Title of Invention	A PROCESS FOR THE PREPARATION OF A NOVEL SYNERGISTIC HERBAL COMPOSITION USEFUL IN THE TREATMENT OF ACUTE HEPATITIS E INFECTION
Abstract	This invention relates to an improved process for A process for the preparation of novel synergistic pharmaceutical herbal composition for treatment of acute and chronic viral hepatitis, hepatitis E virus infection, therapeutic effect of hepatitis B virus infection and as a hepatoprotective agent, said process comprising the steps of: a. preparing an extract of whole or parts of essential plants selected from Rheum emodi Wall, Phyllanthus amarus Linn., Eclipta alba Hassk, Andrographis paniculate Nees and Picrorhiza kurroa Royle ex Benih., and optionally adjuvants selected from Fumaria officinalis Linn., Tinospora cordifolia Miers., Terminalia chebula Retz., Cichorium intybus Linn, Tephorosea purpurea Linn, and Boerhaavia diffusa with a solvent such as hereindescribed, wherein the extract per dose of the essential plants ranges from 25 to 250 mg and the extract per dose of the optional plants ranges from 5 to 50 mg, b. evaporating the extract under reduced pressure below 50°C to obtain a residue, mixing the residue with pharmaceutically acceptable neutral agents as hereindescribed, and preparing the herbal composition by methods known per se.

Title of Invention

A PROCESS FOR THE PREPARATION OF A NOVEL SYNERGISTIC HERBAL COMPOSITION USEFUL IN THE TREATMENT OF ACUTE HEPATITIS E INFECTION

Abstract

This invention relates to an improved process for A process for the preparation of novel synergistic pharmaceutical herbal composition for treatment of acute and chronic viral hepatitis, hepatitis E virus infection, therapeutic effect of hepatitis B virus infection and as a hepatoprotective agent, said process comprising the steps of: a. preparing an extract of whole or parts of essential plants selected from Rheum emodi Wall, Phyllanthus amarus Linn., Eclipta alba Hassk, Andrographis paniculate Nees and Picrorhiza kurroa Royle ex Benih., and optionally adjuvants selected from Fumaria officinalis Linn., Tinospora cordifolia Miers., Terminalia chebula Retz., Cichorium intybus Linn, Tephorosea purpurea Linn, and Boerhaavia diffusa with a solvent such as hereindescribed, wherein the extract per dose of the essential plants ranges from 25 to 250 mg and the extract per dose of the optional plants ranges from 5 to 50 mg, b. evaporating the extract under reduced pressure below 50°C to obtain a residue, mixing the residue with pharmaceutically acceptable neutral agents as hereindescribed, and preparing the herbal composition by methods known per se.

Full Text	FIELD OF THE INVENTION : The present invention relates to a method for the preparation of a novel synergistic pharmaceutical herbal composition, useful in the treatment acute viral Hepatitis and therapeutic effects on (1) acute hepatitis due to Hepatitis E Virus (HEV), (2) healthy Hepatitis B Virus carrier state with a super infection (intercurrent) by Hepatitis E Virus resulting in acute hepatitis. The present novel herbal composition is derived essentially from four plants namely (1) Phyllanthus amarus, (2) Eclipta alba, (3) Andrographis paniculata, (4) Picrorhiza kurroa. In addition, the present invention also provides a, novel herbal composition comprising essentially extracts from plants namely (1) Phyllanthus amarus, (2) Eclipta alba, (3) andrographis paniculata, (4) Picrorhiza kurroa and (5) Rheum emodi. - The present novel composition is the safe and effective herbal pharmaceutical preparation for the treatment of acute viral hepatitis caused by Hepatitis E virus infection, healthy Hepatitis B virus carrier who develop a superadded acute viral hepatitis due to Hepatitis E virus. Further, the said composition also acts as a hepatoprotective agent and improves the liver cell line functions. BACKGROUND OF THE INVENTION : The Ayurvedic system of Indian medicine provides many formulations for treating many disorders/diseases in human being. A few of the plants have already been investigated for the beneficial medicinal properties. Phyllanthus amarus : Phyllanthus amarus is a herbaceous plant which occurs as a winter