WO2007065314A1

WO2007065314A1 - Compound preparation for treating virus hepatopathy

Info

Publication number: WO2007065314A1
Application number: PCT/CN2006/000007
Authority: WO
Inventors: Hongping Yie; Zuolin Zhu; Meng M. Sun; Qingsheng Zhang; Zuolian Zhu
Original assignee: Pficker Pharmaceuticals, Ltd.
Priority date: 2005-12-08
Filing date: 2006-01-05
Publication date: 2007-06-14
Also published as: CN1895671A; CN1895671B

Abstract

The invention discloses a compound preparation for treating virus hepatopathy comprising the active ingredients as follows: drugs for inhibiting virus duplication and regeneration, drugs for enhancing the immunocompetence of humans, drugs for protecting and renovating liver and drugs for protecting kidney. The compound preparation has high curative effect, high safety and virus resistance, produces no any cross effect, enhances the immunocompetence of patient, as well as has the capacity of preventing infection of B type hepatitis and promoting regeneration of liver cell.

Description

Compound preparation for treating viral liver disease Field of invention:

The present invention relates to the field of pharmaceutical technology, and specifically relates to a compound preparation for treating viral liver disease. Background of the invention - Viral liver disease is one of the potentially fatal chronic diseases, mainly including hepatitis B and hepatitis C. In China, 1 in 10 people is a hepatitis B virus carrier. According to statistics, there are currently about 120 million chronic asymptomatic hepatitis B virus carriers and about 30 million chronic hepatitis B patients in China. 50 to 60% of those infected with hepatitis B virus develop hepatitis, and about one-third of hepatitis patients develop cirrhosis and liver cancer. The results of the Chinese population epidemiological survey show that the infection rate of hepatitis C virus is about 3.0%, that is, about 40 million people are infected with hepatitis C, and the two combined have about 70 million viral hepatitis patients. Safe and effective treatment Specific drugs for viral hepatitis are extremely important.

Although various existing medication methods have certain curative effects, the results are not ideal. For example, interferon has the effect of inhibiting viral reproduction (replication). Since the liver cell damage mechanism of hepatitis C is the result of the direct action of the hepatitis C virus, interferon treatment for hepatitis C is more effective, and the general effective rate is about 50 to 70%. However, interferon can only interfere with the replication of hepatitis B virus, but cannot block the immune damage caused by hepatitis B virus infection. Therefore, the effective rate of applying interferon to HBeAg(+) and HBV DNA(+) patients is only about 30~40%. In addition, the antiviral drug interferon is easily subject to dose-limiting side effects, such as fever, leukopenia and other symptoms (N.EngUMed., 1996, 334, 1422-1427.; N.Engl.J.Med., 1997, 3%, 347-356). Also, short-term (6 months to 1 year) use of the most commonly used reverse transcriptase inhibitor hepatitis B drugs cannot clear CCC DNA (covalently closed circular deoxyribonucleic acid) in cells. J. Virol, 1994, 68, 1059-1065), viruses that relapse after discontinuation of treatment are often mutated viruses that are often drug-resistant and highly lethal. It takes a long time to completely eliminate the virus, such as hepatitis B virus, which generally takes 1 to 5 years. Long-term medication will seriously damage the body's immune system and seriously decline the overall health status (Proc. Natl. Acad. Sci. USA, 1996, 93, 4398-4402), and complications arise. Therefore, the treatment of viral hepatitis needs to focus on two aspects, not only to eliminate the liver virus, but also to keep the patient's various functional systems, such as the immune system, from being too damaged, that is, to prevent the occurrence of complications.

Patients with chronic liver disease generally also experience hypocalcemia, which can cause clinical manifestations of "cramps" at night. (1) Portal hypertension in patients with chronic liver disease can affect kidney function, causing abnormal calcium and phosphorus metabolism, and increasing calcium excretion in urine; (2) Patients with liver disease have poor appetite, resulting in reduced calcium intake; (3) Taking certain drugs, such as Diuretics cause increased calcium excretion. Therefore, patients with liver disease should pay attention to strengthening calcium absorption and appropriate calcium supplementation.

Hepatitis C virus (HCV) is a positive-strand RNA virus. RNA viruses mutate 1 million times faster than DNA viruses, and their body shapes often change. Therefore, it is difficult to develop a vaccine for hepatitis C virus. Hepatitis B Although the genetic signal material of the virus is a double-stranded DNA structure, about one-third of the circular structure of the hepatitis B virus is single stranded. Due to the existence of this single-stranded structure, the hepatitis B virus is also prone to mutation, and the development of a hepatitis B vaccine is It is very likely that the speed cannot keep up with the speed of hepatitis B virus mutation. At present, the international community has not clearly understood the key mechanism of viral liver disease. In addition, the reason why viral liver disease develops into cirrhosis is the continuous necrosis of liver cells. After liver cell necrosis, normal liver tissue "collapses", and the body's regenerative function will regenerate some fibers to fill the "collapsed" parts. This is a normal compensatory function of the body against necrotic tissue. However, if liver cells continue to die and fibers are constantly regenerated in the liver, these fibers replace most of the liver tissue, and they do not have the function of normal liver cells, and the liver will become hard and small, forming liver disease. hardening. Therefore, the key to preventing patients with viral liver disease from developing cirrhosis is to block the necrosis of liver cells. It is necessary to restore normal liver function and at the same time enhance liver regeneration and restore normal liver function. Literature reports (J. Virol. 1994, 68, 5469-5475) pointed out that there are no mature viral core protein capsids (viral nucleocapsids) in Liver cells are rapidly destroyed when they divide. Enhanced liver regeneration in the presence of antiviral drugs means that the speed of clearing liver viruses is accelerated.

Since liver viruses mutate rapidly and cause disorders in the immune system in the body, it may be possible to rebuild effective immunity to liver viruses, thereby suppressing the virus, improving liver inflammation and necrosis, reducing transaminases, maintaining normal liver function, and enhancing liver regeneration. A more fundamental and proven approach to chronic viral liver infection. This can most effectively treat viral liver disease, and can also delay and block the progression of chronic liver disease to cirrhosis and liver cancer, prolong the patient's life, and improve the patient's survival and quality of life.

The most reasonable treatment method for viral hepatitis should be comprehensive care and treatment of patients, including elimination of hepatitis virus; regulating the body's immune function, protecting the integrity of liver cells, promoting the recovery and regeneration of liver cells; and promoting various metabolisms of liver cells. , ensure the normal function of liver cells, promote the decline of transaminases; and treat various complications, etc. Contents of the invention

The technical problem to be solved by the present invention is to research and design new drugs against viral liver diseases that are highly safe and have no drug resistance.

