BRPI0820640A2 - silybinin component for the treatment of hepatitis - Google Patents

Abstract

SILIBININ COMPONENT FOR THE TREATMENT OF HEPATITIS. The present invention relates to the use of a silybinin component for the production of a medicament which is adapted for parenteral administration for the treatment of viral hepatitis, preferably hepatitis B or C, specifically for the reduction of viral load. The drug preferably does not contain silydianin and/or silicristin and/or isosilybin.

Description

re Descriptive Report of the Patent of Invention for "SILIBININ COMPONENT FOR THE TREATMENT OF HEPATITIS". The present invention relates to the use of a silybinin component for the production of a medicament for the treatment of viral hepatitis, preferably hepatitis B or C, specifically for the reduction of viral load. Preferably, the drug is adapted for parenteral administration. Preferably, the silybinin component is a silybinin ester. Silibinin (3,5,7-trihydroxy-2-(3-(3-hydroxy-4-methoxy-phenyl)-2-(hydroxymethyl)-2,3-dihydrobenzo[b][1, 4]-dioxin-6-yl)chroman-4-0ne; or according to Ph. Eu. (2R,3R)-3,5,7-trihydroxy-2-[(2R,3R)-3- (4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzo-dioxin-6-yl]-2,3-dihydro-4H-1 -benzopyran-4-one) is the main constituent of silymarin and the main flavonoid extracted from milk thistle (Silybpum marianum Gaertneri). Silibinin has the following structure x o & o er.on

NEUSA Oh a ow o Silibinina. The silybinin A and silybinin B diastereomers are distinguished in the literature:

OH oo oS ga ACO o H oH o" oo Silibinin A Silibinin B. Silibinin is the major constituent of silymarin (in a 50:50 mixture of S7lybinin A and Silibinin B). Additional constituents include isosilybinin (isosilybinin A e isosilybin B), silydianin, silicristin, isossily-

IM cristina, taxifolin and others. Methods for isolating silybinin are known from the prior art (eg US 4,871,763). SNARAh Silibinin and silymarin were investigated and described in detail. Thus reference is made, for example, to N-C Kim et al., Org. —Biomol. Chem. 2003, 1, 1684-9; DYW Lee et al., J. Nat. Prod. 2003, 66, 1171-4; DJ Kroll et al., Integrative Cancer Therapies, 2007, 6, 110-9; Z Wen et al., DMF Fast Forward, doi:10.1124/dmd. 107,017566; and us

4,871,763.

Silibum marianum has a history as a medicinal plant for nearly two thousand years. Silymarin, milk thistle seed extract, is an ancient herb used to treat some liver and gallbladder ailments, including hepatitis, cirrhosis, and as a hepatoprotectant against wild mushroom poisoning, alcohol, chemicals, and environmental toxins. The mode of action of silymarin is diverse. The largest randomized, controlled trial conducted in the 1970s indicated that long-term treatment with silymarin can decrease patient mortality. patients with cirrhosis (P. Ferenci et al., J. Hepatol. 1989, 9, 105-13). Nevertheless, the role of the drug in the treatment of liver diseases remains controversial (S. Verma et al., Clinical Gastroenterology and Hepatology 2007,5,408-16; F. Rainone, A. Farm. Phys. 2005, 72( 7), 1285-8). Part of this uncertainty is due to limited data on its pharmacokinetics and optimal dosing regimens. Silymarin is poorly soluble in water and oral preparations have limited bioavailability. Pharmaceutical applications of silybinin are also known. Silibinin has strong antioxidant properties (cf. Pietrangel et al., Gastroenterology 1995, 109, 1941-49; MI Lucena et al., Int. J. Clin. Pharmacol. Ther. 2002, 40, 2-8; and L. Mira et al., Biochem. Pharmacol. 1994, 48, 753-9) and antifibrotic properties (cf. G. Bolgk et al., Hepatology 1987, 26, 643-9; and C Dehmlow et al., Hepatology 1996, 23,749-54 ) which makes it a potentially useful drug for the treatment of chronic liver diseases. The pure substance, silybinin, is administered intravenously, for example, in the case of poisoning.

The ment of the liver by poisonous mushroom (amanitin, phalloidin) in order to man-; have the liver protected from further injury (cf. K Hruby et al., Hum vas Toxicol 1983, 2, 138-195). The effect on mushroom poisoning is in part explained by stimulation of nucleolar polymerase A, which enhances ribosomal protein synthesis and inhibits lipid peroxidation (J. Sonnenbichler et al., Prog. Clin. Biol. Res. 1986) , 213, 319-31). Clinical trials have also shown success in preparing and treating certain types of cancer (L Varghese et al., Clin. Cancer Res. 2005, 11(23), 8441-7; K. Letschert et al., Toxicological Sciences 2006, 91, 140 -9).

Silibinin ester is marketed as an infusion solution, for example, under the name LegalonO SIL in the Federal Republic of Germany.

Viral hepatitis refers to infections that affect the liver and are caused by viruses. This is a major public health issue worldwide. Not only does viral hepatitis carry high morbidity, it also stresses measured resources and can have serious economic consequences. Most all cases of viral hepatitis are preventable.

Viral hepatitis includes five distinct disease entities that are caused by at least five different viruses. Hepatitis A and hepatitis B (infectious and serum hepatitis, respectively) are separate diseases and both can be diagnosed by a specific serological test. Hepatitis C and hepatitis E comprise a third category, each being a distinct type, with hepatitis C being parenterally transmitted and hepatitis E being enterally transmitted. Hepatitis D, or delta hepatitis, is another distinct virus that is dependent on hepatitis B infection. This form of hepatitis can occur as a superinfection in a hepatitis B vehicle or as a co-infection in an individual with acute hepatitis B.

Hepatitis C is an infectious disease in humans that is caused by the hepatitis C virus (HCV). Infection with HCV can lead in its course to severe liver damage, for example, inflammation of the liver parenchyma, liver fibrosis, liver cirrhosis, and liver carcinoma. In

In more than 80% of cases of infected patients, HCV infection becomes chronic. Transmission of HCV usually takes place parenterally and through the blood.

It is estimated that about 170 million people worldwide are infected with the hepatitis C virus (HCV). Infected patients can remain asymptomatic for decades, until the development of liver cirrhosis and/or hepatocellular carcinomas finally occurs.

Approximately 40-50% of liver transplants in the United States of America are based on HCV infections.

Six HCV genotypes have been identified (HCV1-HCV6), which differ in their geographic spread and in their responses to medicinal therapies.

HCV proteins showed the induction of STAT-3 activation through oxidative stress and Ca?* signaling (K.

Koike et al., Hepatol Res 2006; 34:65-73; G Waris et al., J.

Virol. 2005, 79, 1569-80) as well as lipid peroxidation products and anti-oxidant ki gene expression (M.

Okuda et al., Gastroenterology 2002, 122, 366-375). It appears "that the balance of oxidative and reductive potentials within the cell (cellular redox state) has profound consequences on signal transduction pathways (YM Janssen et al., Am.

J.

Physiol. 1997, 273:789-96) including compromised IFN-alpha signaling (D Di Bona et al., J.

Hepatol. 2006, 45, 271-9). HCV infection is divided according to ICD10 (WHO, Version 2007) into acute (B17.1) and chronic (B18.2) hepatitis C. HCV is one of the most important causes of acute or chronic hepatitis.

The clinical course of the disease, however, can be very different and subject to wide variation.

Thus, it is not possible to talk about a typical course of the disease, since HCV infection is essentially manifested by a broad clinical spectrum, that is, by variable symptoms, different clinical pictures and variable hepatitis in addition to secondary diseases extrahepatic.

In approximately 20% of patients with acute hepatitis, liver inflammation must be attributed to an HCV infection.

In the acute ac phase, however, hepatitis C usually proceeds asymptomatically and is therefore undiagnosed in approximately 85% of cases. In some cases, only nonspecific symptoms of a putatively flu-like syndrome occur. The infection usually does not manifest itself during the acute phase.

Type C hepatitis becomes chronic in about 85% of patients with acute HCV infection. This rate of the chronic form appears to be a result of the ability of the HCV virus to vary; that is, the gene encoding a coat of HCV undergoes a high mutation rate.

Due to the high variation capacity of the virus, and specifically the high variation capacity of the antigenic epitope of HCV, mutated HCV escapes recognition by the human immune system. In about 25% of patients, as a result of chronic liver inflammation, the formation of cirrhosis of the liver occurs with an increased risk of developing liver carcinoma (as per, for example, JH Hoofnagle, Hepatology f 1997, 26, Suppl. 1 , 158-20S; M. Memon et al., Journal of Viral Hepatitis E. 2002, 9, 84-100; SL Tan et al., Nature Reviews, Drug Discovery 2002, 1, 867-81).

Patients who have been infected with HCV generally receive a standard medicinal combination therapy consisting of pegylated interferon-a2a or interferon-a2b and ribavirin. In HCV infections due to genotype 2 or 3 (HCV2 or HCV3 infections), this combination therapy is performed for 24 weeks. In HCV infections due to genotype 1 (HCV1), HCV1-positive patients receive combination therapy for 48 weeks. Many of the patients infected with HCV, however, interrupt the treatment due to the side effects that occur and/or the poor adequacy due to the parenteral administration and the long period of treatment. Furthermore, only about 50% of patients presenting with HCV1 infection obtain a result with the long duration of the treatment, that is, the rest do not respond (as, for example, with RET Smith, Nature Reviews, Drug Discovery, 2006, 5, 715). Pegylated interferon plus ribavirin therapy for hepatitis C virus fails to

LE: approximately half of patients of genotype 1. Treatment failure occurs either due to lack of response (minimal declines in viral titers) or eee relapse (strong initial responses followed by repercussions of viral titers during or after therapy). These different patterns could be affected by many factors including host genetics, immune response, and virus genetic differences (cf. MW Fried et al., New England Journal of Medicine 2002, 347, 975-82; HS Conjeevaram et al. , Gastroenterology 2006, 131, 470-7; MP Manns et al., Lancet 2001, 358, 958-65; DB Strader et al., Hepatology 2004, 39, 114771; SJ Hadziyannis et al., Ann. Intern. Med., 2004, 140, 346-55). Genetic differences in viruses would include both different pre-therapy and differences that arise during treatment due to the evolution of the virus in response to pressures applied by therapy.

New treatments are being developed including optimization of the current standard treatment with peginterferon plus ribavirin, antiviral therapy ii specially targeted for HCV, new immunomodulating agents, DP res, and treatment targeted at reducing fibrosis (as per RE Stauber et al., Drugs 2008, 68( 10), 1347). To date there is no vaccine against HCV. Standard medicinal therapies are very expensive, show only mild success in controlling HCV infection, and sometimes cause considerable side effects (SL Tan et al., Nature Reviews, Drug Discovery 2002, 1, 867; R. Bartenschlager, ibid. 911). There is a need for medications for the treatment of viral hepatitis, specifically hepatitis B and BC.

It is an object of the invention to make available a drug for the treatment of viral hepatitis, specifically hepatitis B or C, which has advantages compared to prior art drugs. It would be possible that the drug had no or mild side effects and was effective, for example, for patients with hepatitis C who did not respond sufficiently to conventional combination therapy with PEG interferon/ribavirin. Additionally, the drug

The would have pronounced antiviral properties and thus in a lasting and lasting way, decreasing the viral load. E. E. This object is achieved by the main subject matter of the patent claims.

It has surprisingly been found that silybinin, its pharmaceutically acceptable salts and/or derivatives are suitable for the treatment of inflammatory, viral liver diseases, specifically hepatitis C. Thus, in patients with hepatitis C who do not respond (i.e., so-called "non-responders") to combination immunomodulatory/antiviral therapy, such as PEG interferon/ribavirin, which currently represents standard treatment for hepatitis C, a significant reduction in viral load can be achieved by administration, preferably by parenteral administration of a silybinin component. Additionally, it appears that pretreatment with the silybinin component improves patients' response to subsequent administration of interferon and ribavirin.

f Investigations related to the treatment of E HCV infections, specifically for the inhibition of HCV infections, by the administration of silymarin have been described in the prior art (as per, for example, R. Saller et al., Drugs 2001, 61 (14), 2035-63; KE Mayer et al., Journal of Viral Hepatitis, 2005, 12, 559-67; US 2005/0123628; SJ Polyak et al., Gastroenterology 2007, 132, 1925-1936).

R. Saller et al report that, although silymarin is not known to affect viral replication, from a pharmacological perspective, it can be expected to inhibit the inflammatory and cytotoxic cascade of events triggered by viral infection. Oral administration of a silybinin-phosphatidylcholine complex (IdB1016, 240 mg silybinin twice daily) in a short-term placebo-controlled pilot study in 20 patients with chronic active hepatitis revealed that the evolution of AST levels was significantly reduced in the silybinin group, with no consistent differences in the other liver function tests (cf. A. Vailati et al., Herbal Medicine, Volume LXIV, No. 3, 1993; G. Buzzelli et al., Int. J. Clin. Pharmacol. Ther. Toxicol. 1993, 31, 456-60).

aa om KE Mayer et al describe that oral treatment with silins marina resulted in a decrease in serum transaminases compared to baseline in four studies and compared to placebo in only one study. there is evidence that silymarin affects viral load or improves liver histology in hepatitis B or C (cf. ML Chavez, J. Herb. Pharmacother. 2001, 1(3), 79-90; LB Seeiff et al., Hepatology, 2001 , 34(3), 595-603).The authors concluded that silymarin compounds likely decrease serum transaminases in patients with chronic viral hepatitis, but do not appear to affect viral load or liver histology.

US2005/0123628 discloses among others the preparation and oral administration of compositions comprising glycyrrhizin, magnolia, ascorbic acid, L-glutathione, silymarin, lipoic acid and D-alpha-tocopherol. These compositions are said to be useful for reducing oxidative stress and lipid peroxidation and treating chronic liver disease, chronic hepatitis C virus infection and non-alcoholic steatohepatitis. Several studies » have reported the hepatoprotective effects that silymarin has against a wide variety of toxins, including, acetaminophen, ethanol, carbon tetrachloride, and D-galactosamine, and against ischemic injury, radiation, and iron toxicity. For the first twenty weeks of an open-label, non-randomized, one-centre clinical trial, subjects received oral administration twice daily of a total of 1000 mg of glycyrrhizin three times daily of a total of 1500 mg of schisandra extract ; three times a day of a total of 6,000 mg of ascorbic acid; twice a day of a total of 300 mg of L-glutathione; three times a day of a total of 750 mg of milk thistle extract; twice a day of a total of 300 mg of lipoic acid; and once a day of a total of 800 IU of D-alpha-tocopherol. For the first ten weeks of the study, subjects received an intravenous (iv) injection twice a week of four different parenteral compositions, none of which contained silymarin. After 10 weeks, 12.0% of subjects after 20 weeks 24.0% of subjects showed a 1 log reduction in viral load. There is no suggestion in US2005/0123628 that the

NaN -. silymarin, leaving silybinin alone, might account for this comparatively slight reduction in viral load.

