections by administration of silymarin described in the prior art techniques is (see, for example, R.Sailer and other, Drugs 61(14), 2001, s-2063; Kesayev 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 reported that although not established effects of silymarin on viral replication, by pharmacological evaluations can be expected that it inhibits inflammation and cytotoxic cascade of events triggered by a viral infection. Oral administration of complex silibinin-phosphatidylcholine (IdB1016, 240 mg of silibinin twice a day) in short-term placebo-controlled pilot study of 20 patients with chronic hepatitis b showed that the evolution of AST levels significantly decreased in the group of silibinin in the absence of other significant differences of the studied indicators of liver function (see A.Vailati and others, Fitoterapia, 64(3), 1993; G.Buzzelli etc., Int. J.Clin. Pharmacol. Ther. Toxicol. 31, 1993, cc.456-460).

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

US 2005/0123628 refers inter alia to receive and oral introduction of compositions comprising glycyrrhizin, a drug of lemongrass, ascorbic acid, L-glutathione, silymarin, lipoic acid, and D-alpha-tocopherol. Report that these compositions are applicable for reducing oxidative stress and lipid peroxidation, for the treatment of chronic liver disease, chronic infections of viral hepatitis C and non-alcoholic fatty hepatitis. Numerous studies have reported the hepatoprotective properties that silymarin exerts against a large number of different toxins, including acetaminophen, ethanol, carbon tetrachloride and D-galactosamine, as well as against ischemic damage, radiation and toxicity of iron. During the first twenty weeks of open non-randomized single center clinical study subjects gave for oral administration twice a day total of 1,000 mg of glycyrrhizin; three times per day in a total amount of 1500 mg extract of the herb schisandra; three times per day in a total number of 6000 mg of ascorbic acid; twice per day in a total amount of 300 mg L-glutathione; three times per day in a total amount of 750 mg of milk Thistle extract; two times a day in total to the Icesave 300 mg of lipoic acid; and once a day in amounts of 800 ME D-alpha-tocopherol. During the first ten weeks of the study subjects were administered by intravenous injection, twice a week, four different parenteral compositions, of which neither 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 virus load. In the US 2005/0123628 does not even hint at the fact that silymarin, or that only silibinin may be responsible for a relatively small reduction in viral load.

S.J.Polyak and others compare in vitro standardized extract of silymarin (MC-001) with commercial preparations of silymarin. Reported that both drugs are antiviral effect when using models based on cell culture, although the impact of commercial drugs is not as strong compared to MK-001. MK-001 inhibits the expression of factor alpha tumor necrosis in anti-CD3 stimulated mononuclear cells of peripheral blood and dependent on nuclear factor Kappa b transcription in the cells of the human hepatoma Huh7. In addition, the dose of MK-001 inhibits infection of cells Huh7 and Huh7.5.1 virus JFH-1 dose-dependent manner. MK-001 shows activity against HCV infection in the selected cells and when combined with interferon-α inhibits HBV replication to a greater extent than inhibition of tol is to one interferon-α. For comparison of anti-HCV action of MK-001 commercial silymarin, also test the product Ultrathistle® (firm Natural Wellness, Montgomery, new York and product Silybinin® (the company Indena SpA, Milan). But the report that MK-001 shows a stronger antiviral effect compared with products Ultrathistle® and Silybinin®. On the basis of in vitro studies it was concluded that because of the action of anti-HCV, a standardized extract of silymarin MK-001 exceeds two commercial products. S.J.Polyak nothing about injecting purified silibinin, not to mention the treatment of non-responders. In addition, the findings of Polyak and others, contrary to clinical studies that showed no effects of silymarin on HCV in patients with chronic hepatitis C (M.D.Tanamly and others, Dig Liver Dis. 36, 2004, SS-759; .Gabbay and others, World J Gastroenterol. 13, 2007, SS-5323).

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

Reducing virusnoi load by injecting silibinin component especially unexpectedly, because clinical studies show that silymarin does not affect HCV in patients with chronic hepatitis C (.Torres and others, P.R.Health J Sci 23(2), 2004, SC-74; M.D.Tanamly and others, Dig Liver Dis., 36, 2004, SS-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, which was invited to participate patients aged 21-65 years with chronic hepatitis C have not been exposed to antiviral therapy. Randomisiert 34 patients for treatment S.marianum 160 mg orally three times a week for four weeks, or treatment was 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 of 177 patients with chronic hepatitis caused by hepatitis C virus, were randomly divided to receive or oral silymarin or multivitamin supplements. The study showed that the recommended dose of silymarin does not affect virasami with hepatitis C.

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

.Gabbay and other reported clinical study which involved 100 patients with chronic HCV infection for which treatment with interferon was unsuccessful, and who were randomized to receive seven different antioxidants along with of silymarin capsules, 250 mg, three times per day. The main endpoints of the study were the liver enzymes, the levels of HCV RNA and histology. The study showed that antioxidant therapy does not affect viral load.

L.B.Seeff and others have reported on the study of long-term antiviral treatment of cirrhosis in hepatitis C with cirrhosis (HALT-C), including entities formed with chronic hepatitis C who are non-responders in the primary antiviral therapy, but are willing to participate in long-term treatment paglinawan interferon. Not found the beneficial effects of silymarin on the levels of RNA of hepatitis C virus (HCV). Thus, treated with silymarin had similar levels of HCV when compared to the level of the s those who did not receive such treatment.

In addition, it has been unexpectedly found that the introduction of, especially parenteral administration, a component silibinin contributes to standard treatment with peginterferon/ribavirin. Established that component silibinin activates (reactivates) the sensitivity of patients to the traditional treatment with peginterferon/ribavirin and/or enhancers anti-traditional therapy with peginterferon/ribavirin.

Brief description of figures

Figure 1. Example 1, investigation 1: parameters of oxidative stress before and after infusion of 10 mg/kg silibinin component for 4 h (p-REC = derivative compounds reactive oxygen metabolites, BAP = biological antioxidant potential).

Figure 2. Example 1, investigation 1: HCV RNA (log IU/ml; average ± standard deviation) before (1 day) and after (7 days) intravenous 10 mg/kg silibinin component/day.

Figure 3. The example 1 study 1: changes in HCV-RNA after intravenous injection of 10 mg/kg/day silibinin component within 7 days with subsequent combination therapy with peginterferon Alfa-2A/ribavirin and 140 mg of silymarin three times a day.

Figure 4. Example 1, study 2: changes in HCV-RNA at the time of introduction silibinin component in different doses for 14 days with the consequences is the fact that combination therapy with peginterferon Alfa-2A/ribavirin, started 8 hours.

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

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

7. Example 2, a specific patient, changes in HCV-RNA after intravenous injection of 20 mg/kg/day silibinin component during two intervals of administration, including 14 days in a row, the first interval in intravenous starts in 24 days, and the second interval in the introduction, since 35 weeks, during continuous combined therapy with application of 180 μg of peginterferon Alfa-2A/ribavirin for 60 weeks.

Fig. Example 2, a specific patient, changes in HCV-RNA after intravenous injection of 20 mg/kg/day silibinin component during the interval of administration, including 14 consecutive days, starting from the 32nd weeks of continuous combo receiver is authorized therapy with application of 180 μg of peginterferon Alfa-2A/ribavirin for 60 weeks.

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

Figure 10. Schematically shows the different ways of joint use of ribavirin and/or pagliarulo interferon alpha and medicines containing silibinin component.

11. The data obtained in the study of suppression in vitro NS5B for six purified components of silymarin.

Fig. The data obtained in the study of suppression in vitro NS5B for silibinin-bis(hydrogensulfate).

The present invention relates to the use of silibinin a component of a medicinal product, preferably virusstatus or antiviral, more preferably reducing viral load, for the treatment of viral hepatitis, in particular hepatitis b or C, preferably infections chronic or acute viral hepatitis C, preferably parenteral introduction.

In the context of the present invention the term "drug" preferably is synonymous with "drug treatment".

In prepact the tion embodiment, the present invention relates to the use of silibinin a component of a medicinal product, which contains almost no silidianin, and/or silicristin, and/or isosilybin, for the treatment of viral hepatitis, preferably hepatitis b or C.

In a preferred embodiment of the present invention the treatment of viral hepatitis, in particular hepatitis b or C, is carried out by reducing viral load. It is established that silibinin components are able to reduce viral load in patients with hepatitis b or C. This is particularly unexpected, since in the prior art there is no evidence that silymarin, the mixture of which contains a certain amount of silibinin, the effect on viral load or improves liver histology in hepatitis b or C (see Kesayev and others, Journal of Viral Hepatitis, 2005, 12, 559-567).

In another preferred embodiment of the present invention the treatment of viral hepatitis, in particular hepatitis b or C, carried out in patients who have or who have undergone liver transplantation. Patients who underwent liver transplantation due to hepatitis at risk of resumption of viral hepatitis in the transplanted liver. Usually the virus is not completely removed from the body when infected the liver is surgically removed, and remaining in the body the virus re-infects transplantirovannam liver. In chronic hepatitis C info is lirovannye patients re-infected after liver transplantation in 100% of cases. Unexpectedly, it was found that silibinin can reduce your viral load, the risk of re-infection after liver transplantation can be significantly reduced by introducing, preferably parenteral administration, a component silibinin.

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

Currently installed 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 have the genome from DNA or RNA. Transmission occurs or food, or through tissue fluids, such as semen and blood. Also there are differences in different forms related to the disease and its severity. Although hepatitis a and E are usually in acute form of hepatitis b, C and D can lead to chronic disease, and in some cases, to severe complications.

In the present description the term "viral hepatitis" preferably includes hepatitis b and C.

In a preferred embodiment of the present invention carry out the treatment by reducing the viral load of one or more viruses selected from the group consisting of genotypes VGS, VGS, VGS, VGS, VGS and VGS, preferably VHS, but not only of them.

If the genotype is the genotype is irusa VGS, preferred subtypes 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, 1j, 1k and 1l. If the genotype is the genotype of the virus VGS preferred 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 VGS preferred subtypes 3A, 3b, 3C, 3d, 3E, 3f, 3g, 3h, 3i, 3j and 3k. If the genotype is the genotype of the virus VGS preferred subtypes 4A, 4b, 4C, 4d, 4E, 4f, 4g, 4h, 4i, 4j, 4k, 4l, 4m, 4n, 4o, 4p, 4q, 4r and 4t. If the genotype is the genotype of the virus VGS preferred subtype 5A. If the genotype is the genotype of the virus VGS preferred 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 present invention relates to the use of component silibinin for obtaining a medicinal product which is preferably adapted for parenteral administration for the treatment of viral hepatitis, preferably hepatitis C patients who do not respond to conventional together with immunomodulating/antiviral combination therapy, such as therapy ribavirin/interferon ("non-responders"), and/or patients who partially respond to traditional together with immunomodulating/antiviral combination therapy, for example, therapy with ribavirin/interferon ("partial responders"), and/or patient is, showing a clear initial response and subsequent resumption of viral titers during or after therapy ("relapse").

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

In connection with the traditional treatment of hepatitis C through the introduction of ribavirin/interferon concepts "non-responders, partial responders and patients with relapse" well-known experts in this field. Currently, the treatment of viral hepatitis With paglierani interferon with ribavirin unsuccessfully for about half of patients with genotype 1. Failure in the treatment appears or in the absence of response to treatment (minimum lower titres), or relapse (original clear response to treatment followed by recovery titres during or after treatment).

Order specifications non-responders preferably referred to as patients in whom there is no reduction in viral load <2 log10IU/ml (i.e. 100 times) when introduced and ribavirin/interferon (usually of peginterferon α), preferably within 12 weeks. In a preferred embodiment of the present invention in non-responders titers of the virus is reduced by the amount ≤2,1 log10IU/ml and absolute titers ≥4,62 log10IU/ml at the minimum value.

Order specifications partial responders preferably referred to as patients in whom there is no decrease in viral load of ≥2 log10IU/ml by week 12 with detectable HCV RNA at 24 week.

Order specifications patients with recurrent preferably referred to as patients with lower titres of ≥2,8 log10and absolute title to temporarily fall below the detection limit (2,78 log10IU/ml).

In the present description the term "dosage form" is preferably synonymous with "input form" or "dosage form". For example, if a dosage form intended for oral administration, for example, in the form of tablets, this tablet is preferably dosed the entry form, which contains the dose component silibinin intended to introduce at the appropriate time within the schemes. If dosed unit includes one pill dosage unit corresponds to the input form. However, the dosage form can also be divided into a number of input forms, such as the er, on some tablets, which in each case contain only part of the dose, but together they contain the whole dose component silibinin intended to introduce at the appropriate time in the scheme of administration (tablets dosage units are designed for almost simultaneous introduction).

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

Among gamefire dicarboxylic acids are particularly preferred gamefire, for example, malic acid, glutaric acid, succinic acid, adipic acid, Superboy acid, azelaic acid, sabatinovka acid, fumaric acid, maleic acid, basis of itaconic acid, phthalic acid, terephthalic acid, isophthalic acid, etc. Preferred gamefire are dikemaskini that may be contained in the form of free acids or their Sol is th, for example, salts of sodium, potassium or ammonium. One or more hydroxyl groups silibinin may be etherification. Preferably, 1, 2, 3, 4 or all of the hydroxyl groups of silibinin tarifitsirovana.

In a preferred embodiment of the present invention silibinin component is silibinin-C-2',3-bis(hydrogenating) or its pharmaceutically acceptable salt, for example sodium salts, potassium salts, ammonium salts, etc. and mixtures thereof. Particularly preferred disodium salt.