The purpose of the present invention is to provide a new drug for viral liver disease with significant and comprehensive curative effect, without any cross-effect, high safety, strengthening the body and dispelling evil, good tolerance and no drug resistance. To avoid further damage to the liver caused by patients with viral liver disease taking medications in a hurry, provide workers in the medical field with a rational formula of compound medication, and prevent some personnel from using multiple drugs at will to further damage the virus. Liver disease has consequences for the physical health of patients that are difficult to resolve.

In addition, the compound specific drug for viral liver disease of the present invention also shows unexpected curative effects. For example, research results show that the compound preparation of the present invention has the functions of resisting hepatitis B infection and enhancing liver regeneration. The invention provides a compound preparation for treating viral liver disease.

The active ingredients of the compound preparation described in the present invention include the following:

(a) Drugs that inhibit viral replication and regeneration;

(b) Drugs that enhance human immunity;

(c) Drugs that protect and repair the liver and drugs that protect the kidneys.

Active ingredients used to inhibit viral replication and regeneration include glycyrrhizin, glutathione, alpha-lipoic acid, DL-methionine (DL-2-hydroxy-4-methylthiobutanoic acid), Adefovir dipivoxil, entecavir, lamivudine, tenofovir, remofovir (the prodrug of PMEA), and others Drugs used to fight viruses, such as Aciclovir, Ribavirin, and Vidarabine.

Drugs used to enhance human immunity include Echinacea (also translated as Echinacea in Chinese), vitamin E, selenium, vitamin C, coenzyme Q10, and Levamisole.

Drugs used to protect and repair the liver, as well as drugs to protect the kidneys, include Silymarin, L-Carnitine, vascular endothelial growth factor (VEGF), Astragalus Extract, vitamins C, folic acid, glucuronolactone, inosine, glutathione, etc.; as well as necessary calcium and vitamin D to assist calcium absorption.

Glycyrrhizin Glycyrrhizin is the potassium and calcium salt of glycyrrhizic acid. Glycyrrhizin plays a better role in inhibiting the proliferation of viruses. Glycyrrhizin is a much-researched compound. As early as 1921, Karrer and Chao isolated the compound from Glycyrrhiza glabra [Helv. Chim. Acta 4, 100 (1921)], and its structure was determined in 1950 [J . Chem. Soc. 1983, (1950)], revised structure determination results in 1956 [Bio chem. J. 63, 9 (1956)]. The pharmacological effects of glycyrrhizin involve many aspects, including antiviral, immune function regulation, antibacterial, anti-inflammatory, anti-tumor, anti-mutagenic, corticosteroid-like effects, etc. It also protects the liver and prevents and treats cirrhosis. Glycyrrhizin is a broad-spectrum antiviral substance that has been reported in the literature to be effective against HIV, sandfly fever Sicilian virus, epidemic hemorrhagic fever virus, African swine fever virus, refractory human cytomegalovirus, Marburg virus, cowpox, and simplex virus. Herpes, herpes zoster, chicken viral pneumonia, cerebrospinal disease, vesicular stomatitis virus, influenza virus, hepatitis A, B, C and other hepatitis viruses, etc. Glycyrrhizin achieves its antiviral effect by inhibiting the proliferation of the virus, blocking its replication, and directly inactivating the virus. Glycyrrhizin inhibits the proliferation of HIV. Glycyrrhizin at 0.5 mg/ _ml inhibits the proliferation of HIV in vitro by more than 98%, and at 0.125 mg/ml it can inhibit plaque formation by 50%, suggesting that glycyrrhizin does not inhibit the reverse transcriptase activity of HIV, but rather inhibits HIV reverse transcriptase activity. It works by restoring the function of helper T lymphocytes. Glycyrrhizin can inhibit the proliferation of herpes zoster virus in vitro (ID50=0.71mmol/L), and can directly inactivate the virus. Glycyrrhizin not only inhibits hormone metabolism in the liver, but may also affect local aldosterone (aldosterone) production in the kidneys, membranes, etc. Ketones are hormones secreted by the adrenal glands that promote Na+ absorption and K+ secretion. Aldosterone deficiency causes low blood K+, and excess causes high blood K ⁺ . Hypokalemia stimulates uric acidification, while hyperkalemia weakens uric acidification. ) has a reinforcing effect. Glycyrrhizin is also effective against chronic hepatitis B [Antiviral Res. 1996 May, 30(2-3), 171-7 and J Hepatol. 1994 Oct, 21(4), 601-9.], and its mechanism is related to enhancing NK related to cellular functions. The immune effect of glycyrrhizin is manifested in that it can non-specifically enhance the phagocytic activity of Μ _Φ and eliminate the inhibitory activity of inhibitory Μ _Φ . Glycyrrhizin can inhibit the production of prostaglandin PGE ₂ by activated rat abdominal M _Φ and inhibit the release of arachidonic acid. The inhibition of _PGE2 by glycyrrhizin is due to the inhibition of the activity of phospholipase _A2 , the rate-limiting enzyme for PG synthesis. In vitro treatment of mouse abdominal cavity _{M with} glycyrrhizin can increase interferon production. Glycyrrhizin can induce ΜΦ cells ( _ΜΦ strain established from mouse skeletal leukemia cells) to produce interleukin-1 (IL-1), and has a synergistic effect with γ-interferon (IFN-γ), and can also increase lipopolysaccharide (LPS)-stimulated _MΦ tumors produce IL-1. After intravenous injection of 20 g/kg glycyrrhizin into mice twice, it was found that the IFN production capacity of splenocytes was enhanced. Mice were intraperitoneally injected with 330rag/kg glycyrrhizin, and IFN activity reached its peak 20 hours later. In vitro experiments show that glycyrrhizin itself has no ability to induce IFN, but pretreating human peripheral blood lymphocytes with glycyrrhizin for 12 hours increases the ability of concanavalin A (ConA) to induce IFN, but it cannot enhance PHA-induced human spleen lymphocytes. Cells produce IFN. Glycyrrhizin can enhance the ability of ConA to induce lymphocytes to secrete IL-2. The mechanism by which glycyrrhizin enhances IFN-γ production is believed to be by inhibiting the activity of phospholipase _A2 , the rate-limiting enzyme for PG synthesis, and inducing IL-1 production, thereby promoting IFN-γ and IL - 2 generation. Intraperitoneal injection of 0.5 mg/kg glycyrrhizin into mice can enhance NK activity in the liver, but does not increase the number of NK cells. Injecting glycyrrhizin into patients with chronic hepatitis B can also enhance their NK activity. In vitro experiments show that glycyrrhizin itself has no effect on enhancing NK activity, but can promote IFN-γ and IL-2 to enhance NK activity. Clinical trial research results show that the therapeutic effect of glycyrrhizin and lamivudine is better than that of lamivudine alone [Leuk Lymphoma. 2001, 41(1-2), 191-5 and Hepatol Res. 2001, 20( 1), 1-8], and unlike the use of other synthetic drugs, the use of glycyrrhizin does not have any toxic side effects [Clin Ther. 1989, 11(1), 161-9]. Glutathione Glutathione (L-glutathione-L-cysteine-glycine) exists in all animal cells. Under normal circumstances, it exists in its thiol-reduced form (GSH). It is intracellular Major non-protein thiol compound. It plays a direct or indirect role in many life activities, including gene expression regulation, enzyme activity and metabolism regulation, cell protection, amino acid transport, immune function regulation, etc. Oxidative stress or attack by electrophilic compounds can reduce intracellular GSH content or convert it into disulfide-oxidized form (GSSG), which can be converted into GSH by glutathione reductase using NADPH as a coenzyme. Glutathione is mainly used as a detoxification and antioxidant drug in clinical practice, to prevent and treat chemotherapy and drug-induced liver damage in cancer patients, to treat chronic fatty liver, to assist in the treatment of viral hepatitis and hepatitis cirrhosis, and in combination with sodium fructose diphosphate to assist in the treatment of chronic severe disease. hepatitis. Jiang Lanying et al. [Jiang Lanying, Ye Jianhong, Lou Guoqiang, et al. The efficacy of glutathione in the adjuvant treatment of viral hepatitis, Chinese Journal of New Drugs and Clinical Medicine, 1998, 17(4), 230] on patients with viral hepatitis infected with type B or B and E On the basis of comprehensive treatment, 0.6~1.2g/day GSH intravenous infusion is added for 30~60 days, and combined with comparison with the control group. Results The effective rates in the glutathione treatment group and the control group were 62% and 43% respectively, and the total effective rates were 80% and 55% respectively. The therapeutic effect of the glutathione group was significantly better than that of the control group (P<0.05), and there were no toxic or side effects. Cai Weiping [Cai Weiping, Yan Lutan, Glutathione in the treatment of drug-induced acute renal injury, Chinese Journal of New Drugs and Clinical Medicine, 2000, 291] applied glutathione to treat various drug-induced acute renal failure, and used traditional drug combinations Amino acids and Jinshuibao gelatin were used as controls. The results showed that the total effective rates for acute renal failure in the glutathione group and the control group were 92% and 64% respectively (P<0.05). The total effective rates for hematuria and proteinuria were 89% respectively. % and 85%, 57% and 50% (P<0.01 and P<0.05), showing that glutathione contributes to the recovery of renal function, and the recovery time of renal function can also be shortened, for hematuria and proteinuria without renal damage. It also has obvious curative effects and has few and mild adverse reactions during the medication process.