S.J. Polyak et al compare in vitro a standardized silymarin extract (MK-001) with commercial silymarin preparations. Both preparations are said to reveal antiviral activity within cell culture-based models, although the effects of commercial preparations were not as potent as those of MK-001. MK-001 inhibits tumor necrosis factor-alpha expression in human peripheral blood mononuclear cells stimulated with anti-CD3 and nuclear factor kappa-B dependent transcription in human Huh7 hepatoma cells. Furthermore, the dose of MK-001 independently inhibits the infection of Huh7 and Huh7.5 cells by the JFH-1 virus. MK-001 reveals effects against HCV infection of the isolated cells and when combined with interferon-a, it inhibited HCV replication more than interferon-a alone. To compare the anti-HCV action of —MK-00O1 with the commercial silymarin preparations, Ultrathistle& (Natural á Wellness, Montgomery NY) and SilybininO (Indena SpA, Milano) were also tested. However, MK-001 is believed to promote more potent viral action than Ultrathistle& and SilybininO. The authors concluded from these in vitro tests that, as far as the anti-HOV activity is valid, the standardized silymarin extract MK-001 is superior to the two commercial products. S.J. Polyak did not disclose parenteral administration of purified silybinin, left alone in the treatment of non-responders. Additionally, the findings by Polyak et al do not match clinical studies that found no effect of silymarin on HCV in patients with chronic hepatitis C (MDTanamlye others, Dig Liver Dis. 2004, 36, 752-9; E Gabbay et al., World J Gastroenterol. 2007, 13, 5317-23).

It has now surprisingly been found that administration, specifically parenteral administration of a preferably pure silybinin component reduces the viral load in patients with viral hepatitis in vivo. Thus, the silybinin component is able to reduce the viral load. This check allows to optimize the silybinin dose in the absence of additional silymarin constituents that can cause unwanted side effects.

of ms The reduction in viral load by parenteral administration of an EF silybinin component is specifically surprising, as clinical studies have found no effect of silymarin on HCV in patients with chronic hepatitis C (M Torres et al., PR Health Sci J 2004 , 23(2), 69-74; MDTanamlye et al., Dig Liver Dis., 2004, 36:752-9; A Gordon et al., J. Gastroenterol. Hepatol. 2006, 21, 275-80; And Gabbay et al., World J Gastroenterol. 2007, 13, 5317-23; and LB Seeff et al., Hepatology, 2008, 80(11), 1900-6). M. Torres et al. reported a clinical trial in which patients aged 21-65 years with a diagnosis of chronic hepatitis C who were not using antiviral therapy were asked to participate. Thirty-four patients were randomized to treatment with S. marianum, 160 mg orally three times a week for four weeks, or to a no-treatment (control). The experiment revealed that S. marianum —has no action as an antiviral agent. MD Tanamly and others reported a clinical trial in which! - 177 patients with chronic hepatitis C virus were randomized to receive both oral silymarin and multivitamin supplements. The experiment revealed that the recommended dose of silymarin had no action on hepatitis C virus.

A report by Gordon et al. reports a clinical trial in which 24 subjects with chronic hepatitis C were enrolled in a randomized, placebo-controlled, double-blind, crossover study. Subjects received 12 weeks of S. marianum (either 600 mg or 1200 mg/day) and placebo. Baseline biochemical, virological, psychological and quality of life tests were performed. Seventeen patients completed the experiment. The experiment revealed that mean changes in HCV RNA titers were not significantly different for individuals who received S. marianum compared to those who received placebo.

E. Gabbay et al. reported a clinical trial in which 100 patients with chronic HCV infection who failed interferon treatment were enrolled and randomized to receive er Sa seven different antioxidants including silymarin capsules, 250 mg, 2 tid. Primary endpoints were liver enzymes, HCV RNA levels, and histology. The experiment revealed that antioxidant therapy had no effect on the treatment of viral load.

LB Seeff and others report an experiment on long-term antiviral hepatitis C treatment against cirrhosis (HALT-C) involving people with advanced chronic hepatitis C, non-responders to antiviral therapy but still willing to participate in interferon treatment long-term pegylated. No beneficial effects of silymarin were found on RNA (HCV) levels of the hepatitis C virus. In conclusion, silymarin users had HCV levels similar to non-users. Additionally, it has surprisingly been found that administration, especially parenteral administration of a silybinin component supports conventional treatment by peginterferon/ribavirin. It was found that the silybinin component (re)activates the patient's susceptibility to conventional treatment with peginterferon/ribavirin and/or improves the antiviral effect of conventional treatment with peginterferon/ribavirin. Brief Description of the Figures Figure 1: Example 1, Study 1: Oxidative stress parameters during and after infusion of 10 mg/kg silybinin component for 4 hours. (d-ROMs test = compounds derived from Oxygen Reactive Metabolites, BAP test = Biological Antioxidant Potential). Figure 2: Example 1, Study 1: RNA-HCV (log IU/ml; mean + SD) before (day 1) and after 7 days of iv 10 mg/kg silybinin-india component Figure 3: Example 1, Study 1: Changes in RNA-HCV after iv administration of 10 mg/kg day silybinin component for 7 days, followed by combination therapy with peginterferon alfa 2a/ribavirin and 140 mg silymarin TID. Figure 4: Example 1, Study 2: Changes in RNA-HCV during i.v. administration of silybinin component at various doses for 14 days, followed by peginterferon alfa 2a/ribavirin combination therapy which ae was started on day 8. ms! Figure 5: Example 1, Study 2: Mean (+SD) decreases in HCV RNA-ii during iv administration on day 7 of silibinin component monotherapy and 7 days of iv silibinin component in combination with peginterferon alfa 2a/ribavirin in several doses.

Figure 6: Example 1, Study 2: Changes in RNA-HCV after the end of i.v. silybinin administration (week 2) in 14 patients who received 15 or 20 mg/kg/silibinin/day. Combination therapy with peginterferon alfa 2a/ribavirin was started on day 8 and 280 mg silymarin TID on day 8.

Figure 7: Example 2, individual patient, changes in RNA-HCV after iv administration of 20 mg/kg/day of silybinin component during two dosing intervals comprising 14 consecutive days, the first iv dosing interval starting at week 24 and o: 15 second dosing interval starting at week 35, during continuous combination therapy with 180 µg peginterferon alfa 2a/ ribavirin for 60 weeks.

Figure 8: Example 2, individual patient, changes in RNA-HCV after iv administration of 20 mg/kg/day silybinin component during an administration interval comprising 14 consecutive days and starting at week 32 during continuous combination therapy with 180 ug peginterferon alfa 2a/ribavirin for 60 weeks.

Figure 9: Example 2, individual patient, changes in RNA-HCV after iv administration of 20 mg/Kkg/day silybinin component during an administration interval comprising 14 consecutive days and starting at week 72 during continuous combination therapy with 180 ug peginterferon alfa 2a/ribavirin for 80 weeks.

Figure 10 schematically shows various modes of co-administration of ribavirin and/or pegylated interferon alpha and the drug containing the silybinin component.

Figure 11 shows data generated from the in vitro inhibition study of NS5B for six purified silymarin constituents.

Figure 12 shows data generated from the in vitro Visa inhibition study of NS5B for silybinin bis(hydrogen succinate).

The invention relates to the use of a silybinin component for the production preferably of a viral or antiviral drug, more preferably a viral load reducing drug for the treatment of viral hepatitis, specifically hepatitis B or C, preferable - from chronic or acute infections by the hepatitis C virus, preferably by parenteral administration.

For the purpose of the descriptive report, the term "medication" is preferably synonymous with the term "medication".

In a preferred embodiment, the invention relates to the use of a silybinin component for the production of a medicament which essentially contains no silydianin and/or no silicristin and/or no isosylbinin, for the treatment of viral hepatitis, preferably hepatitis B or C.

In a preferred embodiment, according to the invention, the treatment of viral hepatitis, specifically hepatitis B or C, is carried out by - decreasing the viral load (viral load). It has been found that silybinin components are able to reduce the viral load in patients with hepatitis B or C. It is specifically surprising that in the prior art there is no evidence that silymarin, a mixture thereof containing a certain amount of silybinin, affect viral load or improve liver histology in hepatitis B or C (as per KE Mayer et al., Journal of Viral Hepatitis, 2005, 12, 559-67).

In another preferred embodiment according to the invention, the treatment of viral hepatitis, specifically hepatitis B or C is carried out in patients who will undergo or have undergone liver transplantation. Patients who have undergone liver transplantation for viral hepatitis are at risk of re-establishment of viral hepatitis in the newly transplanted liver. Usually, the virus is incompletely removed from the body when the infected liver is removed by surgery, and the rest of the virus kept in the body can reinfect the newly transplanted liver. In patients infected with chronic hepatitis C, reinfection after e = liver transplantation occurs in 100% of cases.

As it has been found, and surprisingly, silybinin is able to decrease viral load, the risk of reinfection after liver transplantation can be substantially reduced by administration, preferably by parenteral administration of a silybinin component.

The forms of viral hepatitis are known to the person skilled in the art.

In viral hepatitis, at present, at least six different forms are definitely known: hepatitis A, B, C, D, E and G.

The organisms causing these infections are hepatotropic viruses.

They belong to different virus families in each case and have a DNA or RNA genome.

Transmission takes place both through food and through the exchange of body fluids such as sperm and blood.

Differences should also be noted between the various forms regarding the course of the disease and its severity.

Although hepatitis A and E basically occur in the acute form, hepatitis B, C and D can lead to chronic courses, in some cases with severe complications.

For the purpose of the invention, the term "viral hepatitis" preferably comprises hepatitis B and C.

In a preferred embodiment, treatment is carried out by reducing the viral load of one or more viruses selected from the group consisting of, but not limited to, the genotypes HCV1, HCV2, HOCV3, HCV4, HCV5 and HCVG6, preferably HCV1. If the reported genotype is HCV1, subtypes 1a, 1b, tc, 1d, te, 1f,19g,1h,1i,1j, 1k and 11 are preferred.

If the reported genotype is HCV2, subtypes 2a, 2b, 2c, 2d, 2e, 2f, 29, 2h, 2i, 2j, 2k, 21, 2m, 2n, 20, 2p and 2qg are preferred.

If the reported genotype is HCV3, subtypes 3a, 3b, 3c, 3d, de, 3f, 3g, 3h, 3i, 3j and 3k are preferred.

If the preferred genotype is HCV4, subtypes 4a, 4b, 4c, 4d, 4€, 4f, 49, 4h, 4i, 4), 4k, 41, 4m, 4n, 40, 4p, 49, 41 and 4t are preferred .

If the reported genotype is HCV5, the 5a subtype is preferred.

If the reported genotype is HCV6, subtypes 6a, 6b, 6c, 6d, 6e, 6f, 69, 6h, 6i, 6j, 6K, 61, 6m, 6n, 60, 6p and 6q are preferred.

Regarding the nomenclature of the

And hr hepatitis OC virus, genotypes and subtypes, reference may be made, for example, to P. Simmonds et al., Hepatology, 42, 2005, 962-73.

; In a preferred embodiment, the invention relates to the use of a silybinin component for the production of a medicament, which is preferably adapted for parenteral administration, for the treatment of viral hepatitis, preferably hepatitis C, in non-responding patients. to conventional combination immunomodulatory/antiviral therapy, such as ribavirin/interferon therapy ("non-responders") and/or in patients who partially respond to combination immunomodulatory/antiviral therapy, such as, ribavirin/antiviral therapy. interferon ("partial responders") and/or in patients who show a strong initial response by repercussions of virus titers during or after therapy ("relapses").

The invention also relates to the treatment of viral hepatitis C by means of a silybinin component, the treatment being subsequent to a conventional combination therapy, by means of ribavirin/interferon.

Preferably, administration therapy of a silybinin component - begins after ribavirin/interferon therapy has failed (both initially and after a treatment period).

With reference to conventional therapy of hepatitis C by administration of ribavirin/interferon, the terms "non-responders", "partial responders" and "relapsers" are known to those skilled in the art. Currently, pegylated interferon plus ribavirin therapy for hepatitis C virus fails in approximately half of patients with genotype

1. Treatment failure occurs due to both non-response (minimal declines in viral titers) and relapse (strong initial responses followed by repercussions of viral titers during or after therapy).

For the purpose of the descriptive report, a non-responder is preferably considered as a patient who does not show a decrease in viral load by <2 logio IU/mL (ie, factor 100) when administering ribavirin/interferon ( usually peg-interferon a), preferably for 12 weeks. In a preferred embodiment, non-responders have viral titers of < 2.1 log10 IU/ml and absolute titers of > ro 4.62 log10 IU/ML in the Nadir mode. "Ea For the purpose of the descriptive report, a partial responder Á is preferably considered to be a patient who does not show a decrease in viral load by > 2 logio IU/ML at week 12 with HCV RNA — detectable at week 24.

For the purpose of the descriptive report a repeat offender is preferably considered as a patient who has declines in viral titers of > 2.8 log10 and his absolute titre transiently decreases below the detection limit (2.78 log1o IU/ML) .

For the purpose of description, the term "medicament" is preferably a synonym for "form of administration" or "unit dose". For example, if a medicine is listed for oral administration, for example in the form of a tablet, this tablet is preferably the unit dose to be administered, containing the dose of the compound. 15 silybinin component destined for a respective time of administration within a treatment regimen. If the unit dose comprises a single tablet, the unit dose corresponds to the form of administration. However, it is also possible for the unit dose to be divided into several forms of administration, for example several tablets, which in each case contain only a partial dose, but in full, the total dose of the silybinin component intended for the respective administration time within a treatment schedule (these unit dose tablets are then essentially intended for simultaneous administration).