The corresponding esters are esters of gluconic acid.

Preferably silibinin component is a compound with the General formula (I)

in which

R1, R2, R3, R4and R5independently from each other selected from the group consisting of-H, -SO3H, -PO3H2- - 1-C8-alkylen-IT-WITH-C1-C8-alkylene-CO2H, -CO1-C8-alkylen-SO3H, -CO1-C8-alkylen-OPO3H2- - 1-C8-alkylen-PO3H2-(C2-C3-alkylen-O)n-N, where n= from 1 to 20, -CO1-C8-alkylene-N(C1-C3-alkyl)3+X-where X-represents a pharmaceutically acceptable anion,

or their pharmaceutically on the permissible salt. Preferably, R1, R2and R5present-N.

More preferably, silibinin component of General formula (I) has the stereochemistry of the General formula (I-A) or (I-B)

In a preferred embodiment of the present invention the compound of General formula (I-A) is mixed with a compound of General formula (I-B) in any relative weight, for example 50±5:50±5. In a preferred embodiment of the present invention, however, diastereomeric excess (di) compounds of General formula (I-A) is at least 50% di, 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% di and especially preferably at least 99% CI. In another preferred embodiment of the present invention diastereomeric excess (di) compounds of General formula (1-B) is at least 50% di, 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% di and especially preferably at least 99% CI.

Other preferred silibinin compo the patients described in the patent WO 03/090741, on the essence of which in the present description reference is made.

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

In a preferred embodiment, the present invention relates to the use of ester silibinin for obtaining a medicinal product which is preferably processed for parenteral or oral administration, for the treatment of viral hepatitis, in particular hepatitis b or C. Preferably, the drug contains almost no silidianin, and/or silicristin, and/or isosilybin.

In a preferred embodiment of the present invention, the drug is processed for parenteral administration. Parenteral administration can be carried out, for example, subcutaneously, intravenously, intramuscularly, intraarterially, intraperitoneally, intradermally, intra-articular, podvoloshino, intracardiac, in the vitreous body of the eye, retrobulbarno, intra-lungs and nutricote.

Particularly preferably, the drug is processed for injection or infusion, in particular for intravenous or intraarterial administration.

Respective drugs applicable for injection or infusion, known for the specialists in this field. See, for example, kN.: Knwoing and other "Lehrbuch der Pharmazeutischen Technologie [Textbook of Pharmaceutical Technology]", 1999, 6th ed., WVG Stuttgart.

Medicines used for injections are the usual sterile solutions, emulsions or suspensions, which is obtained by dissolution, emulsification or suspendirovanie active substance and optionally also of the excipients in water, in an appropriate liquid besides water, which should not be sterilized, if there is justification, or in mixtures of these solvents.

Drugs for infusion are the usual sterile aqueous solutions or emulsions with water as the continuous phase.

Drugs for injection or infusion can optionally contain additional excipients. The excipients of this type are preferably solvents, for example lecithin, poloxamer 188, substances to give isotonicity, for example sodium chloride, glucose and mannitol, buffers, such as acetate, phosphate and citrate, antioxidants, such as ascorbic acid, sodium materialographic, sodium sulfite and sodium hydrogensulphite, chelating agents such as disodium editat, preservatives, for example, esters of hydroxybenzoic acid, benzyl alcohol and cholesterol, as well as emulsifiers, such as lecithin, fatty alcohols, sterols, esters SOR the ITA and fatty acids, polyoxyethylene esters of sorbitol and fatty acids, polyoxyethylene glycerides of fatty acids, polyoxyethylene esters of fatty acids, polyoxyethylene ethers of fatty alcohols, esters of glycerol and fatty acids and poloxamer.

Especially preferred drug is a powder for solution for infusion, including silibinin-C-2',3-bis(hydrogenating) preferably disodium salt, and optional inulin as excipient. Containers containing 598,5 mg powder silibinin-C-2',3-bis(hydrogensulfate) disodium salt and inulin, adapted for solution for infusion and manufactured in Germany under the brand name Legalon® SIL. In a preferred embodiment of the present invention, the drug of the present invention bioequivalence this structure.

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

With the introduction of silibinin component by mouth, you should ensure that the bioavailability component silibinin in personallogserver form is quite high. Therefore, the limiting factor is expressed lipophilicity of silibinin.

In a particularly preferred embodiment, the present invention relates to the use of silibinin a component of a medicinal product, which is recycled for oral administration and contains almost no silidianin and/or silicristin, and/or isosilybin, 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) is most effective, especially for reducing viral load. Thus, with the introduction of silymarin, i.e. a mixture of silibinin, silidianin, silicristin, isosilybin and other components, the total dose of silymarin should be relatively high to provide a certain number of silibinin. For example, if silymarin contains, for example, 42 wt.% silibinin, the introduction 125 mg of silymarin provides only about 52 mg of silibinin and about 73 mg other compounds also have physiological effects (but not the desired effect). The risk of unwanted side effects increases with the dose of the physiologically active substance. So about what atom, because the complication is the profile of unwanted side effects, the introduction of 52 mg of highly pure silibinin exceeds introduction 125 mg of silymarin with silibinin content of 42 wt.% (see .Ding and others, J.Pharm. Biomed. Anal. 26(1), 2001, SS-161).

Patterns of silibinin (silybin), silidianin, silicristin and isosilybin (isosilybin), described below, are the works D.Y.-W. Lee and others, J. Nat. Prod. 66, 2003, SS-1174; N.-C. Kim and others, Org. Biomol. Chem., 1, 2003, SS-1689):

Appropriate forms for injection, which is applicable for oral administration (oral medicines), known to specialists in this field. See, for example, kN.: Knwoing 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 with sugar, syrups, juices, solutions, effervescent powders, effervescent granules, effervescent tablets, liofilizatow and capsules. Particularly preferred form of oral administration is a tablet, tablet with a coating of sugar, granules, pills or powders, particularly preferably tablets.

Appropriate excipients for the compositions in f is rmah oral administration is known to specialists in this field. See, for example, .P.Fiedler, Lexikon der Hilfstoffe für 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 silibinin component with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate and lactose, disintegrating agents such as corn starch or alginic acid, binders, such as starch and gelatin, lubricating agents such as magnesium stearate or talc and/or agents to achieve a depot, for example, carboxymethylcellulose, acetamitaphen cellulose or polyvinyl acetate. Tablets can also consist of several layers. In addition to these solvents tablets can also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various additional substances, such as starch, preferably potato starch, gelatin, etc. in Addition, for tabletting can be applied to the slip agents, for example magnesium stearate, sodium lauryl sulphate and talc.

Tablets with a coating of sugar can be obtained, for example, a coating on the core, which get way close to the way to obtain tablets with agents commonly used to obtain coatings of Sakha is for tablets, for example, kollidon or shellac, gum Arabic, talc, titanium dioxide or sugar. To avoid the effect of depot or incompatibility, the core can also consist of several layers. Tablets coated with sugar can also consist of several layers to achieve the effect of the depot, and you can get them using the above excipients for tablets.

Juices, syrups, emulsions, suspensions and solutions for oral administration can additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavoring agent, such as a flavoring, such as vanilla or orange extract. In addition, they may contain additional agents to obtain a suspension or thickeners such as sodium carboxymethyl cellulose, moisturizing agents, for example condensation products of fatty alcohols with ethylene oxide, or preservatives such as esters of p-hydroxybenzoic acid.

Capsules can be obtained, for example, by mixing silibinin component with inert carriers such as lactose or sorbitol, and placed in gelatin capsules. The excipients that can be used are, for example, water, pharmaceutically acceptable organic solvents, such as paraffins (for example, fractions of crude oil), oils of plant origin (for example, Arakishvili sesame), mono - or polyfunctional alcohols (e.g. ethanol or glycerol), solvents, for example natural minerals (e.g. kaolins, clays, talc, chalk), ground synthetic materials (e.g., highly dispersed silicic acid and silicates), sugars (for example sucrose, lactose and dextrose), emulsifiers (for example lignin, sulphite-alcohol bard, methylcellulose, starch and polyvinylpyrrolidone) and lubricating agents (e.g. magnesium stearate, talc, stearic acid and sodium of Laureth sulfate).

The drug can allocate silibinin component immediately or from a controlled form. If there is a release from a controlled form, preferably of such form is formulated. Delayed release in the present invention preferably involves the release profile, which silibinin component is released over a relatively long perid with a reduced speed for a prolonged therapeutic action. This can be, in particular, achieved by oral administration. The expression "at least partially slow release" of the present invention includes any medicinal product, which guarantees a modified release contained in the dosage form component cilib is Nina. The medicinal product is preferably in the form of the introduction of coated or uncoated, which receive, using special excipients, for certain processes, or by combining both forms, for selectively modified speed of release or liberation. In connection with the duration of release in the case of medicines according to the present invention includes the following types: delayed release (extended release), the release of repeated actions, extended release and sustained release. See, for example, kN.: Knwoing and other "Lehrbuch der Pharmazeutischen Technologie [Textbook of Pharmaceutical Technology]", 1999, 6th ed., WVG Stuttgart.

The appropriate dimensions of the controlled release of active compound known to specialists in this field. If the medicinal product in the form for oral administration, for example in the form of a tablet, delayed release can be achieved, for example, by immersing silibinin component in the polymer matrix and/or coating form of oral administration with a membrane.

In the present invention can be applied to solid, semi-solid or liquid medicines with controlled type release. Hard drugs are preferred, for example oral emotions the e system, coated tablets, matrix tablets, multilayer tablets, jacket-pill jacket-coated tablets sugar, pills to control the diffusion of the adsorbates and soft gelatin capsules depot. Oral drugs with controlled release of active compound is especially preferred in the form of tablets, coated (film-tablets), jacket-matrix tablets or pills, especially preferred matrix tablets.

Drug controlled release of the active substance may contain silibinin component in soluble, suspended and/or solid, amorphous or crystalline form.

To get dosage forms with controlled release of active compound of the present invention with controlled release of active compound, silibinin component can be used in the form of particles of different sizes, for example unground, crushed particles or microform.

In drug controlled release current connection, silibinin component is preferably contained 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.

Facialcarmen means controlled by diffusion preferably consist of many particles, i.e. they preferably consist of a set of cores with a coating, for example, neutral pills, which apply the mixture silibinin component with a conventional binder and a thickener, optionally together with conventional softeners and solvents, and then they glaze for diffusion, softener and other excipients. Drugs with controlled diffusion of the present invention, moreover, can consist of a homogeneous core, including silibinin components that receive, for example, by granulation, rotary granulating, agglomerating in the fluidized bed, tabletting, wet extrusion or extrusion melting, without necessarily giving a spherical shape and glaze for diffusion, which may contain softeners and other excipients.

Particles containing silibinin component may contain excipients, for example acid or buffer substances, which modify the pH and thereby affect the dependence of the release silibinin component from pH environment of the release.

Controlling the diffusion membrane may also include additional excipients, which due to pH-dependent solubility affect the permeability of the membrane at different pH values and thus affect minimizera the s dependence of the release silibinin component from pH.

Binders and thickeners used to obtain neutral pills coated, preferably are hypromellose (HPMC) and polyvinylpyrrolidone (PVP). In a similar manner can be used other natural, synthetic or partially synthetic polymers, such as methylcellulose (MC), hydroxypropylcellulose (GOC), other hydroxyethylcellulose and hydroxyethylmethylcellulose, carboxymethylcellulose and its salts, polyacrylic acid, polymethacrylates, gelatin, starch and derivatives of starch.

To obtain pills, particles and mini-tablets containing silibinin component, preferably used cellulose, microcrystalline cellulose, derivatives of cellulose, for example GMPC, the GOC and hydroxypropylcellulose with a low degree of substitution (GOC-NHS), decalcify phosphate, lactose, PVP and sucrose as a binder and fillers, methods of granulation, agglomeration in a fluidized bed, layer, wet extrusion, tabletting.

To obtain pills extrusion melting silibinin component is dipped in thermoplastic excipients. Preferably the respective thermoplastic excipients are preferably GOC, GPMC, ethylcellulose, acetosella hydroxypropylmethylcellulose, PVP, copolymer of vinylpyrrolidone/vinylize is the the polyethylene glycol, polyethylene oxide, polymethacrylates, polyvinyl alcohols, partially hydrolysed polyvinyl acetate, polysaccharides such as alginic acid, alginates, galactomannans, waxes, fats and derivatives of fatty acids.

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

The excipients that are used to modify the pH in the hearts containing silibinin component are, for example, adipic acid, malic acid, L-arginine, ascorbic acid, aspartic acid, benzolsulfonat acid, benzoic acid, succinic acid, citric acid, econsultancy acid, 2-hydroxyethanesulfonic acid, fumaric acid, gluconic acid, glucoronosyl acid, glutamic acid, hydrogenated potassium, maleic acid, malonic acid, methanesulfonate acid, toluensulfonate acid, trometamol, tartaric acid. It is preferable to use citric acid, succinic acid, tartaric acid and hydrogentartrate potassium.

For the glaze to diffusion especially preferred is Vlada ethyl cellulose (for example, products Aquacoat® and Surelease®) and polymethacrylates (for example, products Eudragit® NE, Eudragit® RS and RL). However, other materials, such as cellulose acetate and acetobutyrate cellulose, can also be used as a film forming coating controlling the diffusion of polymers.