weed throughout the hotter parts of India. The plant is bitter and astringent in taste and the extract of the roots and the leaves are used as a remedy for jaundice and other liver disorders. Eclipta alba : Eclipta alba is a herbaceous plant which grows in moist conditions throughout India. The extracts of Eclipta alba are largely used for the treatment of the liver and the ga11 bladder. The plant juice and extracts are used in combination with other aromatics in the treatment of jaundice. Andrographis paniculata : Andrographis paniculata is an annual herb which is grown as a hedge plant throughout the plains of India. The plant is reputed in the Ayurvedic system of medicine to be useful in the treatment of sluggish liver and jaundice. Picrorrhiza kurroa : P. kurroa is a perennial herb found in the Alpine Himalayas from Kashmir to Sikkim. Its use in the Ayurvedic system of medicine is described as being used in the disease states of jaundice, liver disorders and urinary disor-ders. Fuaaria officinalis : This plant, reputed to be useful in disor-ders of the liver, is found throughout India, from the Indo-gangetic plain to the Nilgiri Hills, Tinospora cordifolia : This species is a succulent climbing shrub and it occurs in most districts of Southern India. The extracts of T cordifolia are effective in promoting the regenera-tion of liver tissue, and preventing fibrous changes in the incidence of hepatotoxicity. The crude drug itself, and the tincture prepared from it are now official in the Indian pharma-copea. Terrainalia chebula : The fruits of this large deciduous tree are used for its purgative, tonic and carminative properties- In combination with Embellica myrobalans and Belleric mYroballan, under the Indian name TRIPHALA, these fruits are used as adjuncts to other medicines in the treatment of almost all disease state in the Ayurvedic system of medicine. Cichorum intybus : This is a rough and glandular perennial herb found throughout northwest India. The root of the plant is known to be useful in the disease states of the enlargement of the liver and the spleen. Tephrosia purpurea : The root of this branched herbaceous plaint has been found to be useful in the treatment of sluggish liver by improving its function and in enlarged spleen. Rheum emodi : Rheum emodi is a plant grown in sub Himalayan regions of India and its neighbouring countries. The traditional preparation consists of dried rhizome of the plant and roots which are cut into pieces and dried. Rhubarb root contains a large proportion of Chrysophanic acid, sometimes called Chrysophan, an allied substance Emodin, a glucoside rhapantiein, a tannin named Rheo tannic acid several resins, an albuminoid principle, mucilage, extractives, tannic and gallic acids, sugar, starch, pectin, lignan, calcium oxalate and various inorganic salts. Acute hepatitis is usually viral in origin and it is a diffuse necro-inflammatory disease of the liver as a result of infection by primary seven hepatotropic viruses A {HAV), B .(HBV) parentral transmitted non-A non-B (HCV), Delta (HDV) and enteti-cally transmitted non-A non-B (HEV), F (HFV) and G (HGV). HEPATITIS E VIRUS (HEV) : The absence of serological markers for either Hepatitis I A Virus (HAV) or Hepatitis B Virus (HBV) led to the recognition of a viral hepatitis agent (s) which were collectively grouped as non-A, non-B hepatitis (NANBH) virus. Two epidemiologically distinct forms of NANBH were identified which appeared to be transmitted by either (a) parenteral route or (b) fecal/oral route. The virus responsible for most cases of parenterally transmitted NANBH has been termed hepatitis C virus (HCV). A second, epidemiologically distinct form of NANBH was referred to as enterically transmitted NANBH (ET-NANBH). Major outbreaks of ET-NANBH have occurred in Asia, the Soviet Union, North America and Africa. The etiological agent of ET-NANBH has been identified cloned and termed the hepatitis E virus (HEV). The serological tests to diagnose acute HEV hepatitis as demon-strated by the presence of HEV-IgM/IgG have recently been commer-cially available and been useful in identifying the aetiological agent in patients of