For the purpose of description, the term "silibinin component" preferably refers to silybinin, including all stereoisomers thereof, for example silybinin A and silybinin B, their salts and/or derivatives, specifically esters. Preferred esters are derived from inorganic acids such as phosphoric acid and sulfuric acid; or organic acids, such as formic acid, acetic acid, propionic acid, citric acid, malic acid, mandelic acid, and the like.

Dicarboxylic acid hemiesters are specifically

Preferred E are, for example, from malonic acid, glutaric acid, succinic acid, and adipic suberic acid, azelaic acid, sebacic acid, fumaric acid, maleic acid, itaconic acid, phthalic acid, terephthalic acid, isophthalic acid, etc.

Hemiesters are the dihemisuccinates, which can be present as free-moacids or as salts, for example, as sodium, potassium or ammonium salts.

One or more of the silybinin hydroxyl groups can be esterified.

Preferably 1, 2, 3, 4 or all hydroxyl groups of silybinin are esterified.

In a preferred embodiment, the silybinin component is — silybinin C-2',3-bis(hydrogen succinate) or a physiologically acceptable salt thereof, such as sodium salts, potassium salts, ammonium salts and similar as well as their mixtures.

Disodium salt is specifically preferred.

Suitable esters are also glycolic acid esters.

Preferably, the silybinin component is a compound of the general formula (1): E HOR, is Te Rs Re o (1) where: R1, Ro, Ra, Ra and R; are independently selected from the group consisting of -H, -SOsH, -PO3H2, -CO-Cy-C; alkylene-OH, -CO-C;-CC; alkylene-COH, -CO-C;-C; alkylene -SO3gH, -CO-C;-C; alkylene-OPOszH2, -CO-C1-C-alkylene-POgH2, -(C2-Ca-alkylene-O))-H where n= 1 to 20, -CO-C1-Csg-alkylene-N(C1-C3-alkyl) )a'X, where X' is a pharmaceutically acceptable anion, or pharmaceutically acceptable salts thereof.

Preferably, R1 , Rx Rs is -H.

More preferably, the silybinin component of the general formula (1) has the stoichiometry of the general formula (I-A) or (I-B):

oo R PRE a : hollow Ao A IAEA om oo (A) (B) In a preferred embodiment, the compound of formula (IA) is mixed with the compound of formula (1I-B) at any relative weight ratio, for example, 50+5:50+5. In a preferred embodiment, however, the diastereomeric excess of the compound of the general formula (IA) is at least 50% of, more preferably at least 75% of, even more preferably at least 90% of, even more preferably at least 95% of de, more preferably at least 98% de and specifically at least 99% de. In another preferred embodiment, the diastereomeric excess of the compound of the general formula (1-B) is at least 50% of, more preferably - 10 at least 75% of, even more preferably at least 90% of, even more preferably at least 95% of de, more preferably at least: 98% de and specifically at least 99% de. Other preferred silybinin components are described in WO 03/090741, whereupon reference is made in its entirety.

Preferably, the silybinin component in pure water at room temperature has a better solubility than silybinin as such.

In a preferred embodiment, the invention relates to the use of the silybinin ester for the production of a medicament, which is preferably formulated for parenteral or oral administration, for the treatment of viral hepatitis, specifically hepatitis B or C. Preferably, the drug essentially does not contain silydianin and/or silicristin and/or isosilybinin.

In a preferred embodiment, the drug is formulated for parenteral administration. Parenteral administration can be carried out, for example, subcutaneous, intravenous, intramuscular, intraarterial, intraperitoneal, intracutaneous, intraarticular, intrathecal, intracardial, intravitreal,

. ul retrobulbar, intrapulmonary and intraossely. Specifically and preferably the medicament is formulated for injection or infusion, specifically for intravenous or intra-arterial administration.

Appropriate medications that are suitable for injection or infusion are known to those skilled in the art. In this connection, for example, reference may be made in its entirety to K.H. Bauer et al., Lehrbuch der Pharmazeutischen Technologie [Textbook of Pharmaceutical Technology], WVG Stuttgart 1999.

Medicines that are suitable for injection are generally sterile solutions, emulsions or suspensions, which are prepared by dissolving, emulsifying or suspending the active substance and optionally additional excipients in water, in a suitable non-aqueous liquid that does not need to be sterile. if this is warranted, or in a mixture of these 2 15 vehicles. Medicines which are suitable for infusion are generally sterile, aqueous solutions or emulsions with water as the continuous phase. Medicines for injection or infusion may optionally contain additional excipients. Excipients of this type are preferably solubilizers such as, for example, lecithin and poloxamer 188, substances for isotonicization such as, for example, sodium chloride, glucose and mannitol, buffers such as, for example, acetate buffers , phosphate and citrate, antioxidants such as, for example, ascorbic acid, sodium metahydrogen sulfite, sodium sulfite and hydrogenated sodium sulfite, chelating agents, such as, for example, disodium edetate, preservatives, such as, for example, p-hydroxybenzoic acid esters, benzyl alcohol and chlorocresol and emulsifiers such as, for example, lecithin, fatty alcohols, sterols, these of sorbitan fatty acid, polyoxyethylene sorbitan fatty acid esters , polyoxyethylene fatty acid glycerides, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters and poloxamers.

A specifically preferred drug is a powder for preparation.

ration of an infusion solution comprising silybinin C-2',3-bis (hydrogen succinate), preferably as disodium salt and optionally inulin as an excipient. Containers containing 598.5 mg of silybinin C-2',3-bis(hydrogen succinate) disodium salt and inulin that are adapted for the preparation of an infusion solution are marketed in Germany under the trademark Legalon&6SIL. In a preferred embodiment, the medicine according to the invention is bioequivalent to this formulation.

In another preferred embodiment, the drug is formulated for oral administration. Preferably, the medicament is in an oral administration form selected from the group consisting of tablets, capsules, sugar coated tablet, pellets and sachets.

When administering a silybinin component via the oral route, it must be ensured that the bioavailability of the silybinin component from the oral dosage form is sufficiently high. In this regard, the limiting factor is the pronounced lipophilicity of silybinin.

. In a specifically preferred embodiment, the invention relates to the use of a silybinin component for the production of a medicament which is formulated for oral administration and which essentially does not contain silydianin and/or silicristin and/or isosylbinin for the treatment of viral hepatitis, preferably hepatitis B or C.

It appears that these additional silymarin constituents also have a physiological effect (eg, they can cause side effects), but with regard to the treatment of viral hepatitis, silybinin (or its —analogues) is more effective, specifically in reducing the burden. viral. Thus, when administering silymarin, that is, a mixture of silybinin, silydianin, silychristin, isosylibinin and other constituents, the total dose of silymarin needs to be comparatively high in order to provide a specific amount of silybinin. For example, when silymarin contains, for example, 42% by weight of silybinin, the administration of 125 mg of silymarin provides only about 52 mg of silybinin and about 73 mg of additional compounds that also have physiological effect (but not the desired effect.

The pejdo). The risk of unwanted side effects increases with the dose of its physiologically active substance. Thus, as far as the side effect profile is concerned, the administration of 52 mg of substantially pure silybinin is superior to the administration of 125 mg of silymarin — having a silybinin content of 42% by weight (as per T. Ding et al., "Determination of active component in silymarin by RP-LC and LC/MS", J.

Pharm. Biomed. Anal. 2001, 26(1), 155-161). The structures of silybinin (silybin), silydianin, silychristin and isos-silybinin (isosilybin) are described in the present document below according to D.Y.-W. Lee et al., J. Nat. Prod. 2003, 66, 1171-4; N.-C. Kim et al., Org. Biomol. Chem., 2003, 1, 1684-9): .CHOoM " NO A oo " i " e. om os o Silibinin Silicristin and Ho. ocH AE: ER om o ENA To or o Isosylibinin Silidianin. are suitable for oral administration (oral medicines) are known to those skilled in the art. In this regard, reference can be made in their entirety to, for example, KH Bauer et al., Lehrbuch der Pharmazeutischen Technology [Textbook of Pharmaceutical Technology] , WVG Stuttgart 1999.

The form of oral administration is preferably selected from the group consisting of tablets, powders, spheres, granules, sugar coated tablets, syrups, juices, solutions, effervescent powders, granules

A = effervescents, effervescent tablets, lyophilisates and capsules. Specifically preferred form of administration is a tablet, a tablet coated with sugar, granules, pellets or powder, specifically and preferably a tablet.

Suitable excipients for formulating oral administration forms are known to those skilled in the art. In this regard, reference may be made, for example, to H.P. Fiedler, Lexikon der Hilfstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete [Encyclopedia of excipients for pharmacy, cosmetics and related areas), Editio Cantor Aulendorf,

2001.

Tablets can be obtained, for example, by mixing the silybinin component with known excipients, for example, inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and/or agents to achieve the depot effect such as carboxymethylcellulose, cellulose acetate phthalate. cellulose or polyvinyl acetate. Tablets can also consist of several layers. Apart from the vehicles mentioned, tablets may also contain additives such as, for example, sodium citrate, calcium carbonate and dicalcium phosphate, together with various additional substances such as starch, preferably potato starch, gelatin and the like. Additionally, glidants such as magnesium stearate, sodium lauryl sulfate and talc can additionally be used for tabletting purposes.

Sugar-coated tablets can be produced, for example, by coating the cores produced analogously to tablets with agents generally used in coatings for sugar-coated tablet, e.g. collidone or lacquer, gum arabic, talc, carbon dioxide. titanium or sugar. To avoid the deposit effect or to avoid incompatibilities, the core can also consist of several layers. The sugar-coated tablet coating may also consist of several layers to obtain a depositing effect, it being possible to employ the excipients mentioned above in the case of tablets. Ô Juices, syrups, emulsions, suspensions and solutions for oral administration may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a taste-improving agent, for example, flavoring agents such as , vanillin or orange extract. They may also contain suspension aids or thickeners such as sodium carboxymethylcellulose, wetting agents, for example, condensing products of fatty alcohols with ethylene oxide, or preservatives such as p-acid esters. hydroxybenzoic.

Capsules can be produced, for example, by mixing the silybinin component with inert carriers such as lactose or sorbitol and encapsulating in gelatin capsules. Excipients which may be mentioned are, for example, water, organic pharmaceutical solvents.

2. 15 acceptable products such as paraffins (eg petroleum fractions), plant oils (eg peanuts or sesame oil), mild or polyfunctional alcohols (eg ethanol or glycerol), vehicles , such as, for example, ground natural minerals (eg kaolins, clays, talc, gypsum), ground synthetic minerals (eg highly dispersed silicic acid and silicates), sugars (eg sucrose, lactose and dextrose), emulsifiers (eg lignin, sulphite waste liquors, methylcellulose, starch and polyvinylpyrrolidone) and glidants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulphate). The drug can release the silybinin component immediately or in a controlled manner. If release takes place in controlled form, release preferably takes place in delayed form. Prolonged release is understood according to the invention as meaning preferably a release profile where the silybinin component is released for a relatively long period of time with a reduced rate of ingestion with the aim of a prolonged therapeutic action. This is achieved in particular in the case of oral administration. The expression "with at least a partially extended release" according to the invention comprises

and the -. This is any drug that guarantees a moderate release of the silybinin component contained in it. Drugs are preferably coated or uncoated forms of administration that are produced using special excipients, according to specific processes or by a combination of both possibilities, in order to selectively modify the release rate or the release site . With respect to the time course of release, in the case of drugs according to the invention, the following types are included: extended release (extended release), repeated action release, extended release, and constant release . With regard to further details, reference may be made, for example, to K. H. Bauer et al., Lehrbuch der Pharmazeutischen Technologie [Textbook of Pharmaceutical Technology], 6th edition, WVG Stuttgart,

1999.

Appropriate measures for the controlled release of the α-active compound are known to a person skilled in the art. If the drug is an oral administration form, for example a tablet, an extended release can be achieved, for example, by soaking the silybinin component in a polymer matrix and/or film coating of the oral administration form. with a membrane.

According to the invention, solid, semi-solid or liquid drugs with controlled release behavior can be used. Solid drugs are preferred, such as, for example, oral osmotic systems (OROS), coated tablets, matrix tablets, multilayer tablets, jacketed tablets, sugar coated and coated tablets, diffusion pellets, adsorbates and soft depot gelatin capsules. The oral drug with controlled release of active compound is specifically and preferably a coated tablet, jacketed tablet or matrix tablet, specifically and preferably a matrix tablet.

Drugs with controlled delivery of the active compound may contain the component in dissolved, suspended and/or solid, amorphous or crystalline form.

For the production of the drugs according to the invention with controlled release of the active compound, the silybinin component can be used in various particle sizes, for example, in unground, ground or micronized form.

In drugs with controlled release of the active compound, the silybinin component is preferably present in the form of particles containing the active substance, such as, for example, pellets, granules, microcapsules, tablets, extrudates or crystals that are coated with a controlled diffusion membrane.

These diffusion-controlled drugs are preferably multiparticulate, i.e. they preferably consist of several coated cores, such as, for example, neutral pellets, to which a mixture of the silybinin component with a customary binder and thickener is applied, optionally in together with usual excipients and vehicles, and are sub-

2. 15 sequentially coated with a diffusion lacquer, plasticizer and other excipients. The diffusion-controlled drugs according to the invention may furthermore consist of homogeneous nuclei comprising the silybinin component which are produced, for example, by granulation, rotor granulation, fluidized bed agglomeration, tabletting, wet extrusion or melt extrusion optionally with spheronization and are coated with a diffusion lacquer which may contain plasticizer and other excipients.

Particles containing the silybinin component may contain excipients, such as, for example, acids or buffer substances, which modify the pH and thereby contribute to reducing the dependence of the release of the silybinin component on the pH of the release medium.

The diffusion-controlled membrane may, in addition, contain additional excipients which, due to their influence on pH-dependent solubility, influence the permeability of the membrane at various pHs and thus — contribute to minimizing the pH dependence of the release of the chemical. silybinin component.

The binders and thickeners used in the production of neutral pellets

These coated others are preferably hydroxypropyl methylcelluloses (HPMC) and polyvinylpyrrolidone (PVP). Likewise, other natural, synthetic or partially synthetic polymers such as, for example, methylcellulose (MC), hydroxypropylcellulose (HPC), other hydroxyalkylcelluloses and hydroxyalkylmethylcelluloses, carboxymethylcelluloses and their salts, polyacrylic acids, polymethacryl - lattes, gelatin, starch or starch derivatives can be used.