Lipoic Acid Lipoic acid is a natural antioxidant found in the human body and produced by the mitochondria of cells. It can simultaneously increase the concentrations of water-soluble vitamin C and fat-soluble vitamin E inside and outside cells, and regenerate vitamin C and vitamin E through the redox properties of lipoic acid. Lipoic acid can be a "stand-in" when other antioxidants are in short supply. That is, if there is a lack of vitamin E or C in the body, lipoic acid will temporarily take over their work. The antioxidant effect of lipoic acid is better than that of vitamins A, C, and E, and it can eliminate free radicals that accelerate aging and cause disease. It may be the most powerful natural antioxidant currently known to mankind. Lipoic acid can treat liver necrosis and hepatitis B and hepatitis C [p _0S it. Health News. 1998, (No 17), 19-21]. American doctors once treated three patients with liver necrosis caused by eating poisonous mushrooms with lipoic acid. As a result, the conditions of the three patients were controlled within a short period of time, and their liver functions returned to normal [Vet. Hum. Toxicol. 1986, 28(4), 318-22, Ann Neurol. 1978, 3(2), 177-9] . Lipoic acid can bind and decompose intrahepatic toxins, reduce hepatitis symptoms, and restore liver function. The antioxidant defense system of patients with AIDS (HIV) and viral hepatitis is usually weak. Due to the lack of antioxidants, they are unable to prevent the virus from multiplying when oxidants stimulate the virus. Lipoic acid can stimulate the concentration of vitamin C, total glutathione [Posit. Health News. 1998, (No 17), 14-5], and total sulfide in the patient's blood, improve the ratio of T4/T8 lymphocytes, thereby reducing free Basic damage to patients [J. Appl. Toxicol. 2004, 24(1), 21-6.].

DL-methionine DL-methionine is an essential amino acid for the human body. It has a strong detoxification effect and can inhibit the replication and regeneration of viruses. The methyl group in its molecule interacts with hormones in the body to produce bile. Bile then reacts with fatty acids, glycerol, and phosphoric acid to become phospholipids, which are then absorbed by the body to strengthen liver function. If lacking, it will cause liver and kidney disorders. Especially necessary to protect liver function.

Others: Adefovir dipivoxil, entecavir, lamivudine, tenofovir, and remofovir mesylate are all small molecule chemical drugs synthesized by humans for anti-hepatovirus.

In the past two to thirty years, numerous clinical trials of Iconicia have proven from the perspective of modern medicine that Iconicia has good therapeutic effects and drug safety, including its therapeutic effect on congenital immune system deficiency diseases [ Pol. J. Vet. Sci. 2003, 6(3 Suppl), 3-5. and Z. Phytother. 1989, 10, 67-70. and Phytomed. 1996, 3, 95-102]. The application of Iconicia in modern medicine mainly focuses on Because of its strengthening effect on the immune system, it is mainly used to treat viral infections [Exp Biol Med (Maywood). 2003, 228(9), 1051-6], bacterial infections, protozoal diseases, and fungal infections. (Alternative Medicine Review, 2001, 6, 411-414), six clinical trials and in vitro experiments have proven that Iconicia juice can stimulate the production of leukocytes and increase the phagocytic activity of leukocytes [Arzneimittelforschung. 1985, 35(9 ), 1437-9·and J. Altern. Complement Med. 1995, 1, 145-160]. In clinical trials involving more than 3,900 people, Iconicia juice has been proven to be effective in reducing the incidence of colds and flu and relieving symptoms in patients (Nutrition Science News, September 1999 and March 1999, etc. ). In addition, it was found that Iconicia juice can effectively inhibit the division of viruses and control the derivative replication of viruses (Planta Med. 1978, 89-102). Iconicia stimulates non-specific defense mechanisms that attack virus-infected cells. There are also some clinical trials showing that Iconicia can prolong the survival of patients with hepatocellular carcinoma [Arch Geschwulstforsch. 1990, 60(5 people 379-83).