acute infection, healthy HBV carriers who develop a superadded (intercurrent) infection with HEV. Due to the commercial availability of the diagnostic tests for HEV infection (HEV IgM/IgG) a clear epidemiological data, natural history of the disease and drugs/natural plant products which might be useful in treating patients of acute HEV infection will emerge in future. The first direct evidence for a new viral agent of ET-NANBH came in 1983 from human volunteers and cynomolgns monkeys transmission studies. The feces inoculum was found by Immune Electfon Microscopy (lEM) to contain 27-30 nm virus like particles which reacted to serum from the human and cynomolgus monkeys during acute phase of the disease. Feces obtained during the course of the experimental infection were also found to contain 27-30 nm particles which reacted to acute phase sera from the monkeys, the human volunteer and the inoculum source individuals. The absence of a cell culture system lead to use of cyno or human specimens for molecular cloning of the HEV agent. The first well characterized epidemic for HEV was in Delhi, India in 1955 in which 29300 individuals were involved. Since then over 30 epidemics of ET-NANBH have been identi-fied in the last 10 years m 17 different countries all over the world. Sporadic cases of HEV have been known to occur in the same geographic areas of epidemics. Sporadic cases have also been reported among persons from Europe and the U.S. traveling to areas endemic for HEV. Sporadic HEV accounts upto 50% of clini-cal hepatitis in areas endemic for the HEV disease. If all of these cases are due to HEV then this viral agent is the most common cause of acute viral hepatitis occurring in the developing world. Large outbreaks of HEV infection generally occur in tropifral climates and are usually associated with fecal contamination of drinking water caused by flooding during the rainy reason.The disease seems to have its highest attack in young adults. Epidemics appear to be cyclical, occurring every few years in areas endemic for the virus probably due to a short-lived immunity acquired after exposure HEV. The incubation period of HEV has a mean of about 6 weeks. The disease appears to be self limiting without the development. of chronicity and long term sequelae. However, there is a much higher degree of mortality associated with HEV than with HAV. In epidemics it has been known to be as high as 1.2%. The preicter-ic stage lasts for 1-10 days and this includes gastrointestinal symptoms such as pain, nausea, vomiting and loss of appetite. The icteric phase includes jaundice, dark urine and clay-coloured stools along with tender hepatomegaly. There is a gross altara-tion in liver function tests e.g. Serum Bilirubin, SGPT, SCOT and Alkaline Phosphatase along with the presence of anti HEV IgM which establishes the aetiological diagnosis of the disease This period usually lasts for about three to four weeks and complete recovery characterised by clinical improvement in sings and symptoms along with normalization of liver function tests usually occurs in approximately three months after onset of symptoms. Histopathological examination of needle biopsy specl-men obtained during the course of Hepatitis E have no features that distinguish this form from other forms of acute viral hepa-titis. There is a high rate of fulminant hepatitis associated with HEV, particularly among pregnant woman in the third trimes-ter with a fatality rate of between 10-40%. Immunity to HEV. i-s transient. There is a strong IgM response during the acute phase followed by a rise in IgG anti-HEV antibody, which begins to disappear after about 9 months post infection. HEV infection does not appear to lead to chronic liver disease but it aan aggravate the course of chronic hepatitis B virus infection or produce a superinfection (intercurrent) in a healthy hepatitis B virus carrier state thereby resulting in increased morbidity and mortality. The control measure for acute HEV hepatitis incli provision of clean water supplies, safe disposal of human excreta and sound personal and food hygiene practices. No specific treatment for infection caused by Hepatitis