In addition to controlling the diffusion of the polymer sprayed coating may also contain additional excipients with pH-dependent solubility, such as polymers, enteric dissolution, for example cellulose phthalate, in particular acatitla cellulose phthalate of hydroxypropylmethylcellulose, succinate cellulose, in particular acetosella pulp and acetosella hydroxypropylmethylcellulose or polymethacrylates (for example, product Eudragit® L). By adding such substances can reduce the dependence of the release silibinin component from pH.

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

To prevent clumping tactics coating during the process and in the final product, to glaze can be added agents to lower viscosity, for example talc, magnesium stearate, glycerol monostearate and Aerosil.

The rate of release is controlled by the composition of the glaze and the thickness of the layer of glaze. Additives that increase the permeability of the coating, are agents of the formation of pores that can be added to the glaze or particles that are coated and which contain silibinin component. The agents forming the dispute - soluble polymers, such as polyethylene glycols, PVP, PVA, HPMC, GOC, hydroxyethyl cellulose (SCE), MC, carboxymethyl cellulose and their salts, dextrins, maltodextrin, cyclodextrins, dextrans or other soluble substances such as urea, sodium chloride, potassium chloride, ammonium chloride, sucrose, lactose, glucose, fructose, maltose, mannitol, sorbitol, xylitol and lactic.

The excipients with pH-dependent solubility, which can be components of the diffusion coating are, for example, enteric-soluble polymers, for example cellulose phthalates, in particular acatitla cellulose phthalate of hydroxypropylmethylcellulose, succinate cellulose, in particular acetosella pulp and acetosella hydroxypropylmethylcellulose and polymethacrylates (for example, product Eudragit® L).

In addition, drug controlled release silibinin opponent can be a form for entering coated, which contains one or more swelling of excipients, which greatly increase the penetration of liquid through the membrane and cause rupture of the cladding as a result of swelling and increase volume. As a result of rupture of the release of the pharmaceutical agent from the drug becomes possible (pulsating release). Such medicines as swelling of excipients preferably contain polyvinylpyrrolidone, crospovidone, cross-linked sodium carboxymethyl cellulose, cross-linked sodium salt of carboxymethyl amylum, oxides, polymethacrylates, hydroxypropylcellulose with a low degree of substitution (GOC-NHS). The respective coating materials are preferably cellulose acetate, ethylcellulose and polymethacrylates.

Drug coated controlled by diffusion and pulsatile release can be used directly as finished pharmaceutical forms. They, however, can also be additionally processionary, optionally with the addition of excipients to obtain the final form of the introduction (e.g., capsules, tablets, sachets). To achieve the desired release profile, the various particles of the coating can also be combined with other what their particles in pharmaceutical form, and the initial dose can be administered, for example, by combining particles of a quick release, for example pills without coating, pellets or powders.

Drugs controlled release, which can be used are compounds which contain silibinin component in the matrix. Such a matrix formulations release silibinin component diffusion and/or erosion. Preferably these medicines are in the form of a pill or several pills, which, for example, can be encapsulated. Tablets may have a coating (film-tablet) or varnishing. Such medicines receive, for example, by mixing the components and direct pelletizing, or a dry or wet granulation followed by pelletizing.

The agents forming the matrix may be water-soluble, swellable in water or water-insoluble substances. Preferably medicines contain one or more swellable polymers in water.

Apply water-soluble and swellable in water of the polymers that form the matrix, preferably are hypromellose (HPMC), hydroxyethylmethylcellulose, hydroxypropylcellulose (GOC), hydroxyethyl cellulose, methyl cellulose (MC), ethyl cellulose, other alkylsilanes, hydroxyalkenals the PS and hydroxyethylmethylcellulose, sodium salt of carboxymethylcellulose, alginates, galactomannans, such as gourova gum and flour beans carob, xanthane, polyethylene oxides, polyacrylic acid, polymethacrylate acid derivatives polymethacrylate acid, polyvinyl alcohols (PVA), partially hydrolysed polyvinyl acetate, polyvinylpyrrolidone, agar, pectin, gum Arabic, tragakant, gelatin, starch or starch derivatives and mixtures of these substances. Application GPMC particularly preferable.

In addition, water-insoluble substances can be used as agents that form the structure of, for example, unsaturated or saturated (hydrogenomonas) fatty acids and their salts, esters or amides, mono-, di - and triglycerides of fatty acids, waxes, ceramides, derivatives of cholesterol and mixtures of these substances.

Medicines, in addition, may contain conventional excipients for tableting, preferably highly disperse silica (Aerosil®), magnesium stearate, talc, PVP, lactose or microcrystalline cellulose.

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

Matrix containing silibinin component can also be in a special geometric shapes, and the release of matrix depends on the special geometry and the surface of the matrix. The surface of the matrix and releasing the surface can be controlled, for example, compression for special formats (for example, a ring-shaped tablets), and/or applying subband, or applying barrier layers using a multilayer press.

Formulations with different release properties can preferably be combined to obtain a pharmaceutical form of a multi-layer tablets or pellets with jacket-core. For example, using a multi-layer tablet comprising a layer of fast release, or tablets with jacket-core with a shell quick release, controlled release is achieved according to the present invention with a high initial release silibinin component, although it can be achieved using tablets with jacket-core with quick release core and an elevated release at the end.

Other drug controlled release silibinin comp is the component is a drug, in which silibinin component is added to the matrix consisting of one or more physiologically acceptable excipients melting. Release silibinin component of these "fused extrudates" occurs due to the diffusion and/or erosion. Preferably such compositions with controlled release silibinin component are in the form of granules, pills or tablets. The forms obtained by extrusion of the melt include, in particular, pills and granules, which can be processionary for other pharmaceutical forms, for example, by encapsulating or tableting, optionally with the addition of other conventional pharmaceutical excipients. In addition, fused extrudates of the present invention can be pulverized and subsequently applied in such a crushed form for other drugs, such as matrix tablets. Additional processing also includes a combination of compounds having different pharmaceutical release, for example, retard-particles and particles of a quick release to get the drug.

On fused extrudates and/or pharmaceutical form, which is obtained from a mass of molten extrudates may be covered with a coating or they can be varnished. Fused ek is crudity preferably produced by mixing silibinin component at least one fusible physiologically acceptable (by the media) and not necessarily the usual additional pharmaceutical substances melting at a temperature of from 50 to 250°C., preferably 60 to 200°C. by the injection of the melt or of the extrudate and shaping it. In this way, the mixing of the components can be made to melting or during melting, or some of the components of the alloy and other components are added to this melt. A mixture of solvents, silibinin component and optionally additional substances amenable thermoplastic deformation and, therefore, can be extruded. Numerous methods based on their names, give an idea of the way the shape of the mixture, for example hot granulation, cold pelleting, calendering, extrusion and deformation of the still plastic mass or giving a rounded shape.

Used thermoplastic carriers, which are preferably swell and dissolve in physiological environments, preferably are: polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone (N) and vinyl esters, in particular vinyl acetate, copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, polyvinyl alcohol, esters of cellulose, in particular methylcellulose and ethylcellulose, hydroxyethylcellulose, in particular hydroxypropylcellulose, hydroxyethylmethylcellulose, in particular hydroxypropylmethyl is lulzy, and hydroxyethylmethylcellulose, carboxymethylcellulose, cellulose phthalates, in particular acetated cellulose phthalate of hydroxypropylmethylcellulose, cellulose succinate, in particular acetosella pulp and acetosella hydroxypropylmethylcellulose, polyhydroxyalkanoate, polyhydroxyethylmethacrylate, polyacrylates and polymethacrylates (food type Eudragit®), copolymers of methyl methacrylate and acrylic acid, polylactide, polyethylene glycols, polyethylene oxides and polysaccharides such as galactomannan and alginic acid and its alkali metal salts and ammonium.

Preferred thermoplastic excipients to obtain drugs controlled release silibinin component are hyproxypropyl, polyvinylpyrrolidone, copolymers of vinylpyrrolidone/vinyl acetate, polymethacrylates, in particular the product Eudragit® L, acetosella hydroxypropylmethylcellulose, polyethylene glycols, polyethylene oxides and mixtures thereof. Softening excipients that can be used to reduce the glass transition temperature of the mixture are, for example, propylene glycol, glycerol, triethylene glycol, butandiol, pentanol, for example, pentaerythritol, hexanol, long-chain alcohols, glycols, polypropylenglycol, polyethylene/polypropylenglycol, silicones, produced the water and phthalic acids (for example, dimethylphthalate, diethylphthalate, dibutyl phthalate), benzoic acid and esters of benzoic acid and other esters of aromatic carboxylic acids (for example, esters trimellitic acid), derivatives of citric acid (for example, triethylcitrate, tributyltin, acetyltributyl), esters of aliphatic dicarboxylic acids (for example, dialkyldimethyl, esters sabatinovka acid, in particular dialysability, esters of tartaric acid), monoacetate glycerol diacetate of glycerol triacetate of glycerol, fatty acids and derivatives (for example, monostearate glycerol, acetylated glycerides of fatty acids, castor oil and other natural oils, miglyol), alcohols, fatty acids (for example, cetyl alcohol, Cetearyl alcohol), sugar, polyhydric alcohols and derivatives of sugars (for example, erythritol, smalltit, lactic, mannitol, ▫ maltitol, maltodextrin, xylitol).

In addition silibinin component holder (s) and do not necessarily softener (softeners), extrudable mixture may also contain other pharmaceutical conventional additives such as slip agents and release agents lubricants, slip agents, and agents fluidity, fillers and absorbents, stabilizers, traps free radicals, complexing agents, antioxidants, photostabilizers, propellant, a surface is STN-active substances, preservatives, colorants, sweeteners and flavorings.

Agents slip and mould release preparations may include, for example, stearic acid and stearates, in particular stearates of aluminum, calcium and magnesium, calcium begent, sodium stearyl fumarate, talc, silicones, waxes, mono-, di - and triglycerides, for example glycerol monostearate, distearate glycerin, dibehenate glycerin, monooleate glycerin, palmitostearate glycerin.

Agents apply fluidity preferably are animal and vegetable oils, preferably in hydrogenomonas form with a melting point of at least 50°C., waxes (e.g. Carnauba wax), mono-, di - and triglycerides (for example, glycerol monostearate, distearate glycerin, dibehenate glycerin, monooleate glycerin, palmitostearate of glycerol), phosphatides, in particular lecithin.

Applied materials-fillers, such as titanium dioxide, aluminum oxide, magnesium oxide, silicic acid and silicates, stearic acid and stearates, cellulose derivatives (e.g. methyl cellulose), starch and derivatives of starch, sugars, polyhydric alcohols and derivatives of sugars.

Drug controlled release silibinin component can also be fused extrudates, which contain excipient with a pH-modifying your is Tami and/or pH-dependent solubility. Using these excipients (e.g., acids, bases, buffer substances enteric-soluble polymers already described above), you can minimize the dependence of the release silibinin component from pH.

When receiving a mass of molten extrudates may be the formation of "solid solutions", in which silibinin component is contained in the matrix in molecular disperse form.

Drug controlled release silibinin component can also be osmotic pharmaceutical systems release. In principle, osmotic systems of this type are known in the prior art. In the present invention the pharmaceutical release of the pharmaceutical forms normally based on osmotic pressure as the driving force.

Osmotic system preferably consists of a core, which contains silibinin component, optional hydrophilic swelling agent and optionally a water-soluble substance for inducing osmosis and also optional pharmaceutically acceptable excipients, and shell, which consists of a permeable material, which is impermeable to the components of the core and has at least one outlet through which the components can be released from the core.

The material from which is formed the floor of medicines according to the present invention with controlled release silibinin component, formed from a semi-permeable, i.e. permeable to water, aqueous media and biological fluids and impermeable or very limited permeable to the components of the core, and is suitable for forming a film coating. Selectively semipermeable sheath material insoluble in tissue fluids, not plagued, not destroyed in the gastrointestinal tract and is excreted unchanged, or it is subjected to bioerosion only to the end of the period of release.

Typical materials for the production of coatings for osmotic systems are preferably derivatives of acylated cellulose esters cellulose), which are mono - to tizamidine acetyl groups or from mono - to disubstituted acetyl groups and additionally acyl radical instead of acetyl, such as cellulose acetate, cellulose triacetate, cellulose acetate/ethylcarbamate, acatitla cellulose, acetamidomalonate cellulose, acetosella cellulose, acetametaphine cellulose, acetovanillone cellulose, acetamidomalonate cellulose, acetoacetate cellulose, acetoacetate cellulose, acetamidomalonate cellulose, acetobutyrate cellulose, azeotroping cellulose, acetobacter cellulose, aceturat cellulose, Aceto-p-toluensulfonate cellulose, acetobacter is tons of cellulose and other derivatives of cellulose acetate, and acetate agar and amylose acetate.

Suitable semi-permeable material of the membrane osmotic systems are ethylcellulose, copolymers of accelerated and ether of allylglycidyl, polymeric epoxides, polyglycols and derivatives, polylactic acid. In addition, mixtures of water-insoluble acrylate per se, for example, can be used a copolymer of acrylate and methacrylate.

If necessary, the osmotic membrane system may also contain softeners, such as emollients, above, and other additional substances, such as forming agents today. If necessary, sunscreen glaze can be applied to a semi-permeable membrane, which may consist of, for example, from GPMC and the GOC, and the corresponding softener (for example, polyethylene glycol) and pigments (e.g. titanium oxide, iron oxide).

Order to control the initial dose silibinin component, osmotic system can also be provided with a coating that contains silibinin component from which silibinin component preferably rapidly released upon contact with the release medium before osmotically controlled release silibinin component of the core.