Vitamin E Vitamin E has a significant impact on the reproduction and development of animals. If it is deficient, the reproductive function of the animal will be damaged, but supplementing it can restore its reproductive function. Vitamin E can promote the absorption, utilization and liver storage of vitamin A. Because of the structural characteristics and distribution characteristics of vitamin E in the human body, it has a series of functions such as anti-free radicals, anti-aging, protecting the liver and liver cell regeneration, enhancing immunity, and protecting cardiovascular and skin. Free radicals are active groups that widely exist in various chemical reactions and play an important role in the normal physiological metabolism of the human body. If there are excessive free radicals and cause a free radical chain reaction, it will lead to the lipid metabolism of unsaturated fatty acids in the cell membrane. Oxidation, the newly generated large amounts of lipid peroxides will damage cell membranes and macromolecular proteins and nucleic acids in cells, causing damage to the body. When free radicals enter the lipid phase and a chain reaction occurs, vitamin E acts to capture the free radicals. Vitamin E is highly effective against free radical lipid peroxidation. In research, it was found that the lack of vitamin E has an impact on the immune function of humans or animals. It not only reduces physical immunity, but also has a great impact on cellular immunity. Research in the 1980s demonstrated that vitamin E is one of the important protective factors for liver cell growth. Studies have found that one of the final pathways of liver cell death is the depletion of vitamin E in liver cells [Free Radic Res. 1996, 25(6), 461-6] Vitamin E has a protective effect on a variety of acute liver injuries [Cancer Res. 2003, 63(20), 6707-15], has good efficacy against hepatitis B [Antiviral Res. 2001, 49(2), 75-81 and Ann Intern Med. 1998, 128(2), 156-7], and Significantly enhances the immunity of hepatitis B patients [Lik Sprava. 1992, (4), 90-1 and JAMA. 1997, 277(17), 1380-6], has a therapeutic effect on steatohepatitis without toxic side effects [Aliment Pharmacol Ther. 2001, 15(10), 1667-72], has a delaying effect on chronic liver fibrosis. Clinical trial results also found that the combined use of interferon and vitamin E is more effective in treating acute hepatitis B than the use of interferon alone [Pediatriia. 1992, 60-4].

Selenium Selenium is a substance that has a significant impact on human health that has only been discovered by humans in the past twenty years. Animal experiments have found that adding selenium to drinking water can enhance the activity of natural killer cells in mice, and in vitro experiments have confirmed that it can cause tumor cell apoptosis [Ann Acad Med Singapore. 1984, 13(2), 194-205]. Selenium can not only improve human immunity and prevent cancer [Biol Trace Elem Res. 1988, 15, 231-41 and Cancer Res. 2003, 63(20), 6707-15], but also maintain the youthful vitality of human body tissues. , reduce the pain of burns, inflammation, and burns, and reduce the pain of menopause. According to a report by CNN 98/8/22, Selenium (Selenium), which has been found by the medical community to have anti-cancer and antioxidant properties, can reduce the occurrence of prostate cancer in men by 1/2 to 2/3. More than 40,000 men in the United States die from prostate cancer every year, making it the number one killer of men. This was discovered in a study conducted by the Natioanl Cancer Institute comparing American men on high-selenium versus low-selenium diets. Men need more selenium, and selenium is excreted from the body in semen, causing consumption. If the human body lacks selenium, male sexual ability will disappear early. Selenium plays an extremely important role in the human liver. Follow-up blood tests of hepatitis B patients have found that hepatitis B patients and patients who have converted from hepatitis B to liver cancer have very low levels of selenium and vitamin E in their blood [J Trace Elem Med Biol. 2002, 16 (4), 227-30 and Am J Epidemiol. 1999, 150(4), 367-74]; In 1982, humans confirmed through in vitro experiments that selenium can stimulate the growth and development of liver cells [Cancer Res. 1982, 42(9) , 3858-63]; A three-year clinical trial involving 20,847 people confirmed that selenium can prevent the occurrence of hepatitis B [Biol Trace Elem Res. 1989, 20(1-2), 15-22] and prevent intestinal tumors [China Prevention Medical Journal Zhonghua Yu Fang Yi Xue Za Zhi. 1992, 26(2), 105-7] and reduce the incidence of liver cancer [Biol Trace Elem Res. 1991, 29(3), 289-94 and Chinese Journal of Preventive Medicine, 1992 , 26(5), 268-71]; Further animal comparative experiments (four years) showed that selenium supplementation can reduce the prevalence of hepatitis B by 77.2% and precancerous lesions by 75.8%. A concurrent eight-year prevention experiment using selenium-added salt, including more than 130,000 people, showed that the prevalence of hepatitis B dropped by 35.1%, and none of the hepatitis B patients who used selenium developed liver cancer. Hepatitis B patients who used a placebo For patients, the probability of transforming into liver cancer is about 6% [Biol Trace Elem Res. 1997, 56(1), 117-24]. The protective effect of selenium on human liver has recently been further proved by genomic research results [Biol Trace Elem Res. 1997, 56(1), 63-91 and Nutr Cancer. 2000, 38(2), 179-85] In view of the importance of selenium in the prevention and treatment of hepatitis B, some new selenium-containing compounds have been synthesized and verified to be effective in the prevention and treatment of hepatitis B [J Med Chem. 2000, 43(21), 3906-12], so they are effective in the prevention and treatment of hepatitis B. Selenium supplementation for patients is an important treatment [Exp Mol Pathol. 2004, 77(2), 121-32]. Modern medical research results are also constantly proving the compound theory of traditional Chinese medicine. For example, clinical trials have found that vitamin E and selenium are two synergistic substances. They are more effective when taken together, but less effective when taken separately [Cancer Res. 2003, 63(20) ), 6707-15].

Vitamin C Vitamin C is an essential vitamin for the human body. It is generally believed to play an important role in the redox function of cellular respiration. Vitamin C is required for the formation and maintenance of intercellular matrix and collagen, the synthesis of steroids, the conversion of folic acid and the metabolism of tyrosine. Vitamin C is an antioxidant necessary for tissue growth and repair of healthy gums. It has many functions such as promoting blood circulation, eliminating fatigue, improving white blood cell function, enhancing immunity, preventing scurvy, fractures, etc., and can lower cholesterol and high blood pressure, Prevents arteriosclerosis, protects the liver and detoxifies liver poisoning. Animal test results show that vitamin C and When silymarin is used together, the detoxification effect on the liver of rats with lead poisoning is faster and more complete than when silymarin is used alone [Toxicology. 2005, 206(1), 1-15]. Many research results show that the protective effect of vitamin C on the liver and the prevention and treatment of liver disease are achieved through the antioxidant capacity of vitamin C itself [Free Radic Biol Med. 2003, 34(1), 1-10]. Generally speaking, problems with liver function often increase the burden on the kidneys. Hepatitis B patients with nephropathy have lower vitamin C concentrations in their bodies than normal people, and their kidneys clear out vitamin C faster. This is It may be that kidney disease makes vitamin C easily lost from the kidneys, so the concentration in the body decreases. Researchers boldly theorize that a lack of protection from this antioxidant vitamin is the main reason why patients with nephropathy and kidney disease have an increased chance of heart disease. Also, patients with hepatitis B have lower blood vitamin C concentrations than normal people [Liver Int. 2005, 25(3), 518-26 and Drug Alcohol Depend. 1981, 8(3), 245-55], so In the compound preparation, we recommend that hepatitis B patients take more vitamin C to supplement the accelerated loss of their kidneys and effectively prevent and treat possible renal lesions in hepatitis B patients. Research results at the molecular level of vitamin C's therapeutic effect on hepatitis show that it completely restores the activity of important metabolic enzymes in the liver. Hepatocytes produce excess nitric oxide (NO) after inflammation, and NO severely inhibits important metabolic enzymes in the liver, such as The activities of monooxygenases and cytochrome P450s can be completely restored with vitamin C [Life Sci. 2004, 75(21), 2559-72].