E virus is curreritly available. HEPATITIS B VIRUS (HBV) : Hepatitis B virus is partially double stranded DNA virus that replicates in part through an RNA intermediate. The com-plete virus is known as Dane particle and measures 42 nm in diameter. This consists of a 27 nm core of an incomplete dsDNA surrounded by a coat of surface material. Man is the natural source and reservoir of Hepatitis B virus infection. So far, no effective drug therapy against HBV has been available. Hepatit is B virus is endemic in some population and hyperendemic in many parts of world. Chronic infection occurs in less than 2% of population in North America, Western Europe, Australia, where as high prevalence rate is seen in Asia, the pacific islands, part of China and India. The only way of gradually eradicating the infection is by (1) active universal immunisation in childhood and/or (2) development of treatment modalities for persistently infected persons. The source of infection is HBV infected bloHod or transmission by sexxial route from infected mother to newborn (perinatal). All age groups and both sexes are susceptibly. Endemicity exists and high risk groups include blood recipients, haemophilics, dialysis patients, intravenous drug users, heterp-sexuals, health care workers and children born to HBV infect mothers. The incubation period of acute HBV hepatitis is 4-18 weeks. The first marker appearing in blood is HbsAg followed by a high rise in transaminase levels. HBV infection may lead to both asymptomatic and sever form of liver diseases. Around 5-10% of acute HBV infected population be.come chronic carriers. HBV carrier stage is common if exposure occurs in early childhood. Most of the infections are acquired in early childhood, usually as mother to child transmission and results in a persistent HBV carrier stage. There are more than 200 Hepatitis B virus carriers in world, who besides .developing a chronic liver disease (chronic hepatitis, cirrhosis, hepatocellular carcinomal as a result of persistent HBV infection are also at a constant risk of acquiring a super infection with other hepatotropic viruses which might worsen their clinical condition. Infection with Hepatitis Delta Virus, hepatitis noh-A, non-B ' [both Hepatitis C virus (HCV) , Hepatitis E virus (HEV) and hepatitis A virus (HAV)] is hazardous to healthy carriers of hepatitis B virus. In developed countries e.g. Italy, France, England and United States, Hepatitis Delta or Hepatitis C virus have been found to be major aetiological factor's which usually lead to super infection in HBV carriers. In contrast, the high prevalence of HEV in the Indian continent and being the major aetiological agent responsible for acute hepatitis is postulated to present a big risk of intercur- rrent infection in HBV carrier and may lead to severe liver injury. At present there is no effective therapy is available for such a group of healthy hepatitis B virus carriers who are super infected with Hepatitis E virus and develop acute hepatitis. SUMMARY OF INVENTION : A process for the preparation of a novel synergistic pharmaceutical herbal composition for treatment of acute and chronic viral hepatitis, hepatitis E virus infection, therapeutic effect of hepatitis B virus infection and as a hepatoprotective agent, said process comprising the steps of: a. preparing an extract of whole or parts of essential plants selected from Rheum emodi Wall., Phyllanthus amarus Linn., Eclipta alba Hassk., Andrographis paniculate Nees and Picrorhiza kurxoa Royle ex Benth., and optionally adjuvants selected from Fumaria officinalis Linn., Tinospora cordifolia Miers., Terminalia chehula Retz., Cichorium intybus Linn., Tephorosea. purpurea Linn. and Boerhaavia diffusa with a solvent such as hereindescribed, wherein the extract per dose of the essential plants ranges from 25 to 250 mg and the extract per dose of the optional plants ranges from 5 to 50 mg, b. evaporating the extract under reduced pressure below 50°C to obtain a residue, c. mixing the residue with pharmaceutically acceptable neutral agents as hereindescribed, and preparing the herbal composition by methods known per se . The invention