For the production of pellets, particles and (mini) tablets containing the silybinin component, cellulose, microcrystalline cellulose, cellulose derivatives, such as, for example, HMPC, HPC and lower substituted hydroxypropylcellulose (L-HPC) , dicalcium phosphate, lactose, PVP and sucrose are preferably employed as binders and fillers by means of granulation, fluidized bed agglomeration, wet extrusion and tabletting.

Melt extrusion pellets are made to embed the silybinin component in thermoplastic excipients. Suitable thermoplastic excipients are preferably HPC, HPMC, ethylcellulose, hydroxypropylmethylcellulose acetate succinate (HPMCAS), PVP, vinylpyrrolidone copolymer /vinyl acetate, polyethylene glycol, polyethylene oxide, polymethacrylates, polyvinyl alcohols (PVA), partially hydrolyzed polyvinyl acetate (PVA), polysaccharides, eg alginic acid, alginates, galactomannans, waxes, fats and fatty acid derivatives.

In the particles containing the silybinin component, it is also possible to incorporate pH modifying substances, such as, for example, acids, bases and buffer substances. Through the addition of these substances, it is possible to greatly reduce the pH dependence of the release of the silybinin component and its salts, hydrates, solvates.

The excipients used to modify the pH in the nuclei containing the silybinin component are, for example, adipic acid, malic acid, L-arginine, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, succinic acid, citric acid, ethanesultonic acid, 2-hydroxyethanesulfonic acid, fumaric acid, glycolic acid, glucuronic acid, glutamic acid, hydrogenated potassium tartrate, maleic acid, acid

es x from malonic, methanesulfonic acid, toluenesulfonic acid, trometamol, 2 tartaric acid. Preferably, citric acid, succinic acid, tartaric acid () and hydrogenated potassium tartrate are employed.

For the production of the diffusion lacquer, ethyl cellulose (for example, Aquacoat® or SureleaseO) and polymethacrylates (for example, EudragitO NE, EudragitO RS and RL) are preferably suitable. However, other materials, such as, for example, cellulose acetate and cellulose acetate butyrate can also be employed as film forming diffusion control polymers.

In addition to the diffusion control polymer, a diffusion lacquer may also contain additional excipients with pH-dependent solubility, such as, for example, enteric polymers such as cellulose phthalate, specifically cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, cellulose succinates, specifically cellulose acetate succinate and hydroxypropylmethylcellulose acetate succinate, or polymethacrylates (eg Eudragit&L). By adding these substances, it is possible to reduce the pH dependence of the release of the silybinin component. Plasticizers used are, for example, citric acid derivatives, phthalic acid derivatives, benzoic acid and benzoic acid esters, other aromatic carboxylic acid esters, aliphatic dicarboxylic acid esters, glycerol di- or triacetate, polyols , fatty acids and their derivatives, acetylated fatty acid glycerides, castor oil and other native oils, migliol and fatty acid alcohols.

In order to prevent agglutination of the coated particles during production and in the finished product, disintegrants such as, for example, talc, magnesium stearate, glycerol monostearate and Aerosil may be added to the lacquer.

The release rate is controlled by the lacquer composition and the thickness of the lacquer layer. Additives that increase film permeability are pore-forming agents that can be added to the lacquer or particles to be coated that contain the silybinin component. The pore-forming agents employed are poli-

ea E mers, such as, for example, polyethylene glycols, PVP, PVA, HPMC, HPC, hr hydroxyethylcellulose (HEC), MC, carboxymethylcellulose or its salts, dextrins, maltodextrins, cyclodextrins, dextrans or others soluble substances, such as, for example, urea, sodium chloride, potassium chloride, ammonium chloride, sucrose, lactose, glucose, fructose, maltose, mannitol, sorbitol, xylitol and lactitol.

Excipients with pH dependent solubility which can be the constituents of the diffusion film are, for example, enteric polymers such as cellulose phthalate, specifically cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, cellulose succinates , specifically cellulose acetate succinate and hydroxypropyl methylcellulose acetate succinate and polymethacrylates (eg Eudragit & L).

In addition, the drug with controlled release of the silybinin component can be a coated administration form that contains one or more swellable excipients that swell strongly upon penetration of the liquid through the membrane and cause it to be coated. * time rips open as a result of swelling and volume expansion. As a result of the tearing of the coating, the release of the pharmaceutical substance from the drug becomes possible (pulsed release). As swellable excipients, these medicaments preferably contain polyvinyl-pyrrolidones, crospovidones, cross-linked sodium carboxymethyl cellulose, carbonimethyl starch. cross-linked sodium, polyethylene oxides, polymethacrylates, lower substituted hydroxypropylmethylcellulose (L-HPC). Suitable coating materials are preferably cellulose acetate, ethyl cellulose and polymethacrylates.

The described coated, diffusion- or pulse-controlled drugs can be used directly and unaltered as a pharmaceutical form. However, they can also be further processed and optionally with addition of excipients, to provide the final administration form (eg capsule, tablet, sachet). In order to obtain a desired release profile, several coated particles can also be combined with one another in a pharmaceutical form and an administration of an initial dose can be carried out, for example, by combining with rapid release particles, for example. , pellets, granules are uncoated or powdered.

Controlled release drugs that can be used are also formulations that comprise the silybinin component in a matrix.

These matrix formulations release the silybinin component by diffusion and/or erosion.

Preferably, these drugs are present in the form of a tablet or in the form of several tablets which, for example, can be encapsulated.

Tablets can be coated or lacquered.

Such drugs are produced, for example, by mixing the constituents and forming a direct tablet or by dry or wet granulation with subsequent tablet formation.

The matrix forming agents employed can be water-soluble, water-swellable or water-insoluble substances. Preferably, the medicaments contain one or more water-swellable polymers.

E The water-soluble or swellable matrix-forming polymers employed are preferably hydroxypropylmethylcelluloses (HPMC), hydroxyethylmethylcelluloses, hydroxypropylcelluloses (HPC), hydroxyethylcelluloses, methylcelluloses (MC), ethylcelluloses, other alkylcelluloses, hydroxyal - quilcelluloses and hydroxyalkyl-methylcelluloses, sodium carboxymethylcelluloses (NaCMC), alginates, galactomannans, such as, for example, locust bean agar and flour, xanthans, polyethylene oxides, polyacrylic acids, polymethacrylic acids, polymethacrylic acid derivatives, alcohols polyvinyls (PVA), partially hydrolyzed polyvinyl acetate (PVAc), polyvinylpyrrolidone (PVP), guar, pectin, gum arabic, tragacanth, gelatin, starch or starch derivatives and mixtures of these substances.

The use of HPMC is specifically preferred.

Additionally, water-insoluble substances can be employed as structure-forming agents, for example unsaturated or saturated (hydrogenated) fatty acids and their salts, esters or amides, fatty acid mono-, di- or triglycerides, waxes, ceramides, deriva-

aaa of cholesterol and mixtures of these substances. ... Medicines may additionally contain customary tableting excipients, preferably highly dispersed silica (AerosilO), magnesium stearate, talc, PVP, lactose or microcrystalline cellulose. In addition, controlling substances may be incorporated into the matrix. the pH in the matrix. Due to the addition of such pH-modifying excipients and/or by the addition of substances that dissolve with increasing pH or dissolve outside the matrix and thus increase the porosity or permeability of the matrix and/or promote Matrix erosion is possible for these preferred embodiments of the present invention to achieve near pH dependent release.

The matrix containing the silybinin component may also be present in special geometric shapes where release is influencing. 15 ed by the special geometry and surface of the matrix. The matrix surface and release surface can be controlled, for example, by compression: to provide special shapes (eg, annular tablets) and/or by coating the sub-areas or applying barrier layers by means of a multi-layer press .

Formulations with different release properties can preferably be combined to provide a dosage form in multilayer or shell-encased tablets. For example, by means of multilayer tablets comprising a quick release layer or jacketed core tablets having a quick release jacket, controlled releases according to the invention with high initial release of the silibi component are obtained. nin, although by means of core tablets encased with a quick release core an accelerated release at the end can be obtained.

An additional drug with controlled release of the silybinin component is one where the silybinin component is embedded in a matrix consisting of one or more physiologically acceptable excipients through a fusion process. The release of the silybinin component

Ns = of these "molten extrudates" happens by diffusion and/or erosion. Preferably, these formulations with controlled release of the silybinin component are present in the form of granules, pellets or tablets. Forms obtained by melt extrusion, specifically pellets and granules can be processed to provide other pharmaceutical forms, such as, for example, by encapsulation or tabletting, optionally with the addition of additional pharmaceutically customary excipients. Furthermore, the melted extrudates according to the invention can be ground and subsequently used in this crushed form for the production of other drugs, such as, for example, matrix tablets. Further processing also comprises combining formulations having different pharmaceutical releases, such as, for example, extended and rapid release particles, to provide a medicine.

2515 The cast extrudates and/or dosage forms that are produced from the cast extrudates can be coated or lacquered. Cast extruded products are preferably produced by mixing the silybinin component with at least one physiologically acceptable meltable excipient (vehicle) and optionally additional and customary pharmaceutical substances, melting at a temperature in the range of 50 to 250°C , preferably 60 to 200°C, injection molding or extrusion and shaping. In the course of this, mixing of the components can take place either before melting or during melting or some of the components are melted and the other constituents added to this melting. The mixture of carrier, silybinin component and additional optionally present substances is thermoplastically deformable and therefore can be extruded. Several methods properly suggest the conformation of the mixture, for example, by hot granulation, cold granulation, calendering, extrusion and deformation of the still plastic filament or rounding. The thermoplastic vehicles used which are preferably swellable or soluble in physiological media are preferably: polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone (NVP) and vinyl esters,

ae . specifically vinyl acetate, copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate, polyvinyl alcohol, cellulose esters, cellulose ethers, specifically methylcellulose and ethylcellulose, hydroxyalkylcelluloses, specifically hydroxypropylcellulose, hydroxyalkylmethylcelluloses, specifically hydroxypropylmethylcellulose and hydroxyethylmethylcellulose, carboxymethylcelluloses, cellulose phthalates, specifically, cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate, cellulose succinate, specifically, cellulose acetate succinate and hydroxypropylmethylcellulose acetate succinate, polyhydroxyalkyl acrylates, polymethacrylates hydroxyalkyl, polyacrylates and polymethacrylates (EudragitO&quot; type), copolymers of methyl methacrylate and acrylic acid, polylactides, polyethylene glycols, polyethylene oxides and polysaccharides such as galactomannans and alginic acid and their alkali metal salts and a monium.

Preferred thermoplastic excipients for the production of me-. 15 dications with controlled release of the silybinin component are HPC, PVP, vinylpyrrolidone/vinyl acetate copolymers, polymethacrylates, specifically Eudragit&L, HPMCAS, polyethylene glycols, polyethylene oxides and their mixtures.

Plasticizing excipients that can be used to reduce the glass transition temperature of the mixture are, for example, propylene glycol, glycerol, triethylene glycol, butanediols, pentanols such as pentaerythritol, hexanols, long-chain alcohols , polyethylene glycols, polypropylene glycols, polyethylene/polypropylene glycols, silicones, phthalic acid derivatives (eg, dimethyl phthalate, diethyl phthalate, dibutyl phthalate), benzoic acid and benzoic acid esters, other acid esters — aromatic carboxylic acid (eg trimellitic acid esters), citric acid derivatives (eg triethyl citrate, tributyl citrate, acetyltriethyl citrate), aliphatic dicarboxylic acid esters (eg dialkyl adipates, sebacic acid esters) , specifically diethyl sebacate, tartaric acid esters), glycerol mono-, di- or triacetate, fatty acids and derivatives (eg glycerol monostearate, glycerides of acetylated fatty acid, castor oil and other native oils, migliol), fatty acid alcohols (eg cetyl alcohol, cetylstearyl alcohol), sugars,

In Y sugar alcohols and sugar derivatives (eg erythrite|, isomalt, lactitol, mannitol, maltodextrin, xylite!). ' In addition to the silybinin component, vehicle(s) and optionally plasticizer(s), the extrudable mixture may also contain other substances — customary pharmaceutical additives, for example, lubricants and mold release agents, glidants and flow agents, fillers and adsorbents , stabilizers, free radical traps, complexing agents, antioxidants, photostabilisers, propellants, surface-active agents, preservatives, colorants, sweeteners and flavors.

Lubricants and mold release agents may contain, for example, stearic acid and stearates, specifically aluminum, calcium and magnesium stearates, calcium behenate, sodium stearylfuramate, talc, silicones, waxes and mono and triglycerides, such as by example, glycerol monostearate, glycerol distearate, glycerol dibehenate, glycerol monostearate, glycerol palmitostearate. Flux agents employed are preferably animal and vegetable fats, preferably in hydrogenated form and with a melting point of at least 50°C, waxes (eg carnauba wax), mono-, di- and triglycerides (eg. glycerol monostearate, glycerol distearates, glycerol dibehenate, glycerol monooleate, glyceryl palm stearate), phosphatides, specifically lecithin.

The fillers used are substances such as titanium dioxide, aluminum oxide, magnesium oxide, silicic acid and silicates, stearic acid and stearates, cellulose derivatives (eg methylcellulose), starch and starch derivatives, sugars, alcohols of sugar and sugar derivatives.

Drugs with controlled release of the silybinin component can also be melt-extruded that contain excipients with pH-modifying properties and/or pH-dependent solubility. By means of these excipients (for example, the acids, bases, buffer substances and enteric polymers already described in this document above) it is possible to minimize the pH dependence of the release of the eh E silybinin component.

2 In the production of melted extrudates, the formation of "solid solutions" can occur, where the silybinin component is present in the matrix in a molecularly dispersed form. Drugs with controlled release of the silybinin component can also be pharmaceutical osmotic delivery systems. In principle, osmotic systems of this type are known in the prior art. In the present document, the pharmaceutical release of the pharmaceutical form is generally based on an osmotic pressure as a driving force.

The osmotic system preferably consists of a core which contains the silybinin component, optionally a hydrophilic swelling agent and optionally a water-soluble substance to induce osmosis and optionally and additionally pharmaceutically excipients. 15 acceptable and a coating consisting of a water permeable material that is impermeable to the components of the core and has at least one opening, through which the constituents present in the core can be released.