Coenzyme Q10 The human liver uses protein tyrosine (Tyrosine) and phenylalanine (Phenylalanine) as well as vitamins E, Bl, B6 and folic acid to synthesize Coenzyme Q10 to meet its own needs. Peter D. Mitchell, Ph.D., from the University of Edinburgh, Scotland, discovered that coenzyme Q10 is necessary for human cells to produce energy, and won the 1978 Nobel Prize in Chemistry. Coenzyme Q10 is mainly found in the human heart, liver, kidneys, and pancreas. Its important functions include regulating cell growth and development and cell self-maintenance, as well as antioxidant effects. This antioxidant effect of Coenzyme Q10 can protect important organs such as the heart, liver, kidneys, and pancreas by reducing free radical damage to cells in these organs. Free radical damage to cells within these organs includes damaging effects on DNA. Therefore, if there is sufficient CoQ10 in the human body, especially for patients with hepatitis B disease, their immune function will be improved and viruses in the body will be eliminated. It has a preventive effect on some terrible diseases such as hepatitis B, cancer, chronic infections, candidiasis, AIDS, etc. Coenzyme Q10 can protect the liver from damage by some chemicals such as carbon tetrachloride [Gastroenterol Jpn. 1981, 16(3), 281-5], and there are also results showing that the protective effect of co-administration of L-carnitine and Coenzyme Q10 is stronger than Any single substance [Drugs Exp Clin Res. 1993, 19(2), 65-8]. In a clinical trial, people who took Coenzyme Q10 developed antibodies just thirty days after being vaccinated, while those who took a placebo had no detectable antibodies at this time [Biofactors. 1999, 9(2-4), 351-7], the most popular statins on the market in recent years have a considerable damaging effect on the liver, especially those with liver problems. However, the use of coenzyme Q10 can reduce the damage to the liver to Undetectable levels [Clin Pharmacol Ther. 2002, 72(4), 461-4] ₀

Levamisole Levamisole is a synthetic compound used to treat hepatitis B. clinical trial research It was found that the combined use of levamisole and lamivudine was more effective in patients with chronic hepatitis B than the use of lamivudine or levamisole alone. Levamisole can enhance the body's immunity, but this drug cannot be used continuously, otherwise it will cause bone marrow suppression.

Silymarin Silymarin is the main active ingredient of Milk Thistle (Chinese name: Milk Thistle) extracted from the seeds of the pheasant. As early as more than 2,000 years ago, Europeans discovered that rhizome has the function of protecting and strengthening the liver, and it is very popular among the people. In 1949, the first clinical trial in Germany confirmed that Rujing has a hepatoprotective effect on patients exposed to carbon tetrachloride and has the ability to treat hepatitis. Earlier this year, South Korean scientists discovered through animal experiments that silymarin's preventive effect on liver fibrosis is achieved by inhibiting inflammation and hypoxia in the fibrosis process [World J Gastroenterol. 2005, 1141-8]. In 1968, its main active ingredient, silymarin, was extracted from the seeds in Germany. After nearly thirty years of test tube experiments, animal experiments, clinical trials and research, it has been relatively comprehensively confirmed that silymarin does have liver protection, liver strengthening and detoxification functions. For example, a clinical trial by Italian scientists in 2002 found that silymarin can enhance the therapeutic effect of ursodeoxycholic acid on liver disease [Clin Ter. 2002, 153(5), 305-7]. Another example is the trial on acute hepatitis (Acute Viral Hepatitis): 42 out of 77 people used placebo, and 35 people used silymarin. The average recovery period for the control group was 43 days, while the recovery period for patients taking silymarin was only 29 days [Drugs. 2001, 61(14), 2035-63. and references cited therein]. So far, Milk Thistle has been proven to have the following important functions: preventing damage to liver function caused by alcohol, drugs, chemicals (such as carbon tetrachloride, etc.), pesticides, air pollution and radioactivity [Toxicology. 2005, 206(1), 1-15; Toxicol Sci. 2004, 80(2), 335-42]; Treat and prevent cirrhosis, promote liver cell regeneration; Prevent and treat various hepatitis including hepatitis B [Nephrol Dial Transplant. 1989 , 4(4), 297-301], reduce the index of liver enzymes; promote the circulation of bile, thereby preventing gallstones; treat and prevent wild mushroom poisoning; other functions such as anti-inflammation, lowering cholesterol, lowering blood pressure, blood sugar, etc. There are also some effects.

Folic acid Folic acid occurs naturally in the liver and kidneys of animals. Folic acid is a water-soluble B vitamin composed of pteridine, para-aminobenzoic acid and glutamic acid residues. It is a necessary substance for the growth and reproduction of body cells. It is a water-soluble vitamin that assists in the development and maturation of red blood cells. Folic acid preparations are often used together with liver preparations to treat pernicious anemia. It is an indispensable substance for the production of red blood cells.

L-carnitine L-carnitine, also called L-carnitine, is an essential coenzyme in the process of fat metabolism. It can promote fatty acids to enter the mitochondria for oxidation and decomposition. Blood tests of children with liver disease found that their L-carnitine levels were significantly lower than those of healthy people [Minerva Pediatr. 1989, 41(5), 247-51]. The liver is the main organ that metabolizes, uses and transports L-carnitine throughout the body. Liver disease affects the production and use of L-carnitine, causing systemic damage. Liver disease patients with primary biliary cirrhosis excrete a significant amount of L-carnitine in their urine. increased [Hepatology. 1997, 25(1), 148-53], so it is very important to supplement L-carnitine for patients with liver disease [Life Sci. 1996, 59(19), 1579-99 and Ann Pharmacother. 2000, 34(5) , 630-8]. In addition to its protective effect on the liver, L-carnitine can also increase the body's immunity [Treatmentupdate. 1998, 10(5), 4-6], the latest research results show that the preventive effect of L-carnitine on liver cancer is achieved by inhibiting abnormal mitochondrial function and the effect is very good [Int J Cancer. 2005, 113(5), 719-29].