provides a novel herbal composition which is useful in the treatment of acute viral hepatitis, the said composition consists essentially of extracts from plants namely Phyllanthus amarus, Eclipta alba, Andrographis paniculata and Picrorhiza kurroa. The invention also provides a novel hepatoprotective composition comprising extracts of Phyllani nus amarus, Eclipta alba, Andrographis paniculata, Picrorhiza kurros and Rheum emodi, used for the treatment of acute viral hepatitis (Hepatitis E virus infection)-. The invention further provides a novel hepatoprotective composition optionally includes one or more extracts of plants selected from Fumaria officinalis, tinospora cordifolia, Terminalia chebula, Cichorium intybus Tephrosea /purpurea and Boerhaavia diffusa. The invention relates to a novel herbal composition which is useful in the treatment of acute viral hepatitis infection due to Hepatitis E virus, the composition consists essentially of aqueous extractable components of Phyllanthus amarus, Eclipta alba, Andrographis paniculata, Picrorrhiza kurroa and/or Rheum emodi. In an embodiment, composition of plant extracts comprises the following ingredients (per kg) Rheum emodi Wall- 170 mg, Eclipta alba Hassk- 300 mg, Phyllanthus amarus Linn-300 mg, Tephrosea purpurea Linn-180 mg, Cichorium intybus Linn-180 mg, Boerhaavia diffusa-100 mg, Tinospora cordifolia Miers- 12 mg, Terminalia chebula Retz-12 mg, Andrographis peniculate Nees-60 mg, Picrorrhiza kurroa Royle ex Benth-60 mg, Fumaria officinalis LinnSO mg. The Invention also provides a novel hepatoprotective compo-sition comprising extracts of Phyllanthus amarus, Eclipta alba, Andrographis paniculata, Picrorhiza kurroa and Rheum emodi. . As used herein the expression water extractable coBiponents of above plants includes extracts prepared from whole plants or parts thereof. The invention also relates to a method of treating healthy carriers of Hepatitis B virus patients who develop acute Hepati-tis E virus superinfection (intercurrent) which comprises admip-istering to the patients the present novel herbal pharmaceutical preparation. Further, the invention provides a novel composition uselful in the clinical treatment of acute viral hepatitis caused by hepatitis E virus infection which comprise of fractions of Phyl-lanthus amarus, Eclipta alba, Andrographis paniculata, Picrorhiza kurroa and/or Rheum emodi with optional extracts of plants such as Fumaria officinalis, Tinospora cordifolia, Terminalia chebula, Cichorium intybus, Tephrosea purpurea and Boerhaavia diffusa, said fractions contain aqueous extractable components of the above plants or parts thereof. Moreover, the invention also relates to a process for the preparation of a novel herbal composition by mixing in any known manner the extracts of Phyllanthus amarus, Eclipta alba, Andro- graphis paniculata, Picrorhiza kurroa and/or Rheum eaiodi. The present novel composition is a synergistic mixture showing surprising properties addition, the process includes adding optional ingredients such as extracts of plants namely Fumarla officinalis, Tinostpora cordifolia, Terminalia chebula, cichorium intybus Tephnispa purpurea and Boerhaavia diffusa. DETAILED DESCRIPTION OF THE INVENTION : The invention describes (1) a novel herbal composition and a process foi' the preparation of aqueous extract of plants, its usefulness in (2) treatment of acute viral hepatitis caused by Hepatitis E virus infection, (3) therapeutic effects on Hepatitis B virus healthy carrier state who develop a superadded (intercurrent) infection due to Hepatitis E virus, ^he following description is given merely to illustrate the inventiion and this should not be g onstrudeto limit the scope of the invention. XAMPLE 1 : Describes the pnarmaceutical preparation of plant extract. Pharmaceutical preparation of plant extracts : The plant extracts which are mixed together to obtain the present novel composition can be obtained by any known manner. All batches of plants used in the preparation the present movel composition were botanically authenticated. The solvent used in the extraction of the plants may be any suitable solvent such as ethanol, methanol, chloroform