The material from which the coating of these drugs according to the invention with controlled release of the silybinin component is formed is semipermeable, that is, permeable to water, aqueous media and biological fluids and not or very restrictively permeable to core components and suitable for film formation. The selectively semipermeable encapsulating material is insoluble in body fluids, does not erode, is not degraded in the GI tract, and is excreted unchanged, or it shows bioerosion only towards the end of the release period.

Typical materials for the production of coatings of the osmotic system are preferably acylated cellulose derivatives (cellulose esters) which are mono to trisubstituted by acetyl groups or mono to disubstituted by acetyl groups and an additional non-acetyl acyl radical, by example, cellulose acetate, cellulose triacetate, cellulose acetate/ethyl carbamate, cellulose acetate phthalate, cellulose acetate methylcarbamate, cellulose acetate succinate, dimethylamino acetate cellulose acetate, cellulose acetate diethylamino acetate , cellulose acetate ]ethyl sulfonate, cellulose acetate chloroacetate, cellulose acetate ethyl oxalate, cellulose acetate methyl sulfonate, cellulose acetate butyl sulfonate, — cellulose acetate propionate, cellulose acetate octate, cellulose acetate laurate, sulfonate of p-toluene cellulose acetate, cellulose acetate butyrate and other cellulose acetate derivatives and also acetate agar and the amylose cetate.

A suitable semipermeable membrane material of the osmotic system is additionally ethylcellulose, copolymers of alkylene oxide and glycidyl alkyl ether, polymeric epoxides, polyglycols and polylactic acid derivatives.

Furthermore, mixtures of water-insoluble acrylates properly may be employed, for example a copolymer of ethyl acrylate and methyl methacrylate. 215 If necessary, the coating of the osmotic system can also contain plasticizers, such as, for example, plasticizer substances mentioned above and other additional substances, such as, for example, pore-forming agents.

If necessary, a photoprotective lacquer can be applied to the semi-permeable coating which can consist, for example, of HPMC or HPC, and a suitable plasticizer (eg, polyethylene glycol) and pigments (titanium dioxide, iron oxides) . In order to be able to administer an initial dose of the silybinin component, the osmotic system can also be provided with a coating containing the silybinin component, from which the silybinin component is preferable and rapidly released on contact with the medium. of release before osmotically controlled release of the core silybinin component begins.

Suitable water swellable polymers which may be present in the core of the osmotic system are preferably polyethylene oxides (eg PolyoxO), xanthan gum, vinylpyrrolidone and vinyl acetate copolymers, polyvinylpyrrolidones, crospovidones, carboxymethylce-

o Cross-linked sodium H lulose, cross-linked carboxymethyl sodium starch, hydroxy- oo lower substituted propyl-methylcellulose (L-HPC), polyhydroxy-alkyl acrylate), alginates and galactomannans and also additionally hydrophilic polymeric swelling agents and mixtures of the same.

Suitable osmotically active substances that can be added to the core for inducing osmosis are water-soluble salts of inorganic and organic acids or non-ionic organic substances with high water solubility, such as, for example, carbohydrates, specifically sugars or amino acids . By way of example, some substances can be mentioned which can be incorporated into the core of the osmotic system individually or as a mixture for the induction of osmosis; inorganic salts such as chlorides, sulfates, sulfites, carbonates, bicarbonates, phosphates, hydrogenated phosphates and dihydrogenated phosphates of alkali metals and alkaline earth metals such as, for example, sodium, lithium, potassium, calcium or magnesium, organic acids such as adipic acid, ascorbic acid, succinic acid, citric acid, fumaric acid, maleic acid, tartaric acid, benzoic acid and its alkali or alkaline earth metal salts, acetates, pentoses, such as, for example, arabinose, ribose or xylose, hexoses, such as, for example, glucose, fructose, galactose or mannose, disaccharides, such as, for example, sucrose, maltose or lactose, trisaccharides, such as for example raffinose, sugar alcohols such as, for example, mannitol, sorbitol, matltitol, xylitol or inosite! and urea. Sodium chloride and sodium carbonate are specifically and preferably used.

Furthermore, the osmotic system may contain other additional pharmaceutically customary substances, such as, for example, lubricants and mold release agents, glidants, binders, dye pigments, thickeners, protective colloids, stabilizers and surface-active agents.

The production of the osmotic delivery system is preferably carried out with the aid of standard techniques, such as, for example, wet granulation or dry compaction, tabletting and subsequent organic coating.

The coating of the osmotic system has at least one

NS outlet opening, through which the silybinin component, optionally together with other core constituents, is released.

The opening can be introduced into the casings in a variety of ways, eg punching, mechanical drilling or by means of a laser drill.

The term "opening" also encompasses materials which undergo bioerosion, which dissolve the coating upon administration of this medicament in accordance with the invention and thus lead to the formation of the exit openings in situ.

In a further embodiment for the controlled release of the silybinin component, the silybinin component may also be present as an ion exchange complex (adsorbate). Preferably, the drug is formulated for administration once a day (q.d.), twice a day (b.i.d.), three times a day (ti.d.) or four times a day.

In a preferred embodiment, 0.5 to 70% by weight of the compo-. 15 originally contained silybinin component were released from the drug after 1 hour under in vitro conditions.

Appropriate conditions for determining the in vitro release of active substances are known to those skilled in the art.

In this regard, reference can be made, for example, to the European Pharmacopeia.

Preferably, the determination of release is carried out with the aid of a blade stirrer in an artificial gastric juice (buffer, pH 1.2) or artificial intestinal juice (buffer, pH 7.6). The amount of silybinin component released can be analyzed, for example, with the aid of HPLC and UV detection.

Preferred release profiles A; a As are summarized in the table below. [arerm A and ar E Re se Ra Rae | 6 by wt | by wt | %bywt | %bywt | Sbywt | %Cbywe |%bywt | %bywe]| | 05 | 503 | 6033 | 7032 | 9031 | 1130 | 1330 | 1529 | 17-28 [—1 11253 | 1552 | 1850 | 2048 | 2246 | 2444 | 27-42 | 3040 | | 2 257 wing a598 ae ae Tae wing one | 3 | 3385 | 3682 | 3979 45:73 50-69 | 52-67 | | 4 | 4192 | 4489 | 4786 | 5083 | 5381 | 55:79 | 5877 | 6075 | 1 8 | 5298 | 5597 | 5696 | 60-54 | 6392 | 6690 | 69868 | 72686 | Fo es ER St 76-98 [nr 57 >76 | >79 | >83 | >84 | >86 Table Legend: After (h), % by weight.

NEEM In a preferred embodiment, the medicament contains an eo cyclodextrin and/or a phospholipid.

Pharmaceutical formulations containing silybinin and cyclodextrins are known in the prior art (as per, for example, EP 422497). Preferably, silybinin forms an inclusion complex with cyclodextrin. Preferred cyclodextrins are α-, B- and y-cyclodextrins, their O-Cy 1 -C 1 -alkyl and their hydroxy-C 1 -C 1 -alkyl derivatives. Pharmaceutical formulations containing silybinin and phospholipids are likewise known in the prior art (according to US

4,764,508). Preferably, silybinin forms a complex with the phospholipid. Preferred phospholipids are phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine. Preferred silybinin phospholipid complexes are ternary complexes additionally containing vitamin E (o-tocopherol). Complexes of this type are known in the prior art as "SPV complexes".—15 (cf. A Federico, Gut. 2006, 55(6), 901-2).

In addition to the silybinin component, the medicine may contain one or more terpenes. Through the action of terpene, both the absorption requirements and the absorption processes and thus absorption can be improved as a whole. Terpenes can be either natural or synthetic ethereal oils and/or their terpenoid constituents in the form of pure substances or mixtures or derivatives of these pure substances. Among the ethereal oils, specific mention can be made of thyme oil, eucalyptus oil, pine needle oil, tea tree oil, cajuput oil, cardamom oil, peppermint oil, sage oil and rosemary oil, preferably thyme oil. For terpenes, as substances which are also intended to include tepenoid substances, specific mention may be made of hemiterpenes, such as, for example, isoprene, tiglycic acid, angelic acid, isovaleric acid; monoterpenes, including acyclic monoterpenes, such as, for example, 2,6-dimethyloctane, a-myrcene, (E)-p-ocimene, perylene, linalool, geranial, (S)-(+)citronelial and monocyclic monoterpenes, such as, for example, cyclopropane monoterpenes and cyclobutane monoterpenes, such as, chrysanthemic acid or junionone;

and those of cyclopentane, such as, for example, iridoides or nepetalactones or (-)-secologanin and (-)oleuropein, cyclohexane monoterpenes, such as, o-menthane, cis or trans-p-menthane, ( R)-(+)-limonene, terpinols, (+)-perylaldehyde, (-)-menthone or (+)-carvone, bicyclic monoterpenes such as oxygen-bridged terpenes 1,4-cineole, 1,8-cineole or ascaridol; the carano and thujan cyclopropane bicycles, the pinane cyclobutane bicycle, and the canfano and fenchano bicycloheptanes; sesquiterpenes such as famesane, bisabolane, germacrane elemane, and humulane.

Specifically preferred terpenes are thymol, menthol, cineole, borneol, carvone, limenone and pinene, generally preferably thymol.

The medicine contains a silybinin component.

Silibinin is a constituent of silymarin.

Preferably, in addition to silybinin or silybinin components, the medicament does not contain any of the other constituents of silymarin.

If the silybinin component is silybinin as such the drug preferably does not contain the other silymarin constituents.

If the silybinin component is not silybinin as such, for example a silybinin ester, the medicament preferably does not contain silymarin constituents, i.e. no silybinin.

Preferably, one or more substances selected from the group consisting of isosylibinin, silydianin, silicristin, taxifolin, isosylcristin, silymonin, silandrin, silermin and neosiliermin are not contained in the drug, i.e. the drug is preferably essentially hair free minus one of the substances mentioned above.

In this regard, "essentially free" means that the residual content of the substance in question is preferably less than 2.0% by weight, more preferably less than 1.0% by weight, even more preferably less than 0.5% by weight. weight, more preferably less than 0.1% by weight and specifically less than 0.05% by weight, based on the total weight of the drug.

Analytical methods for determining the residual content of these substances are known to those skilled in the art, eg HPLC.

It was found that the individual silymarin constituents differ in their chemical and physical properties and contribute to the activity.

It is pharmacological of silymarin to a different extent such that it is advantageous to administer silybinin or its derivatives and/or salts as the sole constituent of silymarin, that is, solely. It appears that in this way, both efficacy and patient suitability can be improved. In addition, it has surprisingly been found that the tolerability of the various silymarin constituents differs among them and that sislibinin is more tolerable, specifically less toxic than silymarin (i.e., in relation to the mixture containing compounds other than silybinin). In a preferred embodiment, the invention relates to the use of a silybinin component for the production of a medicament which is preferably formulated for parenteral or oral administration and furthermore the silybinin component does not contain other silymarin constituents for treating hepatitis viral, specifically hepatitis B or C. Specifically preferred medicaments which are adapted for oral administration of the silybinin component are described hereinafter. All of these oral dosage forms have in common that they preferably contain the silybinin component in substantially pure form, i.e., preferably in the absence of other silymarin constituents, specifically in the absence of isossilibinin and/ousylcristine and/or silydianin .

Preferably, oral dosage forms are immediate release dosage forms, that is, the silybinin component is rapidly released from them, thereby leading to a rapid onset of the drug in the gastrointestinal tract. In a preferred embodiment, 30 minutes after administration of the oral dosage form, at least 75% by weight, more preferably at least 80% by weight, even more preferably at least 85% by weight, more preferably at least 90% by weight and specifically at least 95% by weight of the originally contained silybinin component is released from the oral dosage form.

In a preferred embodiment, the drug is provided as a solid solution. The solid solution is preferably obtained by soaking the silybinin component in dispersed molecular form in a

EN" polymer matrix preferably amorphous, highly soluble, having a large specific surface area. The silybinin component would be present in dispersed molecular form, that is, neither microcrystalline nor fine crystalline. An amorphous, highly soluble state can already be obtained by using solid polymeric solvents, which are highly soluble when extracting the silybinin or silybinin component of the silymarin extract. This technical drug formulation increases the solubility of the silybinin component and its dissolution rate.

An example of such a solid solution comprises the silybinin component, a suitable polymer (for example a copolymer of polyvinylpyrrolidone (PVP) or of polyvinylpyrrolidone such as Kollidon& 25), and optionally a dextrin (for example, maltodextrin). The formulation may contain additional excipients such as aerosil and/or talc.

Preferred embodiments B, to Bs of the solid solution are shown in the following table of this document. [| dextin | 10-70] 5.0-50]228+20 | 22.815 |22.8+10 | 22.8+7.0 | | amos! | 010 | 075] 40304025 | 40+20 | 40415 | [| taum [050 | 025]12+10]12+07]1205] 12+03 | Table legend: percentage by weight, silybinin component, dextrin, aerosil, talc.

The formulation can be provided, for example, in a gelatin capsule.

In another preferred embodiment, the medicament is provided as a self-emulsifying microemulsion. Lipid emulsification systems themselves can be used as vehicles and can lead to a high bioavailability of the drug contained therein. The lipid system is colloidal in nature and this allows the resorption of microparticles, especially of colloidal size, also through the lymphatic system in the gastrointestinal tract. Typically, the dissolved drug is saturated, but recrystallization does not occur. When administering the medication orally

Lipophilic shells, for example, of the silybinin component, the microemulsion serves primarily as an optimized vehicle that improves the dissolution rate of dissolved or highly dispersed drug at the site of absorption. In other words, the lipid system acts as an absorption enhancer.

An example of such a lipid system comprises the silybinin component, a suitable first emulsifier (for example lauroyl macrogolglyceride such as Gelucire® 44/14), and optionally a suitable second emulsifier (for example capryloca macrogolglyceride). prila such as LabrasolO). The formulation may contain additional excipients such as polysorbate.

Preferred embodiments C, to Cs of the solid solution are described in the following table in this document: PF s% Ico To TO cc | ce] | | silybinin component | 0.1-50 | 0.5-20 | 4.043.5 | 4.0+3.0 | 4.0+25 | 4.042.0 | , | frstemulsifer |10-99] 5:87 | 54415 | 54-12 | 54+10 | 547.0 | | second emulsifier | 0-70 | 0:70 | 41+20 | 47+15 | 41+10 | 4147.0 | [Ci Table Legend: Percentage by weight, silybinin component, first emulsifier, second emulsifier, polysorbate.