The corresponding swelling in water of the polymers, which were the t to be contained in the core of the osmotic system, preferred are oxides (for example, product Polyox®), xanthan gum, copolymers of vinylpyrrolidone and vinyl acetate, polyvinylpyrrolidone, crospovidone, cross-linked sodium salt of carboxymethyl cellulose, cross-linked sodium salt of carboxymethyl amylum, hydroxypropylcellulose with a low degree of substitution (GOC-NHS), poly(hydroxyethylmethacrylate), alginates and galactomannans and other hydrophilic polymeric swelling agents and mixtures thereof.

Relevant osmotically active substances that can be added to the core for inducing osmosis, are water-soluble salts of organic and inorganic acids or non-ionic organic substances with high solubility in water, such as carbohydrates, in particular sugars, or amino acids. As an example, some substances that can be included in the core of the osmotic system separately or in a mixture for induction of osmosis: inorganic salts, such as chlorides, sulfates, sulfites, carbonates, bicarbonates, phosphates, disubstituted phosphates, one-deputizing phosphates of alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium or magnesium, an organic acid, such as adipic acid, ascorbic acid, Yantar the traveler acid, citric acid, fumaric acid, maleic acid, tartaric acid, benzoic acid and their salts of alkaline or alkaline earth metals, acetates, pentoses, such as arabinose, ribose or xylose, hexose, for example glucose, fructose, galactose or mannose, and sugars, for example sucrose, maltose or lactose, trisaccharide, such as raffinose, polyhydric alcohols, for example mannitol, sorbitol, ▫ maltitol, xylitol or Inositol, and urea. Preferably using sodium chloride and sodium carbonate.

In addition, osmotic system can include other conventional pharmaceutical additives, for example, lubricating and separating agents, slip agents, binders, colorants, thickeners, protective colloids, stabilizers and surfactants.

Osmotic system release preferably receive standard methods, such as wet granulation or dry pressing, pelletizing and subsequent application of organic coatings.

Floor osmotic system has at least one open outlet through which released silibinin component optionally together with other components of the core. The output can be made in the membranes of different ways, such as punching, machining or laser drilling. On the first "open" also includes biorstwami materials, which protrude from the shell during the administration of a medicinal product according to the present invention and result in the formation of public outputs in situ.

In another embodiment of the present invention for controlled release silibinin component, silibinin component may also contain as ion-exchange complex (adsorbate).

Preferably the drug is processed for administration once daily, twice daily, three times daily or four times daily.

In a preferred embodiment of the present invention from 0.5 to 75 wt.% originally contained silibinin component released from the drug after 1 h in vitro. Appropriate conditions for determination of release of active substances in vitro known to specialists in this field. In this regard, information may be obtained, for example, in the European Pharmacopoeia. Preferably the determination of the release is carried out using an instrument with a blade stirrer in artificial gastric juice (buffer, with pH 1,2) or in artificial intestinal juice (buffer, with pH of 7.6). The number of released silibinin component can be investigated, for example, using HPLC and UV microscopy.

Preferred release profiles is t A 1to A8summarized in the table below

On
after
time
[h]
A1And2And3And4And5And6And7And8
wt.%wt.%wt.%wt.%wt.%wt.%wt.%wt.%
0,55.0-346.0-337.0-329.0-3111-3013-3015-2917-28
112-5315-5218-5020-4822-4624-4427-4230-40
2 25-7427-7129-6831-6533-6236-6039-5842-56
333-8536-8239-7942-7645-7348-7150-6952-67
441-9244-8947-8650-8353-8155-7958-7760-75
652-9855-9758-9660-9463-9266-9069-8872-86
8>62>65>6871-9974-9876-9878-9780-9
12>70>73>76>79>82>84>86>88

In a preferred embodiment of the present invention, the drug contains a cyclodextrin and/or a phospholipid.

Pharmaceutical compositions containing silibinin and cyclodextrins, known from the prior art (see, for example, EP 422497). Preferably, silibinin forms a complex with cyclodextrin. The preferred cyclodextrins are α-, β - and γ-cyclodextrins, their O-C1-C4-alkyl, hydroxy-C1-C4-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 phospholipid. Preferred phospholipids are phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine. Preferred silibinin phospholipid complexes are tertiary complexes, optionally containing vitamin E (tocopherol). Complexes of this type known from the prior art and the hereafter is evidence of "complexes SPV (see A.Federico, Gut. 55(6), 2006, SS-902).

In addition silibinin component medicinal product may contain one or more terpenes. Due to the action of the terpene and the necessary conditions for adsorption and adsorption processes in General can be improved. Terpenes can be natural or synthetic essential oils and/or their terpenoid components in the form of pure substances or mixtures, or derivatives of such pure substances. Among the essential oils can be noted, in particular, oil of thyme, oil of eucalyptus, oil of pine needles, tea tree oil, oil chepucavage wood, cardamom oil, peppermint oil, sage oil, and rosemary oil, preferably an oil of thyme. From terpene substances, is also intended to include, in particular, you can use hemiterpene, which include, for example, isoprene, Tihonova acid, isovalerianic acid; monoterpene, including acyclic monoterpene, for example, 2,6-dimethyloctan, α-MIRCEN, (E)-p-Ozimek, perillan, linalool, geraniol, (S)-(+) - citronellol and monocyclic monoterpene, for example cyclopropane monoterpene and cyclobutanone monoterpene, for example Hrizantema acid or unionon, cyclopentane monoterpene, such as iridoid or nepetalactone or (-)-secologanin and (-)-oleuropein, monoterpene cyclohexane, for example, o-Menten, CIS - or TRANS-p-ment is, (R)-(+)-limonene, terpinol, (-)-menthol, (+)-perillaldehyde, (-)-menthone or (+)-carvon, bicyclic monoterpene, for example, terpenes with oxygen bridges 1,4-cineole, 1,8-cineole or ascaridole; cyclopropenone Bicycle Karana and toyana, cyclobutanone bicikl of Pinna, and bicycloheptane campan and fenhann; sesquiterpenes, for example, famosas, bisabolol, germacrene, elements and gamelan. Especially preferred terpenes are thymol, menthol, cineole, borneol, carvon, Simenon and pinene, usually preferably thymol.

The drug contains silibinin component. Silibinin is an integral part of silymarin. Preferably, in addition silibinin or silibinin components, drug product does not contain any of the other components of silymarin. If silibinin component is itself silibinin, the drug is preferably does not contain any of the other silibinin components of silymarin. If silibinin component is not itself silibinin, and, for example, silibinin ether, the drug is preferably does not contain any of the other components of silymarin, which is also not contains silibinin.

Preferably one or more substances selected from the group consisting of isosilybin, silydianin, silychristin, Taxifolin, isoliquiritin, si is Konina, salandrino, Silvermine and neotrigonia are not present in the medicinal product, i.e. the drug is preferably does not contain at least one of the above substances. In this regard, the notion of "almost does not contain" means that the residual content of the substance, and preferably less than 2.0 wt.%, more preferably less than 1.0 wt.%, even more preferably less than 0.5 wt.%, most preferably less than 0.1 wt.% and especially less than 0.05 wt.% from the total mass of the drug. Analytical methods determination of residues of these substances known to specialists in this field, for example, HPLC.

It is established that separate components of silymarin differ in chemical and physical properties and affect the pharmacological action of silymarin in varying degrees, so it is useful to assign silibinin, or its derivatives and/or salts as the sole component part of silymarin, i.e. exclusively. Obviously, in this way, and effectiveness of, and compliance of the patient can be improved.

In addition, it has been unexpectedly found that the tolerance of different components silymarin different, and that silybin better move, especially less toxic compared with silymarin (i.e. compared with a mixture containing other components in addition to forces Benin).

In a preferred embodiment, the present invention relates to the use of silibinin a component of a medicinal product, which is preferably processed for parenteral or oral administration and which is in addition to silibinin component does not contain any of the components of silymarin for the treatment of viral hepatitis, in particular hepatitis b and or C.

Described below is particularly preferred medicines which are adapted for oral administration silibinin component. All these oral dosage forms together preferably contain silibinin component in substantially pure form, i.e. preferably in the absence of other components of silymarin, especially in the absence of isosilybin, and/or silicristin, and/or silidianin.

Preferred oral dosage forms are oral dosage forms for immediate release, i.e. silibinin component is rapidly released from the dosage form, which leads to rapid uptake of the drug in the gastrointestinal tract. In a preferred embodiment of the present invention after 30 min after administration of oral dosage forms, at least 75 wt.%, more preferably n is at least 80 wt.%, even more preferably at least 85 wt.%, most preferably at least 90 wt.% and especially at least 95 wt.% originally contained silibinin component is released from the oral dosage form.

In a preferred embodiment, the present invention provides a drug as a solid solution. Solid solution is preferably obtained by immersion silibinin component in molecular disperse form highly soluble, preferably an amorphous polymer matrix with a large specific surface area. Silibinin component can be contained in a molecular dispersion form, i.e. not in microcrystalline, and not in fine crystal. Highly soluble amorphous state can be achieved by applying vysokorazvityh solid polymer solvent at the extraction of silibinin or silibinin component from the extract of silymarin. Such technical pharmaceutical composition increases the solubility silibinin component and the rate of dissolution.

An example of such a solid solution includes silibinin component corresponding to the polymer (e.g. polyvinylpyrrolidone (PVP) or a copolymer of polyvinylpyrrolidone, for example, is the product Kollidon® 25) and do not necessarily dextrin (e.g., maltodextrin). The composition may contain additional excipients, for example aerosol and/or talc.

Preferred options solid solution from the In1to b6presented in the table below.

Wt.%B1B2In3B4B5B6
Silibinin component1,0-502,5-208,0±5,08,0±4,08,0±3,08,0±2,0
PVP1,0-9710-8064±1564±1264±1064±7,0
Dextrin1,0-705,0-5022,8±2022,8±1522,8±1022,8±7,0
Aerosil0-100-7,5 4,0±3,04,0±2,54,0±2,04,0±1,5
Talc0-5,00-2,51,2±1,01,2±0,71,2±0,51,2±0,3

The composition may be provided, for example, in a hard gelatin capsule.

In another preferred embodiment, the present invention provides a drug in the form of a self emulsifiable microemulsions. Self emulsifiable lipid systems can be used as carriers and can lead to high bioavailability contained in a medicinal agent. The lipid system is colloidal in nature and allows you to absorb the microparticles, particularly of colloidal size, also through the lymphatic system in the gastrointestinal tract. Typically the dissolved drug is saturated, but the recrystallization does not occur. By oral administration of lipophilic drugs, such as silibinin component, the microemulsion is mainly used optimized vector, which increases the degree of solubility of the dissolved or highly dispersed drug in place of suction. Otherwise the of Evora, lipid system acts as an amplifier of adsorption.

An example of such lipid system is silibinin component corresponding to the first emulsifier (for example, neuroimmunological, for example, the product Gelucire® 44/14), and optionally a corresponding second emulsifier (for example, caprianavillage, for example, the product Labrasol®). The composition may optionally include excipients, such as Polysorbate.

Preferred options solid solution from C1to C6presented in the table below.

Wt.%C1C2With3C4C5C6
Silibinin componentof 0.1-500,5-204,0±3,54,0±3,04,0±2,54,0±2,0
The first emulsifier1,0-995-9754±1554±1254±1054±7,0
The second emulsifier0-700-7041±2041±1541±1041±7,0
Polysorbate0-100-7,51,5±1,01,5±0,71,5±0,51,5±0,3

The composition, which may be solid or preferably semi-liquid, can be provided, for example, in a hard gelatin capsule or a soft gelatin capsule.

In another preferred embodiment, the present invention provides a drug in the form of nanotechnology composition. The average particle size preferably less than 1 μm. Nanoparticles are able to penetrate through biological cell structures. Silibinin component is preferably adsorbed on the surface of these nanoparticles. The nanoparticles are preferably selected from the group consisting of inorganic nanoparticles and organic nanoparticles.

Inorganic nanoparticles include crystalline silicates, for example, mineral or synthetic silicates, such as metroselect, such as aluminosilicates (e.g., zeolite is). Such inorganic nanoparticles are preferably chemically modified so that they carry electrostatic charges. Silicates are ultrathin basis for nanoparticles and silibinin component associated (adsorbed) with the porous surface of the nanoparticles.

Organic nanoparticles include clusters or agglomerates of low molecular weight proteins or oligopeptides, or lipids. An appropriate carrier protein is, for example, Protamine.

Methods of obtaining nanoparticles of well-known experts in this field. For example, colloidal nanoparticles as carriers for oral release of the medicinal product, can be obtained by spraying the medicinal product, i.e. silibinin component, together with the relevant materials-media under pressure at a temperature of, for example, 60°C. through a nozzle equipped with perforated sieves (matrices) in a very chilled towers. Spontaneous cooling forms an amorphous phase consisting of nanoparticles.

Solid lipid nanoparticles can be obtained, for example, gomogenizirovannom high pressure and subsequent cooling spray. Preferably the drug, i.e. silibinin component, applied as a solution in an appropriate solvent or nominally in the ideal of submicroscale. Silibinin component can be dispersed and homogenized pressure, respectively, when mixed with a lipid solvent and a surface-active agent at a temperature of, for example, 60°C. After the optional addition of finely divided fillers as an external phase, as well as slip agents and other surfactants, the resulting composition can be filled hard gelatin capsules.