and water. Preferably, the plants extract can be obtained by any known manner. Most preferably, the whole plants and parts thereof wert powdered and extracted with water. The extract was evaporatsed under reduced pressure below 50°C leaving a residue. For human administration, the residue is mixed with pharmaceutically acceptable neutral excepients and converted into suitable oral dosage form. Alternatively, the method of preparing the novel composi-tions comprising blending and extracting in any known ratio of all the plants or plant materials together by any known manner.. The hepatoprotective herbs used for the formulation of the present composition contains the extracts, preferably aquetous extracts of the following : Common Name Botanical Name Range of Extract in mg per dose Bhumyama Laki Phyllanthus amarxus 25-250 Bringraj Eclipta alba 25-250 Kalmegh Andrographis paniculata 25-250 Kutki Picrorhiza kurroa 25-250 What is unexpected in the present invention is that earlier, the above four plant extracts were combined in the range of 10 to 20 mg individually, the hepatoprotective property of this comlli'-nation is identified only when the amounts of these ingredients are enhanced to the rage of 25 to 250 mg per dose. In otrter words, the applicants for the first time noticed the hitherfto unknown hepatoprotective property of the composition comprising extracts of plants namely Phyllanthus amari»s, Ecllpta alba Andrographis paniculata and Picrorhiza kurroa when the amounts of these plant extracts are enhanced to the range of 25 to 250 :. mg per dose. The present invention also provides a hepatoprotective in the liver disease resulting from acute Hepatitis E virus infec-tion and anti hepatitis B virus composition comprising the fol-lowlng plant extracts : Coanon Name Botanical Name Range of Extract in rag per dose Bhumyama Laki Phvllanthus amarus 25-250 Bringraj Eclipta alba 25-250 Kalmegh Andrographis paniculata 25-250 Kutki Picrorhiza kurroa 25-250 Rheum emodi Rheum emodi Wall 25-250 The above novel compositions also comprising optional ingre-dients such as extracts, preferably aqueous extracts of the following plants : CoiRBion Name Botanical Name Range of Extract in rog per dose Pitpapra Fumaria officinalis 5-50 Gilo Tinospora cordifolia 5-50 Haritaki Terminalia chebula 5-50 Kasni Cichoriumiinlybus 10-50 Sarphunka Tephrosea purpurrea 10-50 Punarnava Boerhaavia diffusa 10-50 The present composition is a synergistic composition exhib-iting surprising properties such as enhanced hepatoprotective activity in the liver disease caused by Hepatitis E virus infec-tion and anti hepatitis B viral properties. The present inven-tion is illustrated with reference to the following examples and such examples should not be construed at any extent to limit the scope of the invention. The most preferred method of preparing the polyherbal compo- sition in tablet form is given below : COMPOSITION : Ingredients Qty of crude Qty of crude Herb/Tablet Herbs for 20 lac tablets Bhringraj (Eclipta alba) 300 mg 60 kg Bhumyamalaki (Phyllanthus amarus) 300 mg 60 kg Sarpaunkha (Tephrosea purpurea) 180 mg 36 kg Kasni (Cichorium intybus) 180 mg 36 kg Revand chini {Rheum emodi) 170 mg 34 kg Punarnava (Boerhaavia diffusa) 100 mg 20 kg Glio (Tinospora cordifolia) 72 mg 14.4 kg Haritaki (Terminalia chebula) 72 mg 14.4 kg Kalmegh (Andrographis paniculata) 60 mg 12 kg Kutki (Picrorrhiza kurroa) 60 mg 12 kg Pitpapra (Fumaria officinalis) 30 mg 6 kg Total 304.8 kg 1. EXTRACTION : The above mentioned herbs were weighed accurately and re-duced to moderately coarse powder. The herbs (304. fl kg) were extracted in a steam jacketed boiling pan using 8-9 times puri-fied water for 3.0 hours and filtered. The aiarc was again subjected to extraction as earlier using 6-7 tiaes purified water for three more hours and filtered and both the filtrates were combined together. 2. CONCENTRATION, DRYING AND PULVERISATION OF HERBAL EXTRACT The combined filtrate was concentrated and dried by spray drying method where no excipient is used. Sometimes it is dried by tray drying method also where the combined filtrate is concentrated to a semisolid consistency and was poured on to, a thin bed of Starch-Microcrystalline cellulose powder (each 10% of herbal extract) over trays of electric tray drier and dried at 70-80°C. The dried extract was pulverised through micro-pulverifer and sieved through No.40 sieve. 