Practical formulas in the present invention include all the above active ingredients. Each single formula may contain only one of each active ingredient, or several may be used at the same time. The selection of the active ingredients in the present invention is also based on the absence of any cross-toxic and side effects between them. All of the active ingredients used in the present invention have not been reported to have any cross-toxic or side effects.

In the unit dosage form of the invention:

The content of glycyrrhizinate is 500 mg ~ 1500 mg, and the most suitable dose is 1000 mg; the content of glutathione is 50 mg ~ 1500 mg;

The content of DL-methionine is 1.0 mg ~ 800 mg;

The content of adefovir dipivoxil is 10 mg;

The content of entecavir is 0. 25-0. 5 mg;

Lamivudine is present in 100 mg;

The content of tenofovir is 100-400 mg;

The content of remofuvir mesylate is 400-600 mg;

Iconicia raw grass or extract concentrate, the dosage is 5-10 mg converted into phenolic resin; the content of vitamin E is 50 international units ~ 3000 international units, the common dosage is 100 international units ~ 1200 international units, the most suitable dosage From 150 IU to 600 IU;

The content of selenium is 1.0 micrograms ~ 1000 micrograms, the common dosage is 10 micrograms ~ 400 micrograms, and the most suitable dosage is 50 micrograms ~ 300 micrograms;

Levamisole content is 50 mg;

The content of silymarin is 1 mg ~ 800 mg, the common dose is 50 mg ~ 600 mg, and the most suitable dose is 200 mg ~ 500 mg;

The content of folic acid is 50 micrograms ~ 2000 micrograms, the common dosage is 100 micrograms ~ 1000 micrograms, and the most suitable dosage is 200 micrograms ~ 900 micrograms;

The content of L-carnitine is 100 mg ~ 1000 mg, the common dose is 50 mg ~ 800 mg, and the most suitable dose is 200 mg ~ 500 mg;

The content of the astragalus extract is 1500 mg ~ 3000 mg; (the astragalus extract used in the present invention is brown powder and is a standardized product containing 70% of astragalus polysaccharide).

The content of vitamin C is 10 mg ~ 2000 mg, the common dose is 50 mg ~ 800 mg, and the most suitable dose is 100 mg ~ 700 mg;

The content of glucuronolactone is 50 mg ~ 200 mg;

The content of inosine is 200 mg ~ 1500 mg; The content of lipoic acid is 1. 0 mg ~ 3000 mg, the common dosage is 5. 0 mg ~ 1200 mg, and the most suitable dosage is 40 mg ~ 700 mg; in other words, the effective dosage of lipoic acid should reach 2. 0 mg/kg Body weight to 200 mg/kg body weight, preferably 8. 0 mg/kg body weight to 70 mg/kg body weight;

Calcium content is 400 mg ~ 600 mg;

Vitamin D content is 400 international units;

The content of coenzyme Q10 ranges from 1.0 mg to 1000 mg, the common dosage is 5.0 mg~800 mg, and the most suitable dosage is 40 mg to 600 mg.

In addition to the above-mentioned active ingredients, the present invention also contains pharmaceutically acceptable carriers.

Essentially all excipients currently used in multivitamins can be used as excipients in the present invention. Such as the following excipients: (Corn starch) corn starch as filler and disintegrant; (Cellulose gel and pregelatinized starch) cellulose gum and pregelatinized starch as plasticizer and binder; (Gelatin) gelatin As emulsifier, binder and disintegrant; (Glycerin) glycerin as flavoring agent; (Hydroxypropyl cellulose) hydroxypropyl cellulose as water-dispersible material; (Magnesium/Zinc stearate, talc, silica) magnesium stearate or Zinc, talc, silica powder, etc. are used as lubricants; microcrystalline cellulose (microcellulose) is used as a binder and disintegrant; (Croscarmellose sodium) croscarmellose sodium is used as a binder and disintegrant; (Lactose ) Lactose as filler and binder; (Acacia) Gum Arabic as emulsifier and binder; (Stearic acid) Stearic acid as emulsifier and binder; (Hydroxypropyl methylcellulose) Methylated hydroxypropylcellulose as Binder and disintegrant; (Sugar) sucrose as flavoring agent; (Polyethylene glycol) polyethylene glycol as filler, emulsifier, and disintegrant; (Modified food starch) modified edible starch as filler and disintegrant Antidote; and (Soybean oil) soybean oil and (Lecithin) lecithin as fat-soluble auxiliary substances; and (Titanium dioxide) titanium dioxide as colorants, etc.

The compound preparations in the present invention can be tablets, pills, capsules, coated tablets, aerosols, and liquid preparations. The liquid preparation can be a wine solution or an aqueous solution, or a suspension, latex, etc. In the case of liquid preparations, all active ingredients will be used in their corresponding salt form wherever possible. For solid preparations, all active ingredients can be in the same molding agent, or different active ingredients can be in their own molding agents.

The administration mode of the compound preparation of the present invention is: tablets, pills, capsules, coated tablets and other preparations are taken orally once a day. The dosage for treating specific diseases depends on a variety of factors, including weight, age, gender, necessity. Medical symptoms, disease severity, route of administration, etc.

The preparation method of the compound preparation of the present invention is: the production of solid preparation dosage forms in the present invention can adopt various existing production technologies. If all the active ingredients are in the same molding agent, generally the matching active ingredients and one or two excipients are mixed into a mixture using a wet production process or a dry production process, and then other active ingredients and excipients are added. Mix the ingredients evenly. The mixing process can be granulating, Slugging, blending, etc. The mixed mixture is compressed or pelletized into tablets or pills.

When vegetable oil is used as a lipid or fat-soluble auxiliary substance, such as palm oil, coconut oil, palm fruit oil, soybean oil, safflower oil, Canola oil, grape seed oil, cottonseed oil, etc., usually For use in soft capsule formulations.

The soft capsules in the present invention are produced using various existing production technologies. Generally, the matching active ingredients, lipids or fat-soluble auxiliary substances, and one or more excipients are mixed into a mixture first, and then other active ingredients and excipients are added and mixed evenly, and the mixed mixture is made into a soft capsule. .