Examples of such dense lipid nanoparticles include core silibinin component corresponding to the first emulsifier (for example, stearoylbenzoylmethane, for example, the product Gelucire® 50/13), and optional corresponding macromolecular non-ionic surfactant (for example, poloxamer). The composition preferably also contains an external phase (coating)comprising a first surfactant (e.g. Tween 20), Aerosil and the second surface-active substance (e.g., glycerylmonostearate, for example, the product Percirol®).

Preferred embodiments of D1to D6solid solution presented in the table below.

0-10
wt.%D1D2D3 D4D5D6
Silibinin component0,1-300,5-204,5±3,04,5±2,54,5±2,04,5±1,5
The first emulsifier10-9920-9575±2075±1575±1075±7,5
Macromolecular nonionic surfactant0-500-4015±1015±7,515±515±2,5
The first surface-active substance0,1-7,51,5±0,71,5±0,51,5±0,31,5±0,2
Aerosol0-100,1-7,53,0±2,03,0±1,53,0±1,03,0±0,7
The second surface-active substance0-100,1-7,51,5±0,71,5±0,51,5±0,31,5±0,2

Loaded nanoparticles reach a significantly faster start receiving the drug.

The drug contains silibinin component preferably in a dose of at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 50 mg, 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, at least 350 mg, at least 375 mg or at least 400 mg; even more preferred is compulsory at least 425 mg, at least 450 mg, at least 475 mg, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, or at least 600 mg; most preferably at least 625 mg, at least 650 mg, at least 675 mg, at least 700 mg, at least 725 mg, at least 750 mg, at least 775 mg, or at least 800 mg; and especially at least 825 mg, at least 850 mg, at least 875 mg, 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 silibinin.

The drug contains silibinin component preferably in 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, most preferably at least 7.5 mg/kg, especially at least 10 mg/kg, at least 12.5 mg/kg, at least 15 mg/kg, at least to 17.5 mg/kg, at least 20 mg/kg, at least to 22.5 mg/kg, at least 25 mg/kg, at least of 27.5 mg/kg, or at least 30 mg/kg based on the body weight of the patient and in each case in the form of an equivalent dose of silibinin. Preferably, this dose is a daily dose. Thus, if the medicinal product is adapted, for example, the La injection twice a day, appropriate daily dose is divided into two parts of equal number. Similarly, for example, if the medicinal product is adapted for administration three times per day, corresponding to the daily dose is divided into three parts of equal number.

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

In a preferred embodiment of the present invention, the daily dose silibinin component is 20 mg per kg of body weight, based on equal mass of silibinin. Thus, if the medicinal product is adapted for administration once a day, it preferably contains all of the number silibinin component, for example 1400 mg of silibinin for a patient weighing 70 kg When the drug is adapted for administration twice a day, it preferably contains half the number silibinin component, for example, 700 mg of silibinin for a patient weighing 70 kg When the drug is adapted for administration three times a day, it preferably contains a third number of silibinin the CSO component, for example 467 mg of silibinin for a patient weighing 70 kg When the drug is adapted for administration four times a day, it preferably contains a quarter of the number silibinin component, e.g. 350 mg silibinin for a patient weighing 70 kg

If the medicinal product is adapted for parenteral administration, preferably for infusion, the preferred mode of treatment is 4 equal infusion, lasting 2 hours each. Preferably after 4 h the same infusion is repeated so that during 24 h in total spend 4 infusions. This mode is schematically may be abbreviated as indicated by ""where each number refers to the number of hours and the underlined numbers mean duration of infusion, and nepoddelnuyu numbers mean lag-phase between the two periods of infusion. Preferably the treatment is heterogeneous, i.e. for 24 h all infusion is dosed during equal periods of time, and lag-phase between consecutive limited also identical.

Based on the foregoing, the preferred modes of parenteral administration are summarized in the table below.

Times a day
Twice a day
Three times a day
Four times per day

In a preferred embodiment of the present invention, the drug adapted for the introduction of one, two, three or Quad times a day so that put the total daily dose, administered established by the way, contains at least 300 mg, at least 325 mg, 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, at least 500 mg, at least 525 mg, at least 550 mg, at least 575 mg, or at least 600 mg, even more preferably at least 625 mg, at least 650 mg, at least 675 mg, at least 700 mg, at least 725 mg, at least 750 mg, at least 775 mg, or at least 800 mg, more preferably at least 825 mg, at least 850 mg, at least 875 mg, 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 especially at least 1300 mg, at least 1350 mg, at least 1400 mg, at least 1450 mg or at least 1500 mg; in each case an equivalent dose based on silibinin.

Preferred pharmacokinetic parameters AUC0-tAUCt-∞AUC0-∞and AUC0-∞(fixed) (preferably after several infusions, for example, after 11 infusion; one dose: 12.5 mg/is g; daily dose: 4 infusion; total dose: 11 infusion) are summarized as options for the implementation of E1to E8in the table below.

E1E2E3E4E5E6E7E8
mcg h/mlmcg h/mlmcg h/mlmcg h/mlmcg h/mlmcg h/mlmcg h/mlmcg h/ml
AUC0-t333±200333±150333±125333±100333±80333±60333±40333±20
AUCt-∞322±200322±150322±125322±100322±80 322±60322±40322±20
AUC0-∞655±200655±150655±125655±100655±80655±60655±40655±20
AUC0-∞
(fixed)
414±200414±150414±125414±100414±80414±60414±40414±20

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

In a preferred embodiment of the present invention in addition to silibinin component medication contains additional pharmaceutical agent, which is preferably suitable for the treatment of inflammatory diseases of the liver, particularly preferably viral liver diseases, especially for the treatment of hepatitis b or C.

Preferably, the additional pharmaceutical agent selected from the group comprising treatment of the liver, lipotropic agents [AV]; nucleosides, nucleotides, selective inhibitors of reverse transcriptase [J05AB]; interferons [L03AB] and monoclonal antibodies against HBV (hepatitis b virus). Symbols in square brackets refer to the index PBX, preferably in the German version 2007.

Particularly preferably, if the other pharmaceutical agent selected from the group comprising arginine, glutamate, cicilan, Epidemiol, ornithine oxoglutarate, tigecycline, myoinositol, methionine and N-acetylation, choline, ornithine aspartate, cianidanol, tiopronin, betaine, cyanocobalamin, leucine, levulose, acyclovir, idoxuridine, vidarabine, ribavirin, ganciclovir, famciclovir, valacyclovir, cidofovir, penciclovir, valganciclovir, brivudin, interferon alpha, interferon beta, interferon gamma, interferon alpha-2A, interferon alpha-2b, interferon Alfa-n1, interferon beta-1A, interferon beta-1b, interferon of alfacon-1, Peginterferon Alfa-2b, Peginterferon Alfa-2A and interferon gamma 1b.

In a preferred embodiment of the present invention the treatment of the patient silibinin component is designed to support and/or treatment of viral hepatitis, especially hepatitis b or C, with subsequent treatment of each is m a pharmaceutical agent, which is preferably selected from the group consisting of arginine, glutamate, silymarin, ciciolina, Epidemiol, ornithine of oxoglutarate, tigecycline, myoinositol, methionine and N-acetylation, choline, ornithine aspartate, cianidanol, tiopronin, betaine, cyanocobalamin, leucine, lavolta, acyclovir, idoxuridine, vidarabine, ribavirin, ganciclovir, famciclovir, valaciclovir, cidofovir, penciclovir, valganciclovir, brivudine, interferon alpha, interferon beta, interferon gamma, interferon alpha-2A, interferon alpha-2b, interferon Alfa-n1, interferon beta-1A, interferon beta-1b, interferon of alfacon-1, peginterferon Alfa-2b, peginterferon Alfa-2A and interferon gamma 1b.

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

In a preferred embodiment of the present invention the drug is recovered as part of a subsequent treatment, and the drug first injected during the first period, preferably parenterally, and then another medication administered during the second period. Preference is sustained fashion the first period includes at least 2 days more preferably at least 3 days, more preferably at least 4 days, most preferably at least 5 days and especially preferably at least 6 days. Preferably, the second period includes more day than the first period. Preferably, the second period includes at least two days, more preferably at least 3 days, more preferably at least 4 days, most preferably at least 5 days and especially at least 6 days. In a particularly preferred embodiment of the present invention, the second drug contains a combination of ribavirin and pagliarulo interferon alpha, and the second period lasts for 24-48 weeks.

Preferably, another medicinal product contains one or more pharmaceutical agents selected from the group comprising arginine, glutamate, silymarin, cicilan, Epidemiol, ornithine oxoglutarate, tigecycline, myoinositol, methionine and N-acetylation, choline, ornithine aspartate, cianidanol, tiopronin, betaine, cyanocobalamin, leucine, levulose, acyclovir, idoxuridine, vidarabine, ribavirin, ganciclovir, famciclovir, valacyclovir, cidofovir, penciclovir, valganciclovir, brivudin, interferon alpha, interferon beta, interferon gamma, interferon alpha-2A, inter is Eren Alfa-2b, interferon Alfa-n1, interferon beta-1a, interferon beta-1b, interferon of alfacon-1, Peginterferon Alfa-2b, Peginterferon Alfa-2A and interferon gamma 1b and monoclonal antibodies to HBV, particularly preferably interferon and/or ribavirin, and/or silymarin. If medicine contains interferon, it is preferable paglinawan interferon Alfa (Peginterferon Alfa-2A or Peginterferon Alfa-2b).

In a particularly preferred embodiment of the present invention another medicinal product contains one or more pharmaceutical agents selected from the group comprising isosilybin, silydianin, silikristin, Taxifolin, isoliquiritin, silymarin, silantin, Silverman and nesilerin, more preferably only one pharmaceutical agent selected from the above list. Preferably, another medication includes silibinin component described in connection with the above-described pharmaceutical agent that is administered during the first period, and preferably does not contain at least one, preferably all of the above substances. In this regard, the notion of "almost free" means that the residual content of the substance is preferably less than 2.0 wt.%, more preferably less than ,0 wt.%, even more preferably less than 0.5 wt.%, most preferably less than 0.1 wt.% and especially less than 0.05 wt.% from the total mass of the drug.

Another medication can in principle be recycled for parenteral or oral administration. According to the present invention it is preferably recycled for another way of introduction unlike drug that is administered during the first period. Particularly preferably another medication redesigned for oral administration. In a particularly preferred embodiment of the present invention, the drug that is administered during the first period, adapted for parenteral, preferably intravenous, and another medication that is administered during the second period following the first period, adapted for oral administration.

In a preferred embodiment of the present invention, the mode of treatment of the present invention includes two phases that follow one another, which is called the first period and the second period. Preferably, during the first period of the injected drug, containing silibinin component, preferably parenterally, but other means of treating liver at the same time not the lead. During the second period enter another medication, which preferably contains ribavirin and/or paglinawan interferon alpha. In a preferred embodiment of the present invention, the drug containing silibinin component, also introduced during the second period, preferably parenterally. In another preferred embodiment of the present invention, the drug containing silibinin component that is not injected during the second period, i.e. the type just mentioned another drug.

Preferred embodiments of with F1F15mode two-phase injection are summarized in the table below.

DayF1F2F3F4F5F6F7F8F9F10F11F12F13F14F 15
The first period≥1≥1≥2≥2≥2≥3≥3≥4≥3≥4≥4≥5≥5≥7≥7
The second period≥1≥2≥1≥2≥3≥2≥3≥3≥4≥4≥5≥4≥5≥7≥14

In another preferred embodiment of the present invention, the mode of treatment of the present invention includes three phases that follow one another, which are called the first period, second period and the third period. Preferably, during the first period of the injected drug, sod is rashee silibinin component, preferably parenterally, but other means of treating liver at the same time do not enter. During the second period also introduce another drug, which preferably contains ribavirin and/or paglinawan interferon alpha, and the drug containing silibinin component, preferably parenterally. Preferably, during the third period, impose other specified medicinal product, which preferably contains ribavirin and/or paglinawan interferon Alfa, but the drug containing silibinin component, not injected during the third period, i.e. enter only the specified another medication.

Preferred embodiments of G1to G15three-phase treatment are summarized in the table below.

DayG1G2G3G4G5G6G7G8G9G10G11 G12G13G14G15
The first
period
≥1≥1≥2≥1≥1≥2≥2≥2≥3≥4≥5≥6≥7≥14≥14
The second
period
≥1≥2≥1≥1≥2≥2≥1≥2≥3≥4≥5≥6≥7≥7≥14
The third
period
≥1≥1≥1≥2≥2 ≥1≥2≥2≥3≥4≥5≥6≥7≥7≥7

In yet another preferred embodiment of the present invention, the mode of treatment of the present invention includes three phases that follow one after the other, namely the first period, second period and the third period. Preferably, during the first period of the injected another drug, which preferably contains ribavirin and/or paglinawan interferon alpha, and not injected drug containing silibinin component during the first period. During the second period still enter the specified second drug, which preferably contains ribavirin and/or paglinawan interferon alpha, and also introduce a (shared) drug containing silibinin component, during the second period, preferably parenterally. Preferably, during the third period, impose other specified medicinal product, which preferably contains ribavirin and/or paglinawan interferon alpha, but not administering cf is the rotary, containing silibinin component, during the third period, i.e. enter only the specified medicine. In other words, according to a preferred variant implementation of the present invention constantly introduce other specified medicinal product, which preferably contains ribavirin and/or paglinawan interferon alpha, and during the interim period (= the second period) jointly administered medicinal product containing silibinin component, preferably parenterally.