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

In yet another preferred embodiment, the drug is provided as a nanotechnology formulation. The average particle size of the nanoparticles is preferably below 1 µm. Nanoparticles are able to pass through the biological membranes of cell structures. The silybinin component is preferably adsorbed relative to the surface of said nanoparticles. The nanoparticles are preferably selected from the group consisting of inorganic nanoparticles and organic nanoparticles.

Inorganic nanoparticles comprise crystalline silicates, for example, of mineral origin or artificial silicates, such as metallosilicon.

dear cathodes, eg aluminosilicates (eg zeolites). These inorganic nanoparticles are preferably chemically modified so that they carry electrostatic charges. The silicates are ultra-finely ground into nanoparticles and the silybinin component is bound (adsorbed) to the microporous surface of the nanoparticles.

Organic nanoparticles include clusters or clusters of small proteins or oligopeptides or lipids. A suitable protein carrier is, for example, protamine.

Methods of preparing the nanoparticles are known to those skilled in the art. For example, colloidal nanoparticles as vehicles for oral drug delivery can be prepared by spraying the drug, i.e. the silybinin component, together with appropriate carrier materials under pressure, for example, at 60°C through jets. being equipped with filters (matrices) perforated in strongly cooled towers. Spontaneous cooling forms an amorphous phase consisting of nanoparticles.

: Solid lipid nanoparticles, for example, can be prepared by this high pressure homogenization and subsequent spray cooling. Preferably, the drug, i.e. the desilybinin component, is employed as a solution in an appropriate solvent or internal formation of submicroparticles. The silybinin component can be sprayed and pressure homogenized, respectively, in admixture with a liquid carrier and a surface-active agent, for example, at 60°C. After the optional addition of the fine filler materials as external phase as well as slip and additional surface-active agents, the formulation thus obtained can be filled into hard gelatin capsules.

An example of such solid lipid nanoparticles comprises a silybinin component core, a suitable first emulsifier (e.g., stearoyl macrogolglyceride such as Gelucire® 50/13) and optionally, an appropriate macromolecular surfactant. - ado (eg poloxamer). The formulation preferably additionally contains an outer phase (coating) comprising a first agent and surfactant (eg Tween 20), aerosil and a second surfactant eee (eg glyceryl pallimitostearate such as PercirolO). i Preferred embodiments of D; the Ds of the solid solution are described in the table in this document below.

Lsilibinin component == 01:30] 0.520 | 453.0 | 45425 | 4.542.0 | 451.5 | |firstemulsifier 1069 1 20-95 | 75420 | 75+15 | 75410 | 7547.5 | | macromotecular nonkonic surfactant | 0:50 | 040 | 15410 | 15475 | 1545 | 15225 | | first surfaetant gg [9175 |15+0.7 | 150.5] 150.3 | 15402 | IO eras [0175 /30+70/30+1.5/30+10]/30+6.7 | 52 Lsscona surfaetan the No175| 150.7 | 1.5x0.5 [ 1.5x0.3 | 1.5x0.2 Table Legend: Percentage by weight; silybinin component, first emulsifier, macromolecular nonionic surfactant, first surfactant, aerosil, second surfactant.

Charged nanoparticles obtain a substantially faster onset of action from the drug. - The medicine contains the silybinin 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 225mg, at least 250mg, at least 275mg, at least 300mg, at least 325mg, at least 350mg, at least 375mg or at least 400mg; even 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; more preferably at least 625mg, at least 650mg, at least 675mg, at least 700mg, at least 725mg, at least 750mg, at least 775mg or at least 800mg; and specifically at least 825mg, at least 850mg, at least 875mg, at least 900mg, at least 925mg, at least 950mg, at least 5975mg, or at least 1000mg; in each case as an equivalent dose based on silybinin.

The medicament contains the silybinin component preferably in a dose of at least 1.0 mg/kg, more preferably at a. = minus 2.5 mg/kg, even more preferably at least 5.0 mg/kg, more 200 preferably at least 7.5 mg/kg and specifically at least 10; mg/kg, at least 12.5 mg/kg, at least 15 mg/kg, at least 17.5 mg/kg, at least 20 mg/kg, at least 22.5 mg/kg, at least 25 mg/ kg, at least 27.5mg/kg or at least 30mg/kg, based on the patient's body weight and in each case as an equitable dose based on silybinin. Preferably, said dose is a daily dose. Thus, when the drug is adapted, for example, for administration twice a day, the respective daily dose is divided into two portions of identical amount. Similarly, when the medicine is adapted, for example, for administration three times a day, the respective daily dose will be divided into three portions or the same amount. In a preferred embodiment, the daily dose of the silybinin component is at least 5, more preferably at least 10, still more preferably at least 15 and most preferably at least 20 mg per kg of body weight, based in the equivalent weight of the 3rd silybinin.

In a preferred embodiment, the daily dose of the silybinin component is 20 mg per kg of body weight, based on the equivalent weight of silybinin. Thus, when the drug is adapted for once-a-day administration, it will preferably contain the entire amount of the silybinin component, for example, 1400 mg of silybinin for a patient having a body weight of 70 kg. When the medicament is adapted for twice daily administration, it will preferably contain half the amount of the silybinin component, for example 700 mg silybinin for a patient having a body weight of 70 kg. When the drug is adapted for administration three times a day, it will preferably contain one-third the amount of the silybinin component, eg 467 mg of silybinin for a patient having a body weight of 70 kg. When the component is adapted for administration four times a day, it will preferably contain a quarter of the amount of the silibinin component, eg 350 mg of silibinin for a patient

En having a body weight of 70 kg. 2 When the drug is adapted for parenteral administration, preferably by infusion, a preferred treatment regimen comprises 4 identical infusions of 2 hours duration each. Preferably, after 24 hours, the same infusion is repeated, so that, for 24 hours, 4 infusions in total are administered. Such a regimen can be schematically abbreviated as "2-4-2-4-2-4-2-4", where each figure indicates a number of hours and the underlined figures indicate the duration of an infusion, considering that figures not underlined indicate a lag phase between two infusion intervals. Preferably, the treatment regimen is uniform, that is, for 24 hours all infusions are dosed identically at identical time periods and the delay phases between consecutive infusions are identical.

Following the above indication, the administration regimes . 15 preferred parenterals are summarized in the following table in this document: .5-9.5-2.5-9.5; 3-9-3-9; 3.5-8.5-3.5-8.5; 4-8-4-8; 6-6-6.6; 8-4-8.4; dail 35-3-5: .5-3.5-4.5-3.5-4.5; 444444: 626.2: fourtimes — | 0.5-5.5-0.5-5.5-0.5-5.5-0.5-5.5; 1-5-1-5-1-5-1-5; 1.9-4.5-1.5-4.5-1.5-4.5-1.54.5; 24-24-24-24; Table Legend: Once a day, twice a day, three times a day, four times a day.

In a preferred embodiment, the drug is adapted for administration once, twice, three times or four times a day, so that the total daily dose that is administered when administering the drug in the prescribed manner corresponds to at least 300mg, at least 325mg, at least 350mg, at least 375mg or at least 400mg; more preferably at least 425mg, at least 450mg, at least 475mg, at least 500mg, at least 525mg 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

NNE. at least 700 mg, at least 725 mg, at least 750 mg, at least 775 mg, or at least 800 mg; even more preferably at least 825 mg, i 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; more preferably at least 1,050mg, at least 1100mg, at least 1150mg, at least 1200mg or at least 1,250mg; and specifically at least 1,300 mg, at least 1350 mg, at least 1,400 mg, at least 1,450 mg or at least 1,500 mg; in each case as an equivalent dose based on silybinin.

Preferred pharmacokinetic parameters AUCo., AUCt..., AUC0-. And AUC0-.. (corr.) (preferably after multiple infusions, eg after 11 infusions; single dose: 12.5 mg/kg; daily dose: 4 infusions; total dose: 11 infusions) are summarized as embodiments E1 to E8 in the drying table.

LAUCo, ——|3334200 [3334150 | 333+ 125 | 3334 100 | 3334 80 | 33360 | 333440 | 333% 20 | LAUCK — 3294300 | 3274150 | 3224 125 | 3224 100 | 3224 80 | 3223 60 | 3224 40 | 3223 20 | í LAUC. — | 655200 | 6553150 | 655+ 125 | 6554 100 | 655: 80 | 6554260 | 65540 | 655+ 20 | [AUC,. (corr) [414200 | 4143 150 T 414+ 125 [ 414+ 100 | 414% 80 | 41460 [ 414x 40 [414% 20 | In a preferred embodiment of the invention, the medicament containing the silybinin component is adapted for adjunct therapy, preferably for combination immunomodulatory/antiviral therapies such as interferon/ribovariin.

In a preferred embodiment, in addition to the silybinin component, the medicament contains an additional pharmaceutical substance, which preferably is suitable for the treatment of inflammatory liver diseases, specifically and preferably of viral liver diseases, specifically for the treatment of Hepatitis B or C.

Preferably, the additional pharmaceutical substance is selected from the group consisting of liver therapeutic substances, lipotropics [AO5B]; nucleosides, nucleotides, exclusive reverse transcriptase inhibitors [JO5AB]; interferons [LO3AB] and monoclonal antibodies to HBV (hepatitis B virus). The information indicated in the square brackets

re E se to the ATC index, preferably in the 2007 German version. SA Specifically and preferably, the additional pharmaceutical substance is selected from the group consisting of arginine glutamate, cytolone, epomediol, ornithine oxoglurate, thidiacicarginine, myoinositol, methionine and —N-acetylmethionine, choline, ornithine aspartate, cyanidanol, thiopronine, betaine, cyanocobalamin, leucine, levulose, acyclovir, idoxuridine, vidarabine, ribavirin, ganciclovir, famciclovir, valaciclovir, cidofovir, penci- val- cyclovir, , brivudine, interferon alpha, interferon beta, interferon gamma, interferon alfa-2a, interferon alfa-2b, interferon alfa-n1, interferon beta-ta, interferon Dbeta-lb, interferon alfacon-1, peginterferon alfa-2b, peginterferon alfa- 2a and interferon gamma 1b.

In a preferred embodiment, treatment of the patient with the silybinin component serves to support and/or prepare a treatment for viral hepatitis, specifically hepatitis B or C, thereafter. 15 this treatment, with another pharmaceutical which is preferably selected from the group consisting of arginine glutamate, silymarin, cytolone, epomediol, omitine oxoglurate, thidiacycarginine, myoinositol, methionine and N-acetylmethionine, choline, ornithine aspartate, cyanidanol, thiopronine, betaine, cyanocobalamin, leucine, levulose, acyclovir, idoxuridine, vidarabine, ribavirin, —ganciclovir, famciclovir, valaciclovir, cidofovir, penciclovir, valganciclovir, brivudine, interferon alpha, interferon beta, interferon gamma -2a, interferon alfa-2b, interferon alfa-n1, interferon beta-ta, interferon beta-1b, interferon alfacon-1, peginterferon alfa-2b, peginterferon alfa-2a and interferon gamma 1b.

Thus, preferably following the treatment of viral hepatitis, specifically hepatitis B or C, with the drug containing the silybinin component, the treatment of viral hepatitis, specifically hepatitis B or C, with another drug is carried out.

In a preferred embodiment, the drug is formulated as a constituent of a sequential treatment, the drug being initially administered for a first period, preferably parenterally, and subsequently another drug being administered by

And a second period. Preferably, the first period comprises at least 2 days, more preferably at least 3 days, even more preferably at least 4 days, more preferably at least 5 days and specifically at least 6 days. Preferably, the second period comprises more days than the first period. Preferably the second period comprises at least two days, more preferably at least 3 days, even more preferably at least 4 days, more preferably at least 5 days and specifically at least 6 days. In a specific preferred embodiment, the second drug contains a combination of ribavirin and pegylated interferon alpha and the second period comprises a time span of 24 to 48 weeks.

Preferably, the other medicament contains one or more pharmaceutical substances selected from the group consisting of arginine glutamate, silymarin, cytolone, epomediol, ornithine oxoglurate, thidiacycarginine, myoinositol, methionine and N-acetylmethionine, choline, ornithine aspartate, cyanidanol, thiopronine, betaine, cyanocobalamin, leucine, laevulose, h acyclovir, iodoxuridine, vidarabine, ribavirin, ganciclovir, famciclovir, valaciclovir, cidofovir, penciclovir, valganciclovir, brivudine, alpha interferon, interferon beta, interferon gamma, interferon , interferon alfa-2b, interferon alfa-ni, interferon beta-ta, interferon beta-1b, interferon alfacon-1, peginterferon alfa-2b, peginterferon alfa-2a, interferon gamma 1b and to monoclonal antibodies to HBV, Specifically and preferably an interferon and/or ribavirin and/or silymarin. If the other medicine contains an interferon, it is preferably pegylated interferon alfa (peginterferon alfa-2a or peginterferon alfa-2b).

In a specifically preferred embodiment, the other medicinal product contains one or more pharmaceutical substances selected from the group consisting of isossilibinin, silidianin, silicristin, taxifolin, isosilicristine, silymonin, silandrin, silhermin and neosilihermin, more preferably only one pharmaceutical substance selected from the preceding list. Preferably, the other medicine contains a silybinin component as defined in connection with the medicine described above which is

That administered by the first period, and is preferably essentially free of at least one, preferably all of the aforementioned substances. In this regard, "essentially free" means that the residual content of said substance is preferably less than 2.0% by weight, more preferably less than 1.0% by weight, even more preferably less than 0. 5% by weight, more preferably less than 0.1% by weight and specifically less than 0.05% by weight, based on the total weight of the drug. The other drug can, in principle, be formulated for parenteral or oral administration. According to the invention, it is preferably formulated for another route of administration than that of the drug which is administered for the first period. Specifically and preferably, the other drug is formulated for oral administration. In a specifically preferred embodiment, according to the invention, the drug which is administered during the first period is adapted for administration. 15 parenterally, preferably intravenously, and the other drug which is administered during the second period following the first period is adapted for oral administration.

In a preferred embodiment, the treatment regimen according to the invention comprises two phases that follow each other —consecutively, viz., a first period and a second period. Preferably, during the first period, the drug containing the silybinin component is administered, preferably in parenteral form, but no other drug having a hepatic effect is administered simultaneously. During the second period, another drug is administered which preferably contains ribavirin and/or pegylated interferon alpha. In a preferred embodiment, the medicament containing the silybinin component is also administered during the second period, preferably in parenteral form. In another preferred embodiment, the drug containing the silybinin component is not administered during the second period, i.e., only said other drug is administered. Preferred embodiments F, F15 of the biphasic treatment regimen are summarized in the following table:

| i Table Legend: Number of days, first period, second period.