The compound preparation of the present invention not only has better antiviral ability than the existing viral liver disease drugs on the market, but also can enhance the effectiveness of the drug in patients compared with the use of each single antiviral drug alone. immunity and prevent various chronic complications. In addition, the compound preparation in the present invention also has the functions of preventing hepatitis B infection and enhancing liver cell regeneration. Picture description:

Figure 1 is a graph of the secretion amount of HBsAg measured in the anti-infection cell test of the compound preparation for the treatment of hepatitis B; the abscissa represents the formula serial number, and the ordinate represents the secretion amount of HBsAg;

Figure 2 is a graph showing changes in the levels of viral DNA in duck serum;

In Figure 2, the abscissa represents the number of monitoring days, and the ordinate represents the DHBV DNA value; R represents the use of formula 1, ■ represents the use of formula 9, Y represents the use of adefovir dipivoxil, and X represents the use of adefovir dipivoxil.

Figure 3 shows the changes in CCC DNA in the liver before and after treatment.

Before oral treatment

■After treatment

In Figure 3, the left side of the abscissa represents the data before treatment, and the relative value is 100%; the right side of the abscissa represents the data after treatment; the ordinate represents the relative value of CCC DNA. Detailed ways

Example 1 Formula of compound preparation

The compound preparation in the present invention can be a combination of all the above-mentioned various active ingredients. The formulas given below are only to better illustrate the present invention, and do not mean that the compound preparation in the present invention only includes the following combinations of active ingredients.

Table 1: Formulas of compound preparations for treating viral liver disease

The samples in the table below are of various formulations. These sample formulations are available in both tablets and softgel capsules.

Unless otherwise stated, the units in the table are milligrams; IU is a measure of vitamin D and vitamin E. units, SI units.

Preparation methods of examples of the present invention:

① The general production method of solid dosage forms is as follows-

1. Mix the active ingredients and excipients of the formula together;

2. The homogeneous material obtained in step 1 is further compressed into small particles;

3. Mix lubricant such as magnesium stearate with the small particles obtained in step 2 above for a few minutes;

4. The mixture in step 3 is pressed into tablets or other solid dosage forms;

5. If necessary, spray the coating liquid into mist droplets to cover the tablets obtained in step 4.

② If soft capsule preparation is used, directly mold the homogeneous material obtained in step 1 into soft capsules.

Formula 1 Formula 2 Formula 3 Formula 4 Formula 5 Formula 6 Formula 7 Formula 8 Formula 9 Formula 10 (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) Licorice sweetener Acid 1000 1000 1000 1000 1000 0 1000 0 1000 0 Vitamin C 500 500 500 500 500 500 500 500 500 500 Vitamin D 400I.U. 400I.U. 400I.U. 400I.U. 400 I.U. 400I.U. 400I .U. 400I.U. 400I.U. 400 I.U Vitamin E 500I.U. 500I.U. 500I.U. 500I.U. 500I.U. 500I.U. 500I.U. 500I.U. 500I.U . 500 I.U Glutathione 1000 1000 1000 1000 1000 】0 1000 1000 1000

DL-methionine 600 600 600 600 600 0 0 600 0 0 Adefovir dipivoxil 10 0 0 0 0 10 10 10 0 0 Entecavir 0 0.5 0 0 0 0 0 0 0 0 Lamivudine 0 0 100 0 0 0 0 0 0 0 Tenofovir0 0 0 350 0 0 0 0 0 0

0 0 0 0 600 0 0 0 0 0

800 800 800 800 800 800 800 800 800 800 Folic acid

(microgram) (microgram) (microgram) (microgram) (microgram) (microgram) (microgram) (microgram) (microgram) (microgram) Calcium 500 500 500 500 500 500 500 500 500 500 Silymarin 500 500 500 500 500 500 500 500 500 500

L-Carnitine 500 500 500 500 500 500 500 500 0 0 Astragalus Extract 2000 2000 2000 2000 2000 0 0 0 0 2000

400 400 400 400 400 400 400 400 400 400 Selenium

(microgram) (microgram) (microgram) (microgram) (if.5¾) (microgram) (microgram) (microgram) (microgram)

200 200 200 200 200 200 200 200 0 0 Inosine 1000 1000 1000 1000 1000 1000 1000 1000 0 0 Lipoic acid 1200 1200 1200 1200 1200 1200 1200 120 0 1200 1200 Coenzyme Q10 200 200 200 200 200 200 200 200 200 200 Example 2 Prevent Function of hepatitis B infection - in vitro cell assay

The function of the compound preparation in the present invention to prevent hepatitis B infection is tested with primary human liver cells. The cells are simultaneously infected with 50 times the genetic equivalent of hepatitis B virus (HBV) under the conditions of with and without the compound preparation.

1 hour. The test was performed by adding 3.5 Χ 10- ^δ Μ hydrocortisone succinate (hydrocortisone succinate). hemisuccinate), 2% DMSO, 5% adult serum, and 5% fetal calf serum in H medium. After the infection is completed, wash away all the compound preparations with the medium used, and then change the medium every two days, and use a quantitative ELISA instrument to measure the amount of HBsAg secreted by the cells on the twelfth day after infection. Each formulation has a control sample without the compound and eight replicate samples, and the amount of HBsAg is the average of the eight samples. The dosage of the compound preparation is based on the lipoic acid in the formula (the dosage of lipoic acid in the medication is

Table 2: Hepatitis B surface antigen (HbsAg) secretion measured in the anti-infectious cell test of hepatitis B compound preparations

The test results show that the compound preparation of the present invention has a very good function of preventing hepatitis B infection, and none of the single active ingredients used has been reported to have this effect. Example 3 Animal test of compound preparation for treating hepatitis B - inhibitory effect on hepatitis B virus

The ducklings used in the experiment were kept under normal lighting conditions and fed standard food. Three-day-old ducklings (Pekin Ducklings) were infected with ^1.5 369-376). Three days after infection, treatment with compound formulations 1, 9, and adefovir dipivoxil in Table 1 was started. Three ducklings in each group included the control group. Monitor the changes in the level of viral DNA in the serum of ducklings. The bDNA (branched chain DNA assay) method is used for measurement. The average value of DHBV DNA (pg/ml) of the three ducks is listed in Table 3. The test dosage is ten times the human dosage (mg/Kg body weight), and the drug is administered for four weeks, and the occurrence of hepatitis B viremia (Viremia) is monitored. Table 3. Changes in viral DNA levels in duck serum (pg/ml, units are thousands)