Preferred embodiments of H1to H15three-phase treatment period are summarized in the table below.

DayH1H2H3H4H5H6H7H8H9H10H11H12H13H14H15
The first
period
≥1≥1≥2≥1≥1≥2≥2≥2≥3≥4≥5≥6≥7≥14≥14
The second
period
≥1≥2≥1≥1≥2≥2≥1≥2≥3≥4≥5≥6≥7≥7≥14
The third
period
≥1≥1≥1≥2≥2≥1≥2≥2≥3≥4 ≥5≥6≥7≥7≥7

Figure 10 visualizes the different ways the introduction of ribavirin and/or pagliarulo interferon alpha and medicines containing silibinin component (options from a1) to m2)). Each bar refers to the time period of introduction. For example, for option f1the introduction begins with ribavirin/pagliarulo interferon alpha and continues. During the interim period while introducing silibinin component.

Another object of the present invention relates to a medicinal product, as described above, preferably adapted for parenteral administration, for the treatment of viral hepatitis, as described above.

Another object of the present invention relates to a set comprising at least one drug of the present invention, which includes silibinin component, and at least one other drug. Both drugs of the present invention, which contain silibinin component, and another medication described above so that all similar preferred embodiments, the implementation of this image is etenia also used the kit of the present invention.

In a preferred embodiment of the present invention set contains as many drugs (separate dosage units)as necessary to perform continuous therapy, and medicinal product, which contains silibinin feature, first introduced during the first period, and then the second drug is administered during the second period. Preferably, the first period includes at least 2 days, more preferably at least 3 days, more preferably at least 4 days, most preferably at least 5 days and especially preferably at least 6 days. Preferably, the second period includes more than one day compared to the first period. Preferably, the second period includes at least 2 days, more preferably at least 3 days, more preferably at least 4 days, most preferably at least 5 days and especially preferably at least 6 days.

In a particularly preferred embodiment, the present invention relates to the use of silibinin component, preferably of ester silibinin, to obtain drugs, which is redesigned for parenteral administration, for the treatment of viral hepatitis C in the non-response in the treatment of ribavirin/interferon, i.e. in patients who do not respond to together with immunomodulating/antiviral combination therapy, such as therapy ribavirin/interferon.

Another object of the present invention relates to silibinin component, preferably a complex ether, silibinin, preferably for parenteral administration, for the treatment of viral hepatitis, preferably hepatitis C. the Preferred embodiments of the present invention become apparent from the above description of the preferred options other objects of the present invention and accordingly are not repeated.

Another object of the present invention relates to the treatment of viral hepatitis, preferably hepatitis C, including the introduction, preferably parenteral administration, a pharmaceutically effective amount silibinin component, preferably of ester silibinin, to a subject in need of it. Preferred embodiments of the object of the present invention become apparent from the above description of preferred embodiments other objects of the present invention and, therefore, not repeated.

The following additional examples illustrate the present invention but they do not limit its scope.

Example 1

Si is ibinigay component is administered parenterally in the form of a silibinin-C-2',3-bis(hydrogensulfate) (product Legalon Sil®, Madaus, Cologne) (referred to below by silibinin).

Patients and methods

PatientsProtocol 1Protocol 2
N (men/women)16 (14/2)20 (17/3)
Mean age (years ± standard deviation)to 49.9±9,752,7±12,8
Genotype (1/2/4)15/-/117/1/2
Stage of fibrosis:
0-2310
3-4137
No-3
The pre-treatment*
PEG-interferon-Alfa/ribavirin1418
PEG-interferon-2b/ribavirin 24
Log drop by week 12 of prior therapy:
>2**34
1-241
<1512
No23
1418
24
* some patients undergo more than one cycle of treatment
** all were positive after 24 weeks

For these studies selected patients who have shown themselves to be as non-responders to combination therapy full doses of peginterferon/ribavirin. The lack of response to treatment is manifested in the absence of reduction of >2 log viral load after 12 weeks of treatment, and/or lack of response by the end of treatment. Patients underwent liver biopsy within 2 years prior to inclusion in this study. Apply standard is s criteria for inclusion/exclusion for treatment with peginterferon/ ribavirin.

The study Protocol

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

Protocol 1

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

Protocol 2

After receiving results from the first Protocol treatment with silibinin for 2 weeks and injected with different doses of silibinin. First, patients receive daily 5, 10, 15 or 20 mg/kg silibinin infusion within 4 hours for 14 consecutive days. On the 8th day of treatment begin to enter the 180 µg/week pagliarulo interferon Alfa-2A and 1-1,2 g/day and ribavirin. After 14 days, patients receive 280 mg of silymarin (product Legalon®, Madaus, Cologne) orally three times a day. Over a 14 day period of infusion daily take blood to determine viral load.

In both protocols, in the case of untreated pagliarulo interferon Alfa-2A or ribavirin use the standard recommendations for the selection dosages. Antiviral combination therapy receive for a total of 24 weeks (when you stop the treatment of patients with >2 log reduction at 12 week); the responders to antiviral therapy on 24-week offer to continue treatment for an additional 48 weeks. After the end of infusion patients evaluated after 2, 4 weeks and then monthly until the end of therapy after 24 weeks.

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

Methods

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

Reactive oxidative metabolites in the blood is measured by a method derived compounds reactive oxygen metabolites (p-RCM; firm Diacron, Grosseto, Italy), and the number of antioxidants biological method is ntioxidants potential (BAP; the firm Diacron, Grosseto, Italy), using a portable system for measuring free radicals (FRAS 4, SEAC, Calenzano, Italy), prior to infusion of silibinin, every 30 min during infusion (1 day) and 2 h after infusion. Method p-REC measure of reactive oxidative metabolites (mainly hydroperoxides), released from plasma proteins under the influence of acidic buffer, which in the presence of iron produces CNS and peroxyl radicals, in accordance with the Fenton reaction. These radicals in turn can oxidize the alkyl-substituted aromatic amine (N,N-diethyltoluenediamine), thereby obtaining colored pink derivative, which calculate quantitatively at 505 nm. The results of reactive oxidative metabolites expressed in units of Caratelli (Car; rate: 250-300, 1 Car=0.08 mg of hydrogenperoxide/DL). Method BAP measure the intensity of the bleaching solution ferric chloride, mixed with a derivative of thiocyanate by the added plasma sample photometrically at 505 nm, which is proportional to the ability to recover the iron ions present in the plasma quantities of antioxidants (norm >2200 PM). In the description of the methods the manufacturer does not specify exactly which substances are determined.

Statistics

Initially, the resulting lane is tion is a viral response, expressed as the percentage of patients who are PCR negative by the end of treatment (24 weeks). Secondary effective variables are the degree of viral response at 12 weeks, the safety and tolerability of treatment with peginterferon/ribavirin/silymarin, quality of life relative to baseline, 24 weeks, 48 weeks 72 weeks (SF-36, digital assessment pain scale), and oxidative status after infusion of silibinin. Due to the unexpectedly strong viral response after 7 days of silibinin infusions, infusion pause and study reschedule based on the parameters viral response and using a longer infusion periods and higher doses of silibinin. For initial studies, the size of the sample set, based on the two-stage plan of Gehenna. Based on previous studies, the degree of response >10% seems to be the rationale for further investigation of the mode of treatment. 29 patients recovered in the first stage, respectively (the error probability of β=5%).

Results

Protocol 1

Include sixteen characterized non-responders (see table above). All patients received the full dose of treatment paglinawan interferon (12 of peginterferon Alfa-2A, 2 of peginterferon Alfa-2b) and ribavirin (1000-1200 mg/day) for at the ore 12 weeks. The parameters of oxidative stress do not change during the infusion of silibinin (figure 1).

The content of serum HCV RNA drops all patients with intravenous silibinin monotherapy (figure 2) (baseline: 6,59±0,53, day 8: 5,26±0,81 log IU/ml [mean value ± standard deviation], p<0,001) with an average log reduction of 1.32±0.55 in one week. In parallel, ALT decreased from 162±133 to 118±107 U/l (p=0.004). All patients HCV RNA remains detectable at the initiation of treatment with peginterferon/ribavirin. Three patients refused to combination therapy with peginterferon/ribavirin. In 11 of the remaining 13 patients HCV-RNA again increased after the infusion of silibinin despite the start of treatment with peginterferon/ribavirin. By week 12, all patients remain HCV-RNA-positive, but 5 drop >2 log, and they continue the treatment (figure 3). None of them became HCV-RNA negative by week 24, in one patient it was 5.5 log drop, and he continued his treatment on their own.

Protocol 2

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

Figure 4 shows the kinetics of the contents of the virus in these patients. The virus load is reduced constantly. After 7 days silibinin monotherapy at a dose of 5 mg/kg appears minimal effectiveness (n=3, log drop of 0.55±0,5), with a dose of 10 mg/kg (n=19 [including patients in Protocol 1], log drop 1,41±0,59), 15 mg/kg (n=5, log drop 2,11±1,15) and 20 mg/day (n=9, 3,02±1,01) lead to a high degree significant reduction of virus load (p<0,001).

After 1 week of combined treatment with silibinin and peginterferon/ ribavirin load virus additionally decreases (log drop: 5 mg/kg: 1,63±0,78; 10 mg/kg: 4,16±1,28; 15 mg/kg of 3.69±1,29; 20 mg/kg 4,8±0,89; all values of p<0,0001 baseline) (figure 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 amount of HCV-RNA<15 ME on day 15. HCV-RNA is <15 IU/ml at 8 and 7 patients for 4 weeks (Protocol 5-week study) and 12 weeks (the Protocol 13-week study) after the start of use of peginterferon/ribavirin, respectively. Antiviral combination therapy continued for all patients (6).

Security

Usually silibinin tolerate well. Five patients report moderate symptoms of gastrointestinal disorders (abdominal pain: 5, diarrhea: 2 nausea 1), two complain about goals is th pain and pain in the joints. Patients they assessed as moderate and fall after the infusion; changes in dosing is not required. All patients in groups 15 and 20 mg/kg note a feeling of heat in the beginning of the infusion, which subsides within 30 minutes without treatment. There are no serious side effects. When alone do not reveal changes of hemoglobin, leukocytes, platelets, creatinine. Note the typical side effects of antiviral combination therapy (including one patient increased shortness of breath due to induced Hemophilus influenzae pneumonia requiring discontinuation of treatment with peginterferon/ribavirin for 8 weeks).

This example shows that parenteral administration of silibinin-(C-2',3-bis(hydrogensulfate)) has a pronounced antiviral activity against hepatitis C. This observation shows that this drug can be used for the treatment of chronic hepatitis C, especially in non-responders.

Unexpectedly, it was found that intravenous silibinin-(C-2',3-bis(hydrogenating)) is a potent antiviral agent in patients with chronic hepatitis C not responding to standard antiviral combination therapy. Intravenous silibinin well tolerated, but apparent side effects. Reported that the most frequent side effect I have is a temporary feeling of warmth. The antiviral effect is dose-dependent, but not saved after completion of the infusion period by oral administration of silymarin.

When mapping found that similar amounts of silymarin administered orally, does not affect the load HCV (A.Gordon, etc., J Gastroenterol Hepatol. 21, 2006, SS-80), reflecting differences in the bioavailability and metabolism of silibinin and resulting in significantly lower levels in the plasma. After oral dosing flavonolignan of silymarin quickly glucoronidase and quickly helps eliminate short half-lives (Z.Wen and others, Drug Metab Dispos. 36(1), 2008, SS-72).

Example 2

Patients treated with 180 μg of peginterferon Alfa-2A and depending on the weight amount of ribavirin. Despite such treatment, five patients were HCV-RNA positive after 24 weeks 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 assessed as not subjected to any influence, but one patient can be assessed which is at the stage of relapse relative to the two previous therapies (24 and 48 weeks).

During the course of treatment 180 μg of peginterferon Alfa-2A and depending on the weight amount of ribavirin, all patients injected at least once during the 14 posledovatel the different days 20 mg/kg/day of intravenous silibinin. During this period of combination therapy with peginterferon/ribavirin continue.

All 5 patients become negative for HCV RNA.

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

Fig shows the results of another patient (female, 44 years). From the figure it follows that the peginterferon/ribavirin rarely causes a decrease in viral load from approximately log 7 IU/ml to about 5 log IU/ml after 30 weeks. Joint intravenous treatment with 20 mg/kg/day silibinin-bis(hydrogensulfate) within 14 days after 30 weeks, however, leads to a sharp and constant is reduced viral load approximately log 4 IU/ml to values below the detection limit.

Fig.9 shows the results for one particular patient (male, 52 years). From the figure it follows that the peginterferon/ribavirin results in an effective reduction in viral load from approximately 5 log IU/ml to values close to the detection limit (<15 IU/ml Joint intravenous administration of 20 mg/kg/day silibinin-bis(hydrogensulfate) within 14 days after 72 weeks causes a further reduction of viral load below the detection level.

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

Example 3

In vivo carried out to describe the plasma concentration/time profiles silibinin in 8 patients with chronic hepatitis C, which 7 days of intravenous infusion administered 20 mg silibinin/kg body weight (product Legalon® SIL). For multiple doses of 20 mg/kg of body weight analyse the profiles of the plasma concentration/time and RK pair of the parameters of free and total silibinin for 1 day (= conditions single dose) and compared with the performance on day 7 (= expected conditions of the steady-state mode).