In another preferred embodiment, the treatment regimen according to the invention comprises three phases which follow consecutively, viz. a first period, a second period and a third period.

Preferably, during the first period, the drug containing the silybinin component is administered, preferably in parenteral form, but no other drug having a hepatic effect is administered simultaneously.

During the second period, another medicine containing preferably ribavirin and/or pegylated interferon alpha is administered and the medicine containing the silybinin component is also administered during the second period, preferably in parenteral form.

Preferably, during the third period, said other medicine preferably containing ribavirin and/or pegylated interferon alpha is administered, but the medicine containing the silybinin component is not administered during the third period, i.e. only the other said medicine. - ment is administered.

Preferred embodiments G, to G,5 of the three-phase treatment regimen are summarized in the following table: | second period | = 1 [22] =11=1 | >=2/=2|>1 | =2|=3/=a [=5 | =61=7) =7 [=14] 2nd Lihiaperos 21/21) =1/>2/=2 >1/=2|2=2/>=3 | >4|>=5/26[>7]>27 [27 ) Table Legend: Number of days, first period, second period, third period.

In yet another preferred embodiment, the treatment regimen according to the invention comprises three phases that follow each other — consecutively, viz., a first period, a second period and a third period.

Preferably, during the first period another medicine is administered, which preferably contains ribavirin and/or pegylated interferon alpha and the medicine containing the silybinin component is not administered during the first period.

During the second period, said other medicament which preferably contains ribavirin and/or pegylated interferons alpha is further administered and the medicament containing the silybinin component is also administered (co-administered) during the second period, preferably in parenteral form. , during the third period said other medicine that preferably contains ribavirin and/or pegylated interferon alpha is administered, but the medicine containing the silybinin component is not administered during the third period, that is, only the said period. another drug is administered. In other words, according to this preferred embodiment, said other drug preferably containing ribavirin and/or pegylated interferon alpha is administered continuously and during an interim period (= second period. odo) the medicament containing the silybinin component is co-administered, preferably parenterally.

Preferred embodiments of H, to His of the triphasic treatment regimen are summarized in the following table: | second period | = 1 />2)>1/>1/>=2J1>2/>1/>2 23/24 >5 | =6/>7/>=7 |=14] . 15 Chidpeiog (27/21/>1/27/=2]=1 =2/ 22 =3 za =5] =6 | =7127 1=7 | Table Legend: Number of days, first period, second period, third period.

Figure 10 depicts various modes of co-administration of ribavirin and/or pegylated interferon alpha and the drug containing the silybinin component (embodiments a;) to m2)). Each bar refers to an administration time period. For example, according to embodiment fi), administration begins with ribavirin/pegylated interferon alpha and continues.

During an interim period, the silybinin component is co-administered.

A further aspect of the invention relates to a medicament as described above, preferably adapted for parenteral administration, for treating viral hepatitis as described above.

Still a further aspect, the invention relates to a Kit comprising at least one medicament according to the invention, which contains a silybinin component and at least one other medicament.

Both medicaments according to the invention, the one containing a silybinin component and the other medicament are described above, such that it is effectively effective of a silybinin component, preferably an aryl silybinin ester, to a subject in need thereof. Preferred embodiments of the aspect of the invention become evident from the above description of preferred embodiments of the other aspects of the invention and thus are not repeated. The following examples further illustrate the invention, but should not be taken as limiting its scope. Example 1 The silybinin component was administered parenterally in the form of silybinin C-2',3-bis(hydrogen succinate) (Legalon Sil&, Madaus, Koln) (hereinafter referred to as "silybinin"). Patients and Methods: Protocol! 2 16 (14/2 20 (1713)

49.94+9.7 52.712.8 Genotype (1/2/4 1712 Fibrosis stage: ee ' 02 a gg OT 4 BR Not available pa TS | preceding therapy UU SS UU OR) PEG -interferon-high?2a/RBV a UT PEG- interferon-alpha2h/RBV aa a A OO

AND

E AAA OO OO DA not available RR yy : a O) Table Caption: Patients, Protocol 1, Protocol 2, N (men/women), Middle Age (years + SD), Genotype (1/2/4) , Fibrosis stage, Not available, preceding therapy, PEG-interferon-alpha2/RBV, PEG-interferon-alpha2b/RBV, log drop 12 week preceding therapy, not available. * some patients had more than one treatment cycle ** all were positive at week 24. Patients with no prior response to full-dose peginterferon/ribavirin combination therapy were selected for these studies. Non-response was defined as lack of a >2 log fall in 2057 viral load after 12 weeks of therapy and/or failure to complete the response to treatment. Patients were asked to perform a liver biopsy within 2 years prior to inclusion in this study. Standard inclusion/exclusion criteria for peginterferon/ribavirin therapy were applied.

Study Protocol: During a classification phase within 35 days prior to the first dose of study drug, patient eligibility was established according to inclusion/exclusion criteria. All patients had at least one quantitative HCV-RNA test within 6 months prior to the classification phase.

Protocol 1: Patients first received 10 mg/kg of silybinin daily (Legalon SilO, Madaus, Kôln) as an infusion for 4 hours on 7 consecutive days. Day-old blood was collected to determine the oxidative stress parameters at baseline, every 30 minutes E during the infusion and 2 hours after the end of the infusion. On day 8 treatment was changed to 140 mg silymarin (LegalonO, Madaus, KôIn) TID per os in combination with 180 ul/week PeglFNa-2a (PEGASYSQO, Roche, Basel) and 1-1.29/d of ribavirna (COPEGUSQO , Roche, Basel).

Protocol 2: After obtaining the results for the first protocol, the treatment with silybinin was extended for 2 weeks and different doses of silybinin were administered. Patients first received daily 5, 10, 15 or 20 mg/kg of silybinin infused for 4 hours for 14 consecutive days. On day 8 of treatment 180 µg/week of PeglFNa-2a and 1-1.2 gídia of ribavirin was started. After day 14, patients received 280 mg silymarin (LegalonO&O, Madaus, Koln) TID per os. During the 14-day infusion period, blood was collected daily to determine the viral load.

In both protocols in case of intolerance to PEG-IFN alpha 2a or ribavirin, standard dose adjustment guidelines were used. Antiviral combination therapy was provided for a total of 24 weeks

OO (with the option of stopping treatment in patients with a drop of > 20 log at week 12); virologic responders were offered at week 24 to continue treatment for an additional 48 weeks. At the end of the infusion period, patients were tested after weeks 2, 4 and then monthly until the end of therapy at week 24.

The protocol was approved by the ethics committee of the Medical University of Vienna. The details of the study were explained to the patients and all signed a consent form.

Methods: The serum HCV RNA level was determined by the TaqMan PCR assay (Cobas Ampliprep/Cobas TaqMan HCV Test; limit of detection, 15 IU/mL, Roche Diagnostics).

Reactive oxidative metabolites in blood were measured by the d-ROMs test (Compounds derived from reactive oxygen metabolites; Di-215 acron, Grosseto, Italy) and the amounts of antioxidants by the BAP test (Biological antioxidant potential; Diacron, Grosseto, Italy) using the portable free radical determination system f (FRAS 4, SEAC, Callenzano, Italy), before every 30 minutes during (on day 1) and 2 hours after silybinin infusions. The d-ROM test measures reactive oxygen metabolites (primarily hydroperoxides) released from plasma proteins by an acidic buffer, which in the presence of iron generate alkoxyl and peroxyl radicals, according to Fenton's reaction. Such radicals, in turn, are capable of oxidizing an alkyl substituted aromatic amine (N,N-diethylparaphenylenediamine), thus producing a rose colored derivative that is photometrically quantified at 505 nm. Results for reactive oxidative metabolites are expressed as Caratelli Units (Ucarr; normal: 250-300, 1 Ucarr = 0.8 mg hydrogen peroxide/dl). The BAP test measures the intensity of discoloration of a solution of ferric chloride mixed with a thiocyanate derivative by the plasma sample added at 505 nm, which is proportional to the ability to reduce ferric ions by the amounts of antioxidants in the plasma (normal > 2,200 pM ). The manufacturer's description of the tests does not specify which substances are actually measured.

E Originally, the primary outcome variable was virologic response defined as the percentage of patients being PCR negative at the end of treatment (week 24). Secondary efficacy variables were virologic response rates at week 12, safety and tolerability of treatment with PEG-IFN/ribavirin/silymarin, baseline quality of life at week 24, week 48, week 72 (SF- 36, Fatigue Severity Scale) and the oxidative state after silybinin infusions. Due to the unexpected strong virologic response after 7 days of silybinin infusions, recruitment was stopped and the study was redesigned, based on virologic response parameters using the longest infusion periods and highest silybinin doses. For the original study, the sample size was estimated based on Gehan's two-stage design. According to 215 previous studies, a response rate of > 10% appears to warrant further investigation of the treatment regimen. Consequently twenty-nine f patients needed to be recruited in the first stage (probability of error B = 5%).

Results: Protocol 1: Sixteen lineage non-responders (for details see table above) were included. All patients received full-dose treatment with pegylated interferon (12 peginterferon alpha 2a, 2 peginterferon alpha 2b) and ribavirin (1,000-1,200 mg/d) for at least 12 weeks.

Measured oxidative stress parameters did not change during silybinin infusions (figure 1).

Serum HCV RNA declined in all patients with SIL iv monotherapy (figure 2) (baseline: 6.59:+0.53, DAY 8: 5.26:+0.81 log IU/ml, [mean +SD], p<0.001) with a mean log decline of 1.32+0.55 within one week. In parallel, ALT decreased from 162+133 to 118+107 U/1 (p = 0.004). In all patients HCV RNA remained detectable at the start of PeglFN/RBV therapy. Three patients rejected the

Eds PEGINF/RBV combination therapy. In 11 of the remaining 13 patients, HCV RNA increased again after the end of the silybinin infusions despite the initiation of PegiIFN/RBV. At week 12 all patients were still positive for HCV RNA, but 5 patients had a —fall>2log and continued treatment (figure 3). None of them became HOV RNA negative at week 24, one patient had a 5.5 log drop and continued treatment of their own volition. Protocol 2: Twenty lineage non-responders (for details see table above) were included. All patients received treatment with full dose pegylated interferon (18 peginterferon alfa 2a, 4 peginterferon alfa 2b; 2 patients received 2 courses of treatment) and ribavirin (1,000 -

1,200 mg/d) for at least 12 weeks. Figure 4 shows the viral kinetics in these patients. The viral load has continuously decreased. After 7 days with silybinin monotherapy, the dose of 5 mg/kg was marginally effective (n = 3, log drop 0.55+0.5), considering that 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 doses of 20 mg/day (n = 9, 3.02+1.01) led to a highly significant decrease in viral load (p < 0.001).

After | week of combined silybinin and peginterferon/ribavirin therapy the viral load further decreased (log drop: 5 mo/Kkg: 1.63+0.78; 10 mg/kg: 4.16+1.28; 15 mg/kg 3.69+1.29; 20 mg/kg, 4.8:-0.89; all p<0.0001 versus baseline) (Figure 5). Two of the five patients in the 15 mg/kg group and 4 of the 9 patients in the 20 mg/kg group had CV RNA < 15 IU on day 15. HCV RNA was <15 IU/mL in 8 and 7 patients at week 4 (study protocol week 5) and week 12 (study protocol week 138) after initiation of PEGIFN/RBV, respectively. Antiviral combination therapy continued for all patients (figure 6).

Safety: In general, silybinin was well-tolerated. Five patients complained of mild gastrointestinal symptoms (abdominal pain: 5, dia-

eee rhea: 2, nausea 1), two complained of headache and one of arthralgia. oo All were classified as being mild by the patients and disappeared after the end of the infusions; changes in dosage were not necessary. All patients in the 15 and 20 mg/kg groups observed a sensation of heat when the infusion was started, which disappeared within 30 minutes without treatment. No SAEs occurred. In monotherapy, no changes in hemoglobin, leukocytes, platelets and creatinine were observed. Typical side effects of combination antiviral therapy were noted (including one patient suffering from increased dyspnea due to influenza-induced haemophilus pneumonia, requiring termination of peginterferon/ribavirin therapy after 8 weeks).

This example demonstrates that parenteral administration of silybinin (C-2',3-bis(hydrogen succinate)) has marked antiviral activity against the hepatitis C virus. for the treatment of chronic hepatitis C, specifically in non-responders.

' It was surprisingly found that silybinin iv. (C-2',3-bis(hydrogen succinate)) is a potent antiviral agent in patients with chronic hepatitis C not responding to standard & antivial combination therapy. Intravenous silybinin was well tolerated, no serious adverse effects observed. The most common side effect reported was a transient feeling of heat. The antiviral effect was dose-dependent, but it was not maintained after the end of the infusion period by oral administration of silymarin.

In comparison, similar amounts of silymarin given orally have no effect on HCV load (A. Gordon et al., J Gastroenterol Hepatol. 2006, 21, 275-80) reflecting differences in the bioavailability and metabolism of silybinin resulting in levels very low plasma levels. After oral dosing silymarin flavonolignans are rapidly glucuronidated and rapidly eliminated with a short half-life (Z. Wen et al., Drug Metab Dispos. 2008, 36(1), 65-72).

per Example 2: oo Patients were continuously treated with 180 ug of pe-E ginterferon alfa 2a and ribavirin on a weight basis. Despite this treatment, five patients were HCV RNA positive after 24 weeks of therapy. Three male patients and two female patients: four patients with HOV genotype 1 and one patient with HCV genotype 3a; three patients with cirrhosis. Four patients can be considered as not previously treated, considering that one patient can be considered a recidivist in relation to the two previous therapies (24 and 48 weeks). In the course of ongoing treatment with 180 ug peginterferon alfa 2° and ribavirin-based weight, all patients were treated at least once for 14 consecutive days with 20 mg/kKkg/day iv silybinin. combination with peginterferon/ribavirin continued 215 or All 5 patients became HCV-RNA negative.