4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Recipe 1 0.8 0.7 0.9 1.1 0.9 0.8 0.9 0.8 0.8 0.8 0.9 0.8 0.8 0.9 8 12 7 5 8 Formula 9 1.1 3 12 16 6 3 2 1.8 1.3 0.9 1.2 1.1 1.8 1.6 1.8 2 1.5 2 1.4 Adefovir dipivoxil 0.8 0.9 0.8 1.2 1.1 0.9 0.9 0.9 0.9 0.8 0.8 0.9 0.8 0.9 9.2 14 9 7 7 Control group 1.2 36 79 8 4 6 2 2 4 3 5 1.6 1.2 2 3 6 3 3 5 The results show that the inhibitory effect of adefovir dipivoxil on hepatitis B virus in compound preparation formula 1 is not affected by other compound ingredients. The results are the same as adefovir dipivoxil; neither adefovir dipivoxil nor compound preparation formula 1 can The hepatitis B virus is completely eliminated within four weeks (after stopping the drug, hepatitis B virus reappears in large quantities for 32-34 days). Formulas without synthetic hepatitis B virus inhibitors, such as formula 9, also have good ability to inhibit and clear hepatitis B virus (indicated by the squares in Figure 2). Example 4 Animal test of compound preparation for treating hepatitis B - increasing hepatocyte turnover (hepatocyte turnover)

The ducks used in the experiment were 3 to 4-month-old ducks that were congenitally infected with hepatitis B. They were kept under normal lighting conditions and fed standard food. Compound formulation 1 and adefovir dipivoxil were used for treatment for five weeks respectively, and liver biopsies were performed before and after treatment (Lab. Anim. Sci. 1991, 41, 474-475). Liver tissue samples (0. 07-0. 1 g) were homogenized in 0. 01M Tris-HCl (pH=7. 5) -0. 01M EDTA medium (J. Virol. 1992, 66, 1377-1388 ), using bDNA quantitative analysis method to determine the number of CCC DNA (covalently closed circular DNA) in 1.0 X 10 ⁶ liver cells. The measurement value was taken as 100% before medication. There were three groups of ducks, with six ducks in each group including the control group. The normalized measurements (average of six animals) are listed in Table 4. The test dosage is 10 times the human dosage (mg/Kg body weight). Table 4: Changes in CCC DNA in the liver before and after treatment

This result shows that the compound preparation in the present invention can increase the renewal rate of liver cells, that is, the new compound preparation has the ability to improve liver cell regeneration, while synthetic small molecule anti-hepatitis B drugs, such as adefovir dipivoxil, etc., do not. The ability to enhance liver cell regeneration has been reported, and this trial once again demonstrated that they indeed do not have this ability. According to literature reports (J. Virol. 1994, 68, 5469-5475), immature viral nucleocapsids are rapidly destroyed during liver cell division. When using the same drug that inhibits viral replication and regeneration (the main active ingredients that inhibit viral replication and regeneration are the same), the rate of clearing CCC DNA in the liver will be accelerated only under the conditions of accelerated liver cell regeneration.

Claims

Rights request

1. A compound preparation for treating viral liver disease, characterized in that the preparation includes the following ingredients:

(a) Drugs that inhibit viral replication and regeneration;

(b) Drugs that enhance human immunity;

(c) Drugs to protect and repair the liver and drugs to protect the kidneys;

(d) Pharmaceutically acceptable carrier.

2. A compound preparation for treating viral liver disease according to claim 1, characterized in that: wherein

The drug (a) that inhibits viral replication and regeneration is selected from: glycyrrhizinate, glutathione, lipoic acid, DL-methionine, adefovir dipivoxil, entecavir, lamivudine, tenofovir, One or a combination of two or more of remofuvir mesylate, acyclovir, ribavirin or vidarabine;

The ingredient (b) is a drug that enhances human immunity and is selected from: one or a combination of two or more of iconidia, vitamin E, selenium, vitamin C, coenzyme Q10 or levamisole;

The ingredient (c) is selected from the group consisting of silymarin, L-carnitine, vascular endothelial cell growth factor, astragalus extract, vitamin C, folic acid, glucuronolactone, and glucuronolactone. One or a combination of two or more glycosides, glutathione, calcium or vitamin D.

3. A compound preparation for treating viral liver disease according to claim 1 or 2, characterized in that, in the unit dosage form of the compound preparation:

The content of glycyrrhizic acid is 500 mg ~ 1500 mg; the content of glutathione is 50 mg ~ 1500 mg; the content of DL-methionine is 1.0 mg ~ 800 mg; the content of adefovir dipivoxil is 10 mg; The content of entecavir is 0. 25-0. 5 mg; the content of lamivudine is 100 mg; the content of tenofovir is 100-400 mg; the content of remofovir mesylate is 400-600 mg;

Iconicia raw grass or extract concentrate, the dosage is 5-10 mg converted into phenolic resin; the content of vitamin E is 50 international units ~ 3000 international units; the content of selenium is 1.0 micrograms ~ 1000 micrograms; levamisole The content of Coenzyme Q10 is 50 mg; the content of Coenzyme Q10 is 1.0 mg ~ 1000 mg;

The content of silymarin is 1 mg ~ 800 mg; the content of folic acid is 50 micrograms ~ 2000 micrograms; the content of L-carnitine is 100 mg ~ 1000 mg; the content of astragalus extract is 1500 mg ~ 3000 mg; the content of vitamin C is 10 mg ~ 2000 mg; the content of glucuronolactone is 50 mg ~ 200 mg; the content of inosine is 200 mg ~ 1500 mg; the content of lipoic acid is 1. 0 mg ~ 3000 mg; the content of calcium is 400 mg ~ 600 mg; Vitamin D content is 400 IU.

4. The compound preparation for treating viral liver disease according to claim 1 or 2, characterized in that, in the unit dosage form of the compound preparation - The content of glycyrrhizic acid is 1000 mg; the content of vitamin E is 100 IU ~ 1200 IU; the content of selenium is 10 micrograms ~ 400 micrograms; the content of silymarin is 50 mg ~ 600 mg; the content of folic acid is 100 micrograms ~ 1000 Micrograms; the content of L-carnitine is 50 mg ~ 800 mg; the content of vitamin C is 50 mg ~ 800 mg; the content of lipoic acid is 5. 0 mg ~ 1200 mg; the content of coenzyme Q10 is 5. 0 mg ~ 800 mg.

5. A compound preparation for treating viral liver disease according to claim 1 or 2, characterized in that the content of vitamin E in the unit dosage form of the compound preparation is between 150 and 600 international units; the content of selenium is between 150 and 600 international units. The content of silymarin is 200 mg ~ 500 mg; the content of folic acid is 200 mg ~ 900 mg; the content of L-carnitine is 200 mg ~ 500 mg; the content of vitamin C is 100 mg ~ 700 mg; the content of lipoic acid is 40 mg ~ 700 mg; the content of coenzyme Q10 is 40 mg ~ 600 mg.

6. A compound preparation for treating viral liver disease according to claim 1, characterized in that the compound preparation is a tablet, pill, capsule, coated tablet, aerosol, or liquid preparation.

7. Application of a compound preparation for treating viral liver disease as claimed in claim 1 or 2 in the preparation of drugs for preventing viral liver disease.

8. Use of a compound preparation for treating viral liver disease as claimed in claim 1 or 2 in the preparation of drugs that increase liver cell regeneration.