Analytical method

Examine samples using a known method HPLC-UV. Throughout the study, an analytical method to confirm the two calibration curves for each analytical run. Analysis of the chromatograms with the data presented on the calibration curves and sample quality control shows that the result of the determination of the concentration of total and free silibinin a and silibinin In this study is reliable.

Pharmacokinetic parameters are summarized in the table below.

Total silibinin1 days7 days
Silibinin AndSilibinin InSilibinin AndSilibinin In
AUC(0-∞) [h ng/ml]61733±2748913745±76040--

Silibinin And
Total silibinin1 days7 days
Silibinin InSilibinin AndSilibinin In
AUC(0-tz) [h ng/ml]50019±20048109038±51342-
AUCss [h ng/ml]--84299±25111150780±47780
Cmin[h ng/ml]--1967±8313311±1426
Cmax[ng/ml]4550±9289539±28435791±97711083±2269
Cav[ng/ml]--3512±10466282±1991
t1/2[ng/ml]8,30±2.26 and8,29±2,9813,32±3,6612,02±2,91
HVD [h]9.28 are±3,36for 9.47±3,2915,20±409 13,17±3,62
MRT [h]13,17±3,7413,44±4,3919, 22 the±5,2817,34±4,20
CL [ml/(h kg)]0,435±0,3360,233±0,2370,269±0,1280,156±0,091
Vz [ml/kg]4,7±1,32,4±1,14,67±0,732,43±0,55
tmax[h]4,14±0,184,17±0,18--
% PTF [%]--121,89±54,43137,59±52,51

Free silibinin1 days7 days
Silibinin AndSilibinin InSilibinin AndSilibinin In
AUC(0-∞)[h ng/ml] 3614±1648753±397--
AUC(0-tz) [h ng/ml]3302±1551559±339--
AUCss [h ng/ml]--4095±1942104U627
Cmin[h ng/ml]--59±403.3V±8,7
Cmax[ng/ml]316±10890±44315±119120±54
Cav[ng/ml]--171±8143±26
t1/2[ng/ml]4,58±1,355,16±4,966,85±1,294,35±1,66
HVD [h]10,12±4,296,09±2,1411.87 per±2,647,17 the 1,63
MRT [h]8,49±2,648,81±6,129,88±1,866,27±2,39
CL [ml/(h kg)]7,0±4,244,8±42,55,9±2,926,8±16,7
Vz [ml/kg]51,4±12,7285,8±163,955,3±18,5140,4±49,0
tmax[h]to 3.73±1,224,03±0,04--
% PTF [%]--164,00±45,33305,24±80,46

Example 4

An in vitro study performed to assess the cytotoxic action of silymarin, silibinin, silibinin-bis(hydrogensulfate) disodium salt and succinic acid using the XTT test, using the cell line of mouse L929 (see D.A.Scudiero and others, Cancer Res. 48, s-4833; O.S.Weislow and others, J.Natl. Cancer Inst., 81, 577-586; N.W.Roehirm others, J. Immunol. Methods, 142).

Explore the following concentrations in the studied positions: 9,77, 19,53, 39,06, 78,13, 156,25, 312,5, 625, 1250 µg/ml of Complete medium (RPMI 1640 containing Ob.% FTS) is used as a negative control. Control solvent for the analyzed position is medium RPMI 1640 containing 10% vol. FTS and 1% DMSO. Control solvent for the positive control is also medium RPMI 1640 containing 10% vol. FTS and 10.0 vol.% deionized water. Sodium dodecyl sulphate is used as a positive control. Use the following concentration: 3,125, 6,25, 12,5, 25, 50, 100, 125, 250 µg/ml incubation Time is 24 h at 37±1,5°C.

The negative control and the control of solvent do not show decreased viability of cells. The positive control (SDS) induces a special dose-dependent decrease in viability of the cells.

Toxic effects observed after incubation with silymarin with 39,06 μg/ml and up to the highest investigated concentration (1250 µg/ml). The calculated value of XTT50is of 35.2 mg/ml

Toxic effects observed after incubation with silibinin with 78,13 μg/ml and up to the highest investigated concentration (1250 µg/ml). The calculated value of XTT50is 67,5 mg/ml

Not see significant cytotoxic effects after incubation with sodium salt of silibinin-bis(hydrogensulfate) until most of the analyzed concentration (1250 µg/ml). Because of the loss of cytotoxicity value HHT50may not be counted.

Not see a significant cytotoxics the x effects after incubation with succinic acid to the highest tested concentration (1250 µg/ml). Because of the loss of cytotoxicity value HHT50may not be counted.

Studies show that in these conditions the cytotoxic potential of silymarin approximately 100% higher cytotoxic potential of silibinin. Therefore, it can be expected that silibinin may be given in relatively high doses of silymarin without inducing 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, SS-446). Then purified compounds are tested in a cell-free enzyme analysis to identify the HCV RdRp steps: silibinin A, silibinin b, isosilybin And, isosilybin In, silikristin, silidianin and dvunatrievogo salt of ester of silibinin silibinin-C-2',3-bis(hydrogensulfate) (active ingredient product Legalon® SIL).

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

11 shows the data obtained for the six purified components of silymarin (silibinin A, silibinin B, isosilybin And isosilybin In, silicristin silidianin). Fig respectively shows data on complex Efrosinina. Ester silibinin shows the greatest efficiency.

The value of the IC50of ester silibinin determined by curve dose-response in two dimensions. The determined IC50is 47±14 μm. Curves agree on the data points and the value of the IC50interpolate on the resulting curves using the software SigmaPlot 8.0.

1. Application silibinin component with the General formula (I)

in which R1, R2, R3, R4and R5independently from each other selected from the group consisting of-H, -SO3H, RHO3H2- - 1-C8-alkylen-IT-WITH-C1-C8-alkylene-CO2H, -CO1-C8-alkylen-SO3H, -CO1-C8-alkylen-ORO3H2- - 1-C8-alkylen RHO3H2-(C2-C3-alkylen-O)n-N, where n = from 1 to 20, -CO-C1-C8-alkylene-N(C1-C3-alkyl)3+X-where X-represents a pharmaceutically acceptable anion,
or their pharmaceutically acceptable salts,
to obtain medicines created for parenteral administration in the treatment of viral hepatitis, and drug optional contains the cyclodextrin and/or a phospholipid.

2. The use according to claim 1, and silibinin components the NT is an ester of silibinin.

3. The use according to claim 2, and an ester of silibinin silibinin is-s-2',3-bis(hydrogenating) or its physiologically acceptable salt.

4. The use according to claim 1, whereby the drug is, in essence, does not contain silidianin, and/or silicristin, and/or isosilybin.

5. The use according to claim 1, and viral hepatitis is hepatitis b or hepatitis C.

6. The use according to claim 1, whereby the drug is recycled for injection or infusion.

7. The use according to claim 1, whereby the drug is processed for intravenous injection.

8. The use according to claim 1, whereby the medicinal product does not contain any of the components of silymarin in addition to silibinin component.

9. The use according to claim 1, and medication contains silibinin component in a dose comprising at least 50 mg silibinin.

10. The use according to claim 1, and medication contains additional pharmaceutical agents in addition to silibinin component.

11. The use of claim 10, and additional drug selected from the group consisting of arginine, glutamate, ciciolina, epamedia, ornithine of oxoglutarate, tigecycline, myoinositol, methionine and N-acetyl-methionine, choline, ornithine aspartate, cianidanol, tiopronin, betaine, cyanocobalamin, leucine, levulose, is ciclovir, idoxuridine, vidarabine, ribavirin, ganciclovir, famciclovir, valaciclovir, cidofovir, penciclovir, valganciclovir, brivudine, interferon alpha, interferon beta, interferon gamma, interferon alpha-2A, interferon alpha-2b, interferon Alfa-n1, interferon beta-1A, interferon beta-1b, interferon of alfacon-1, peginterferon Alfa-2b, peginterferon Alfa-2A and interferon gamma-1b.

12. The use according to claim 1 for reducing viral load in patients with hepatitis.

13. The use according to claim 1 for the treatment of viral hepatitis in patients who have or who have had a liver transplant.

14. The use according to claim 1 for the treatment of viral hepatitis in a patient who does not respond to treatment with ribavirin/interferon.

15. The use according to claim 1 for maintenance and/or preventive treatment of viral hepatitis pharmaceutical agent selected from the group consisting of arginine, glutamate, silymarin, ciciolina, epamedia, ornithine of oxoglutarate, tigecycline, myoinositol, methionine and N-acetylation, choline, ornithine aspartate, cianidanol, tiopronin, betaine, cyanocobalamin, leucine, levulose, acyclovir, idoxuridine, vidarabine, ribavirin, ganciclovir, famciclovir, valaciclovir, cidofovir, penciclovir, valganciclovir, brivudine, interferon alpha, interferon beta, interferon gam is a, interferon Alfa-2A, interferon alpha-2b, interferon Alfa-n1, interferon beta-1A, interferon beta-1b, interferon of alfacon-1, peginterferon Alfa-2b, peginterferon Alfa-2A and interferon gamma-1b.

16. The use according to claim 1, and after the treatment of viral hepatitis specified drug treat viral hepatitis other drug.

17. The use according to claim 1, whereby the drug is created in the form of component parts for subsequent treatment, the first drug administered during the first period and subsequently injected another drug during the second period.

18. The application 17, and the first period is at least 2 days.

19. The application of article 16, and another medicinal product contains one or more pharmaceutical agents selected from the group consisting of arginine, glutamate, silymarin, ciciolina, epamedia, ornithine of oxoglutarate, tigecycline, myoinositol, methionine and N-acetylation, choline, ornithine aspartate, cianidanol, tiopronin, betaine, cyanocobalamin, leucine, levulose, acyclovir, idoxuridine, vidarabine, ribavirin, ganciclovir, famciclovir, valaciclovir, cidofovir, penciclovir, valganciclovir, brivudine, interferon alpha, interferon beta, interferon gamma, interferon is LLF-2A, interferon Alfa-2b, interferon Alfa-n1, interferon beta-1A, interferon beta-1b, interferon of alfacon-1, peginterferon Alfa-2b, peginterferon Alfa-2A and interferon gamma-1b.

20. The application of article 16, and another medication designed for oral administration.

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



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new pyrimidine substituted macrocyclic compounds of genral formula (I) , wherein A= -C(=O)OR1 or -C(=O)-NH-SO2-R2; R1 = H or C1-6alkyl; R2 = phenyl, thienyl, C3-7cycloalkyl optionally substituted by C1-6alkyl; X = N or CH; E = NR5; R5 = H or C1-6alkyl; n = 4 or 5; R7=H, C1-6alkyl, C1-6alkoxy, phenyl optionally substituted by C1-6alkoxy; R8 =C1-6alkoxy, phenyl optionally substituted by C1-6alkoxy, morpholino or -NRaRb, wherein Ra and Rb independently mean H or C1-6alkyl; R9 = Rq = H; or their pharmaceutically acceptable addition salts, or stereoisomers, and pharmaceutical compositions containing them.

EFFECT: compounds are inhibitors of HCV NS3 serine protease and can find application in treating chronic hepatic disorders, particularly chronic hepatitis.

10 cl, 1 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a pharmaceutical composition for treating and preventing viral and bacterial infections, containing as active ingredients: lysocyme, peroxidase, poviargol, as anti-inflammatory ingredients: escin and glycyrrhizic acid or a salt thereof, as carriers - liposome based on high-active hydrogenated lecithins in a combination with cholesterol and pharmaceutically acceptable carriers and excipients, and the ingredients of the composition are taken in a certain ratio, wt %.

EFFECT: invention ensures maintaining prolonged activity of the enzymes being the ingredients of the composition, fast skin penetration and absorption.

4 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds - substituted 1,3-diethyl-8-vinyl-7-methyl-3,7-dihydropurine-2,6-diones of general formula 1, which exhibit antagonist activity on adenosine A2A receptors. The compounds can be used as an active source of a medicinal agent or adjuvant for pharmaceutical compositions and medicinal agents. The invention also relates to a method of inhibiting and a method of treating diseases of the central nervous system, oncological, viral and bacterial diseases which are mediated by adenosine A2a receptor activity. In general formula 1 , where: Ar is 2,5-dimethoxyphenyl, 4-isobutoxy-3-methoxyphenyl, 3-phenoxyphenyl substituted with pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, C1-C5alkoxy group, amino group, optionally substituted with a mono- or di-C1-C5alkyl; 3-methylthiophen-2-yl, pyrazol-4-yl, substituted with C1-C5alkyl; 2,3-dihydro-benzo[1,4]dioxin-6-yl, optionally substituted with C1-C5alkoxycarbonyl, carbamoyl, which is optionally substituted with mono- or di-C1-C5alkyl, or carbonyl-piperazine, optionally substituted with C1-C5alkyl.

EFFECT: improved properties.

13 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to veterinary science, and concerns a Newcastle disease (ND), reovirus tenosynovitis (RVT) and avian metapneumoviral infection (aMPVI) associated inactivated emulsion vaccine containing an active substance and a target additive. As the target additive, the vaccine contains the oil adjuvant Montanide ISA-70 VG.

EFFECT: invention provides induction in vaccinated poultry of high antibody level to ND, RTV and aMPVI agents in 28 days after the application which appears to remain unchanged for 12 months and transovarially transmitted to offsprings.

7 cl, 7 ex, 7 dwg, 5 tbl

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, namely an antiviral agent. The soluble melanine antiviral agent prepared by extraction of Inonotus obliquus basidium fungus and possessing antiviral activity on viruses of influenza, type 2 herpes simplex, immunodeficiency (HIV-1) and variolovaccine.