E Figure 7 shows the result for an individual patient (male, 55 years old). As can be seen, peginterferon/ribavirin merely causes a decline in viral load from about log 7 IU/mL to about log 4.5 IU/mL after 24 weeks. Co-treatment with 20 mg/kg/day of iv silybinin bis(hydrogen succinate) for 14 days, however, led to a dramatic decline in viral load from about log 4.5 IU/mL to a value below the threshold detection. After the first interval of parenteral silybinin bis(hydrogen succinate) administration, the viral load increased again to about 2 IU/mL, which could, however, be permanently repressed below the detection limit by a second co-treatment with 20 mg/kg/day silybinin iv bis(hydrogen succinate) for 14 days.

Figure 8 shows the result for another individual patient (female, 44 years old). As can be seen, peginterferon/ribavirin merely causes a decline in viral load from about log 7 IU/mL to about log 5 IU/mL after 30 weeks. Co-treatment with 20 mg/kg/day of silybinin i.v. bis(hydrogen succinate) for 14 days after 30 weeks, however,

er led to a dramatic and permanent decline in viral load from about log 4 aco IU/mL to a value below the detection limit.

á Figure 9 shows the result for an individual patient (male, 52 years old). As can be seen, peginterferon/ribavirin causes an efficient decline in viral load from about log 5 IU/mL to a value close to the detection limit of < 15 IU/mL. Co-treatment with 20 mg/kg/day silybinin i.v. bis(hydrogen succinate) for 14 days after 72 weeks caused a further decrease in viral load to well below the detection limit.

These clinical trials demonstrate that parenteral treatment with a silybinin component for a comparatively short time span supports and significantly improves conventional treatment by peginterferon/ribavirin. It appears that parenteral administration of the silybinin component (re)activates patients' susceptibility to conventional treatment with peginterferon/ribavirin (figures 7 and 8) and/or improves the antiviral effect of conventional treatment with peginterferon/ribavirin f (figure 9 ). Example 3 An in vivo study was performed to characterize the plasma concentration/time profiles of silibinin in 8 patients suffering from chronic hepatitis C who received 7 days iv of treatment by infusion with 20 mg silibinin/kg body weight (Legalon & SIL). For multiple doses of 20 mg/kg body weight, plasma concentration/time profiles and PK parameters of free and total silybinin had been observed on day 1 (= single dose conditions) and were compared with those on day 7 ( = expected steady state conditions).

Analytical Procedure: Study samples were analyzed using a validated HPLC-UV method. During the test period, the analytical procedure — was validated by two calibration curves per analytical run. Inspection of the data chromatograms presented in the calibration curves and quality control samples indicates that the result of the determinations and concentrations of total and free silybinin A and silybinin B for the study is reliable. É The characteristics of PK are summarized in the following table: Total Silbinin adC da | | Sbhna | Skbining | Sibininha | Sibirink | AUCIO-=) [h ng/ml] | 61733+27489 | 13745276080 || <A | AUC(O-L) [h nam] | 5001920048 | 1oso3aa51342 [ON OO AesSs ngm nur ua RISGGSo51T1 | 150780+47780 [Cia Ph ngm a a oG7A631 | a31HIA2O | Cnaingimill =| 4550+928 | 95397843 110832269 Ca fg O to 51241046 | G2821991 [teingml | 830226 | g29+298 | 13324366 | 1202+291 [HVDIh — 996+3.36 9,473,298 | 1520409 | 1317362 [MRTIE | 13174374 13,444.39 | 19.22+5.28 17.3434.20 LCLImuhka | 04350336 | 0233+0.237 | 02690126 | 0.156+0.091

4.71.3 2411 4670.7173 2.430.55 414018 | 417048 pp | PTE BB 121895443 | 1375045251 Free Silibinin and Gg [| Sbinina] Sifbiine | SbininA | Silibinin À | AUC(O-=) n ngmi[ | 36741648 | 7osaae [a | AUCIO-t) fh ngmi] | 330241551 [| ssoa ge [Ms O ia auess q gen" to ur uang5 1947 | 10414627 Pi gm nv Ega | 33487 316108 | 90x44 | 3158119 | 120x54 | rg Cv ABA | 43496 Ltebaml "Wu 4583135 | 5162406 | 6.85+1.29 4.3541.68 Table Legend: Total silybinin, day 1, day 7. Free silybinin, day 1, day 7, silybinin A, silybinin B. Example 4: An in vitro study was performed to assess the cytotoxic potential of silymarin. silybinin, disodium silybinin bis(hydrogen succinate) salt, and succinic acid using the XTT test using the L929 mouse cell line (as per DA Scudiero et al., Cancer Res. 48, 4827-33; OS Weislow et al. , J. Natl. Cancer Inst., 81, 577-86; NW. Roehm et al., J. Immunol. Methods, 142). The following concentrations of the test items were tested: 9.77, 19.53, 39.06, 78.13, 156.25, 312.5, 625, 1250 µg/ml. Complete medium (RPMI 1640 containing 10% (v/v) FCS) was used as the control.

He is negative. The solvent control for the test item was RPMI 1640 rr medium containing 10% (v/v) FCS) and 1% DMSO. The solvent control for the É positive control was also RPMI 1640 medium containing 10% (v/v) FCS and 10.0% (v/v) deionized water. SDS was used as a positive control. The following concentrations were applied: 3.125, 6.25, 12.5, 25, 50, 100, 125, 250 puo/ml. Incubation time was 24 hours at 37 ± 1.5ºC.

Negative control and solvent control showed no reduction in cell viability. The positive control (SDS) induced a distinct dose-related reduction in cell viability.

Toxic effects were observed following incubation with silymarin at 39.06 µg/mL to the highest tested concentration (1250 ug/mL). The calculated XTTs59 value is 35.2 ug/ml.

Toxic effects were observed following incubation with silybinin at 78.13 pg/ml to the highest tested concentration (1250 ugml). The calculated XTT50 value is 67.5 ug/ml. No relevant cytotoxic effects were observed following "incubation with silybinin-bis(hydrogen succinate)sodium salt to the highest tested concentration (1,250 ug/mL). Due to the lack of cytotoxicity, an XXT50 value cannot be calculated.

No relevant cytotoxic effects were observed following incubation with succinic acid up to the highest tested concentration (1,250 Vg/mL). Due to the lack of cytotoxicity, an XXTso value cannot be calculated.

These experiments revealed that under given conditions, the cytotoxic potential of silymarin is close to 100% higher than the cytotoxic potential of silybinin. Thus, it can be expected that silybinin can be administered in higher doses than silymarin, without causing serious adverse side effects.

Example 5: NS5B RNA-dependent RNA polymerase (RdRp) is an essential enzyme for viral replication (cf. S.B. Hwang et al., Virology 1997, 227, 439-46). The following pure compounds have been tested.

EEs from a cell-free enzyme assay for detection of HCV activity and RdRp: silybinin A, silybinin B, isossilibinin A, isosylibinin B, 'silychristin, silydianin and the silyphinin ester silyphinin-C2',3-bis (hydrogen succinate) disodium (active ingredient of LegalonO SIL).

Master solutions (100 mM) of compounds in 100% DMSO were prepared. The DMSO concentration in all reactions was kept constant at 5%. The target enzyme for study was a J4 (1b) genotype of HCV NS5BA21 polymerase.

Figure 11 shows the data generated for the six purified silymarin constituents (i.e., silybinin A, silybinin B, isossylybinin A, isosylibinin B, silychristin and silydianin). Figure 12 shows the respective data for the silybinin ester. The silybinin ester revealed was more efficient.

The IC50 value of the silybinin ester was determined from the dose response curve of two measurements. The ICs50 value was 47+14 UM. Curves were fitted to data points and IC50 values were interpolated from the resulting curves using SigmaPlot 8.0 software.

This claim 1. Use of a silybinin component for the production of a drug, which is formulated for parenteral administration, for the treatment of viral hepatitis.

Use according to claim 1, wherein the silybinin component is a silybinin ester.

Use according to claim 2, wherein the silybinin ester is silybinin C-2',3-bis(hydrogen succinate) or a physiologically acceptable salt thereof.

Use according to one of the preceding claims, wherein the medicament contains essentially no silydianin and/or no silicristin and/or no isosylibinin.

Use according to one of the preceding claims, wherein the viral hepatitis is hepatitis B or hepatitis C.

Use according to one of the preceding claims, wherein the medicine is formulated for injection or infusion.

Use according to one of the preceding claims, wherein the medicament is formulated for intravenous administration.

Use according to one of the preceding claims, wherein the medicament does not contain any of the silymarin constituents other than the silybinin component.

Use according to one of the preceding claims, wherein the medicament contains the silybinin component in a dose of at least 50 mg, based on the silybinin.

Use according to one of the preceding claims, wherein the medicament contains an additional pharmaceutical substance in addition to the silybinin component.

Use according to claim 10, wherein the additional drug is selected from the group consisting of arginine glutamate, cytolone, epomediol, ornithine oxoglurate, tidiacicarginine, myoinositol, methionine and N-acetylmethionine, choline , ornithine aspartate, cyanidanol, thiopronine, betaine, cyanocobalamin, leucine, levulose, acyclovir, idoxuridine,

and vidarabine, ribavirin, ganciclovir, famciclovir, valaciclovir, cidofovir, penciclo-aovir, valganciclovir, brivudine, interferon alpha, interferon beta, interferon gamma, interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon beta-1ta , interferon beta-1b, interferon alfacon-1, peginterferon alfa-2b, peginterferon alfa-2a and interferon gamma 1b.

12. Use according to any one of the preceding claims, for reducing viral load in patients with hepatitis.

Use according to any one of the preceding claims for treating viral hepatitis in a patient who will have or have undergone liver transplantation.

Use according to any preceding claim for treating viral hepatitis in a patient who does not respond to ribavirin/interferon therapy.

15. Use according to any of the preceding claims for supportive and/or preventive treatment of viral hepatitis with a pharmaceutical substance selected from the group consisting of arginine glutamate, silymarin, citiolone, epomediol, ornithine oxoglurate, tidiacicargi- nin, myoinositol, methionine and N-acetylmethionine, choline, ornithine aspartate, cyanidanol, thiopronine, betaine, cyanocobalamin, leucine, levulose, acyclovir, idoxuridine, vidarabine, ribavirin, ganciclovir, famciclovir, clofoviraciclovir, pendi valganciclovir, brivudine, interferon alpha, interferon beta, interferon gamma, interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon beta-1a, interferon beta-1b, interferon alfacon-1, peginterferon alfa-2b, peginterferon alfa-2a and interferon gamma 1b.

Use according to any one of the preceding claims, wherein following the treatment of viral hepatitis with the drug, the treatment of viral hepatitis is carried out with another drug.

Use according to any one of the preceding claims, wherein the medicament is formulated as a constituent of a sequential treatment, the medicament being initially administered for a first period and subsequently another medicament being administered for a second period.

Use according to claim 17, wherein the first 200 period comprises at least two days. Use according to one of claims 16 to 18, wherein the other medicament contains one or more pharmaceutical substances selected from the group consisting of arginine glutamate, silymarin, cytolone, epomediol, ornithine oxoglurate, thidiacicarginine, myoinositol, methionine and N-acetylmethionine, choline, ornithine aspartate, cyanidanol, thiopronine, betaine, cyanocobalamin, leucine, levulose, acyclovir, idoxuridine, vidarabine, ribavirin, ganciclovir, famciclovir, valaciclovir, cidofovir, pen , brivudine, interferon alpha, interferon beta, interferon gamma, interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon beta-ta, interferon beta-1b, interferon alfacon-1, peginterferon alfa-2b, peginterferon alfa- 2a and interferon gamma 1b.

Use according to one of claims 16 to 19, wherein the other medicine is formulated for oral administration.

21. Kit comprising at least one drug as defi- . defined in one of claims 1 to 11 and at least one other medicament as defined in claim 19 or 20.

o Ss " ZE mo o = 2 DN Qu ar = 8 > oO & 200 Es oo 2 Ss 100 ão o - o À Test d-ROMs o 100 200 Soo f minutes : 4000 s 3000 ã 2 MAD A AAA S 2000

FOR

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NENE EA =. AN A REA == ú o NESSA A = O “o : o ANS y SN X A ANDO. õ 3 *W ES x SF: Ne

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E = = o 3 | Oo H : g2 | | 8 | S | | | dt | | NM 8 RR) o o ! ! 8 . 10 15 20 mg/kg n= 3/3 19*/3 5/5 9/9 i: E * includes patients in study 1

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FIG. 7 Pat. HO, m 55 to 8 Dra SS nº 180 ug PegiFNalpha2a+RBV pu 2O,1ma/tka E 6 intravenous -s In

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FIG. 9 HN,m,52a 8 180 ug PegiFNalphaza+RBV = 20 mg/kg intravenous E mm —

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DID T =

: 12/14" - FIG. 11 "and Silibinin AT $ 10 8 and EM Sa * x 8 4 2 O 20 z 82% E q Sol

And the so 100 150 200 250 300 concentration uM a Silibinin B 6 10

It's S & . O

E 8 & - 8 4 on Zz is m I E, lh Í E)

E o so 100 150 200 250 300 concentration JM T Isosilibinin A o 100 8 3 8 ô & - 8 4 2 sa Í 3 o sr É oi

And the so 100 150 200 250 300 Concentration uM

FIG. 11 (continued) Isosilybinin B — 100$ = 8 8 o 6

It's 8 2 40 && 8 a o zz o o

And o É 2 And o 50 10 150 20 250 30 - concentration one Silicristin 100 z « É m

It's 8 . and. ' - So E » t o Ó t z Zz sl | o &s < o so 100 150 20 250 300 Concentration pM ; Silidinine gm 2 8 80 o 60 8 " = 4 mo S a F Zz o 8 E $ < s E o 100 200 300 40 500 600 concentration pM o

DD vo net o o vo bx o Ss 3 8 2 FR Po 3 g 83 o fe Sg 8 8 ns DB o . No e É Da s o 8 ss e 2 o Õ 9 E Sã uL 8 8 3 o 2 o = Ex

Is o o dn E O r2H If o E 8 = ? ã o o > > Ss o o o o o o o o T Es Ss (Blonuos ouwco %) AssNn ap oBóIquuI an ABSTRACT Variety Patent: "SILIBININ COMPONENT FOR THE TREATMENT OF HEPATITIS".

The present invention relates to the use of a silybinin component for the production of a medicament which is adapted for parenteral administration for the treatment of viral hepatitis, preferably hepatitis B or C, specifically for the reduction of viral load. The drug preferably does not contain silydianin and/or silicristin and/or isosilybin.