EFFECT: agent possess a wide spectrum of antiviral action.

6 cl, 4 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: invention refers to veterinary science and medicine. What is presented is the use as an antivariolic agent of a soapy amphiphilic high-polymer RNA of Saccharomyces cerevisiae recovered from dry baker's yeast with alkali titrated oleic acid or sodium dodecyl sulphate by treating recovered RNA in oleic acid.

EFFECT: invention provides the rapid and effective treatment of the diseases caused by poxviruses, with natural interferon inductor recovered from dry baker's yeast.

1 ex

FIELD: medicine.

SUBSTANCE: invention relates to veterinary science. The method comprises the oral administration of Ribavirin-Lipint 20-25 mg/kg of body weight once a day, before feed intake, for 10 days.

EFFECT: method provides a high therapeutic effect, reduces the length of animal's recovery.

3 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a carbon nanocluster sulpho-adduct which is the polar solvent soluble fraction of the product of a reaction between ground coal-tar pitch and sulphuric acid, followed by washing the unreacted acid with water. The obtained product can be used for low-temperature carbonisation when filling porous bodies and modifying carbon fibres and fabric and as a concrete plasticiser modifier.

EFFECT: improved plasticising and water-reducing properties, powerful antiviral properties.

13 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new substituted phenoxyacetic acids of general formula 1 possessing the properties of a selective antagonist inhibiting A2a adenosine receptor activity. The compounds may be used in preventing and treating central nervous system diseases, such as cognitive disorders, Parkinson's disease, or depression, tumour diseases, inflammatory processes. The invention also refers to an agent for intensification of immune response or action of drug preparations in the combination treatment of the diseases. In general formula

, R1, R2 and R3, optionally simultaneously represent hydrogen. C1-C5alkyl, C3-C5alkenyl or C3-C5-alkynyl; R4 represents hydrogen, a halogen atom, hydroxyl, C1-C3alkyl, C1-C3alkyloxy; R5 represents hydrogen, C1-C3alkyl, the group -C(O)R6;R6 represents hydroxyl, C1-C5alkyloxy, C3-C5alkenyloxy, C3-C5alkynyloxy optionally substituted by an amino group wherein the substitutes optionally identical are specified in hydrogen, C1-C3alkyl optionally substituted by a mono- or dialkylaminogroup, an alkyloxygroup, 5-6-member saturated heterocyclyl containing 1-2 heteroatoms specified in nitrogen and oxygen: pyridyl, phenyl optionally substituted by 1-3 methoxygroups; or optionally substituted 6-member, optionally annulated with 5-member unsaturated heterocyclyl, saturated heterocyclyl containing 2 nitrogen atoms wherein the substitutes are specified in C1-C3alkyl optionally substituted by 5- member heteroaryl containing 1-3 heteroatoms specified in nitrogen and oxygen; or 6- member optionally saturated heterocyclyl containing 1-2 nitrogen atom optionally substituted by C1-C3alkyl, oxo, optionally substituted by phenyl; a dashed line with an accompanying continuous line represents a single, double or triple bond.

EFFECT: preparing new substituted phenoxyacetic acids of general formula 1 possessing the properties of the selective agonist inhibiting A2a adenosine receptor activity.

15 cl, 3 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are 3-hydroximino derivatives of 2,3-secolupane type of general formula: , where R=H or CH3, demonstrating inhibiting activity with respect to influenza A virus. Compound with R=H combines antiviral activity with respect to influenza A virus with anti-HIV activity.

EFFECT: compounds are promising for elaboration of antiviral preparations and as key intermediates for obtaining new biologically active compounds.

3 cl, 2 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new lipid compound of general formula , wherein n=0; R1 and R2 are identical or different, and may be specified in a group of substitutes consisting of a hydrogen atom, a C1-C7alkyl group, a halogen atom and a C1-C7alkoxy group; X represents COR3 or CH2OR4, wherein R3 is specified in a group consisting of hydrogen, hydroxy, C1-C7alkoxy and amino; and R4 is specified in a group consisting of hydrogen, C1-C7alkyl or C1-C7acyl, Y represents C9-C21 alkene with one or more double bonds in E- or Z-configurations with the chain Y being unsubstituted and containing a double bond in the ω-3 position; provided R1 and R2 cannot simultaneously represent a hydrogen atom.

EFFECT: invention refers to pharmaceutical compositions containing the lipid compounds which are used for treating and/or preventing the conditions related to high NFkB functions, treating and/or preventing an inflammatory disease or a condition, lower plasma insulin and/or blood glucose levels, treating insulin resistance, treating and/or preventing peripheral tissue insulin resistance and/or diabetic condition, eg type 2 diabetes mellitus.

45 cl, 1 tbl, 1 dwg, 31 ex

FIELD: medicine.

SUBSTANCE: correction of ischemic disorders caused by reperfusion liver injury in experiment in white Wistar male rats involves modelling an ischemic and reperfusion liver injury. 30 Minutes before, L-norvalin arginase blocker 10 mg/kg is introduced intraperitoneally, and distant ischemic pre-conditioning is conducted. Then, another dose of L-norvalin arginase blocker is introduced immediately after liver ischemia.

EFFECT: effective correction of the hepatocellular damage ensured by minimising the oxidative stress effects.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and is intended for prevention of hepatobiliary dysfunctions in children, living in conditions of contamination of atmospheric air with phenol, formaldehyde, methanol. Complex of medications ia applied. Eslidin in introduced perorally in 14-day course in age dosage from 3 to 7 years - 1 capsule 2 times per day, over 7 years - 1 capsule 3 times per day. Canephron N is introduced perorally, diluted in small amount of water, 2 times per day, to children of pre-school age in dose 10 drops, of school age - 20 drops per day with 10 day course; Flamin is introduced perorally 30 minutes before meal in dose 1-2 tablets per day with 10 day course; Jungle is introduced perorally during or after meal in dose 1 tablet 1 time per day with 21 day course; Immunal is introduced perorallyt 1 time per day with 10 day course in age dosage from 1 year to 6 years - 5-10 drops, from 6 to 12 years - 10-15 drops, over 12 years - in dose 20 drops. Course is repeated 1 time per year in children with light degree of disease course and 2 times per year in case of middle-severe disorders.

EFFECT: method makes it possible to ensure and prolong remission and reduce frequency of recurrences of hepatobiliary dysfunctions in children.

10 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new indole compounds of formula:

wherein A means 5-member heteroaryl or heterocyclyl each of which has 1 to 3 heteroatoms specified in N, O and S, R1 means R5 -X-B-X'-, R2 means -(CR8 R9 )p-Y-R7, R3 means hydrogen, C1-C6-alkyl or -(CH2)q-C3-C6-cycloalkyl, R4 means C3-C6-cycloalkyl (the other radical values are presented in cl.1 of the patent claim), their pharmaceutically acceptable salts or isomers which may be used for preventing or treating cell necrosis and necrosis-related diseases.

EFFECT: preparing the compounds to be used for preventing or treating cell necrosis and necrosis-related diseases.

34 cl, 2 tbl, 263 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to using a compound of formula (I):

wherein R represents a hydrogen atom or CH3, and X represents a physiologically acceptable counter ion for preparing a hepatoprotective agent for treating or preventing a liver injury. The invention also refers to a method for treating or preventing the liver injury which involves a therapeutically or preventive effective amount of said compound of formula (I).

EFFECT: declared group of inventions provides hepatoprotective activity ensured by an ability of the compounds of formula (I) to improve an endothelium function to release endogenic prostacyclin.

14 cl, 7 dwg, 3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to veterinary science and may be used for prevention and pharmacorrection of animal hepatopathy, as well as for improving body productivity and resistance. The treatment product for pharmacorrection of hepatopathy contains holy thistle cakes, germinated oats and ribotan in the following proportions, wt %: germinated oats - 20.0, ribotan - 35.0, thistle cakes - 45.0.

EFFECT: invention provides improved daily average weight gain and higher animal body resistance.

4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, where Q is phenyl or pyridinyl; A is pyrazolyl or triazolyl, where each A is independently additionally unsubstituted or substituted with 1 or 2 substitutes represented by Ra, or A is formula (a); Va is C(R4), Vb is N or C(R5) and Vc is N; or Va is N, Vb is C(R5) and Vc is N or C(R6); R4 is hydrogen, R5 is hydrogen, C1-6alkyl, -ORb, -SRb, aryl, selected from phenyl, heteroaryl, selected from thienyl, or cycloalkyl, selected from cyclopropyl; R6 is hydrogen or aryl, selected from phenyl; R7 is hydrogen or C1-6alkyl; R3 is hydrogen, C1-3alkyl, -OH, -S(O)2R1, or heteroaryl, selected from tetrazolyl, where the heteroaryl is bonded to a nitrogen atom through a ring carbon atom; Rb, Rx, Ry, Rza, Rzb, Rw, Re, Rk, Rm, Rn, Rq and R1, in each case, are independently hydrogen, C1-3alkyl or C1-3haloalkyl; and Rf, in each case, is independently hydrogen, C1-3alkyl or -OH (the rest of the substitutes assume values given in the claim). The invention also relates to a pharmaceutical composition, having inhibiting action on DGAT-1, which contains a compound of formula (I), and a treatment method.

EFFECT: compounds of formula (I) as DGAT-1 inhibitors are provided.

16 cl, 9 dwg, 1 tbl, 127 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel tetrahydroisoquinoline derivatives of general formula (I) or pharmacologically acceptable salts thereof, where R1 is a phenyl aminocarbonyl group which can be substituted with 1-3 groups independently selected from a substituting group A, a heteroaryl aminocarbonyl group, where the heteroaryl is pyridine, pyrazine, thiazole, pyrazole or isoxazole, which can be substituted with 1 group selected from a substituting group A, benzoxazol-2-yl group, which can be substituted with 1 group selected from a substituting group A, benzothiazol-2-yl group, (C1-C6 alkyl which can be monosubstituted with a C3-C6 cycloalkyl group), aminocarbonyl group, (C3-C6 cycloalkyl)aminocarbonyl group or adamantyl aminocarbonyl group; R2 independently represents a C1-C6 alkyl group; R3 is a heterocyclic group, where the heterocycle is oxazole, oxadiazole, pyrazole, isoxazole or tetrazole, which can be substituted with 1 group selected from a substituting group A, a group of formula -C(=O)-O-R4, or a group of formula -C(=O)-N(R5)R6; R4 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with 1-2 groups independently selected from a substituting group B; R5 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with 1 group selected from a substituting group B, a C3-C6 cycloalkyl group which is monosubstituted with a carboxyl group, or a heterocyclic group, where the heterocycle is tetrazole, which can be substituted with 1 group selected from a substituting group A; R6 is a hydrogen atom or a C1-C6 alkyl group; in those cases when both R5 and R6 represent a C1-C6 alkyl group, which can be substituted with 1 group selected from a substituting group B, their carbon atoms can be bonded to each other to form a 5-member saturated ring; X is an oxygen atom, a methylene group, a group of formula -NH-, a methylene group which is monosubstituted with a C1-C6 alkyl group, or a group of formula -N(R7)-; R7 is a C1-C6 alkyl group; L is a single bond, a methylene group, a 1,1-dimethylmethylene group, an ethylene group, a group of formula - CH=, or a methylene group which is monosubstituted with a C1-C6 alkyl group; … denotes a single bond or a double bond (however, … denotes a single bond when L is a group of formula -CH=); m equals 1 or 2; n equals 0 or 1; substituting group A is a group of substitutes selected from a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, a C1-C6 alkylthio group, a carboxyl group, a di-(C1-C6 alkyl)amino group, a cyano group, a hydroxy group, a C1-C6 alkylthionyl group and an oxo group; and substituting group B is a group of substitutes selected from a carboxyl group and a hydroxy group. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treating and/or preventing a disease.

EFFECT: obtaining novel tetrahydroisoquinoline derivatives, having excellent inhibiting action on acyl-coenzyme A: diacylglycerol-acyltransferase and excellent food intake suppression.

31 cl, 113 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely oncology, and may be used for treating liver metastases. That is ensured by introducing the hydrophobic suspension Teraftal® containing a radiopaque substance into a hepatic artery. The introduction is aided by X-ray. It is followed by the introduction of ascorbic acid started one day after the arterial embolisation and continued for seven days daily. A single dose of ascorbic acid makes 100 mg.

EFFECT: invention provides partial metastasis regression in limited hepatic metastatic involvement that leads to prolonging average-expectancy life.

2 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and concerns an ergogenic formulation possessing adaptogenic, hepatoprotective and immunomodulatory action, and may be used in hepatic diseases, in decreases in immunity and increase in performance efficiency and tolerance. The composition contains burnut extract, zinc aspartate, magnesium aspartate, vitamin B6, water in certain proportions of the ingredients.

EFFECT: composition possess higher pharmacological activity and bioavailability.

3 ex

Organic compounds // 2482838

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of reducing tendency of glycopyrronium salt to aggregate and/or form agglomerates during storage. Claimed method includes crushing glycopyrronium salt with obtaining particles with the average size of 10 mcm and processing of crushed glycopyrroneum salt with dry medium at temperature from 40°C to 120°C for from 6 to 96 hours. Invention also relates to inhaled composition of dry powder, which contains glycopyrroneum salt, proceeds by said method.

EFFECT: invention makes it possible to reduce tendency of crushed glycopyrroneum salt to aggregate and/or form agglomerates without application of solvents for provision of medication stability.

8 cl, 1 ex

Up!