3- GRANULATION : Powdered herbal extract was mixed with inert diluents like Microcrystalline cellulose. Calcium carbonate and granulated using starch-gelatin paste. 4. DRYING AND SIZING OF GRANULES : The granules were dried in electric tray drier at 60°C and the entire quantity of granules were passed through No.16 sievei 5. COMPRESSION ; The granules were mixed with lubricants like Starch, Talc and Magnesium stearate and compressed on Rotary Tablet Compres-sion Machine using circular deep concave punches. EXAMPLE 2 : describes the controlled clinical trial of the present composition (with Rheum emodi) in the treatment of acute viral hepatitis caused by Hepatitis E virus infection. MATERIAL & METHOD : Nine (9) patients (6 males, 3 females) of a mean age of 11.5 years (range 18 to 45 years) presenting within one week of the onset of the clinical symptoms suggestive of classical acute viral hepatitis (AVH) were included in the study. The diagnosis of AVH was established by the clinical symptoms (acute onset orf jaundice, gastrointestinal symptoms p.g. abdominal pain, anorexia, vomiting along with tender hepatomegaly). The diagnosis was supplemented by abnormal liver function tests e.g. estimation [of Serum Bilirubin, ALT (SGPT), AST (SCOT), and Alkaline Phospa- J- tase. The diagnosis of the etiological agents (hepatitis viruses A, B, C, D and E) were done by the following parameters : hepatitis B virus - presence of HBcIgM with or without HBsAg, hepatitis A virus - presence of HAV IgM, hepatitis C virus - presence ©f anti HBc, hepatitis D virus - presence of anti HDV IgM, hepatitis E virus - presence of anti HEV IgM. All the serological tests were done by Enzyme Immune Assay (Elisa) at the time of clinical presentation and the subsequent intervals during therapy. In all the 9 patients the serological markers of hepatitis A, B, C and D were absent and only anti HEV IgM was present. Further, the other possible causes which might have led to a similar clinical presentation e.g. surgical jaundice, drug mdaced cholestasis, herpes and cytomegalo virus infection were also excluded in all the 9 patients. A prior consent of all the patients were ob-tained and they were explained about the treatment protocol. The preparation of polyhedral pharmaceutical preparation in the tablet form for clinical use in the above 9 patients has been described in example 1. Each patient was given 2 tablets of polyhedral pharmaceutical preparation, two times a day for a period of 4 weeks. The clinical assessment and the liver fund-tion tests along with the anti HEV IgM (Elisa) was done at two weekly interval, also if required at weekly interval (m pateent No.9). RESULTS : Table 1 - shows the mean values of liver function tests eft the time of diagnosis and at subsequent period of polyher^j^ pharmaceutical composition therapy. Table 2 - summarises the effects of the polyherbal pharita-ceutical composition therapy. Tables 3 to 8 - show the details of liver function tests ^at the time of presentation (prior to start of therapy) and at 2 a^iB 4 week interval of the polyherbal pharmaceutical composit:^» therapy. In all the nine Acute E virus hepatitis patients a clinical as well as biochemical recovery was noted from second week onward. A complete clinical recovery occurred in all the patients by four weeks of therapy. No side effect of the therapy was observed in any of the nine patients. Table 1: Summary of Biochemical Investigations (mean values) from Clinical Trial Data on the Polyherbal Pharmaceutical composition in the patients of Classical Acute E virus Hepatitis. (Table Removed) Normal values: SCOT =10-35 lU/L: SGPT = 10-40 lU/L; S.Bilirubin = 0.3-1.0 mg/dl : Alk. Phosphatase = 60-170 lU/L Table 2 - demonstrates the effects on physical sign and symptoms of the patients of classical Acute E virus hepatitis receiving polyherbal pharmaceutical composition therapy (9 patients). (Table Removed) +, ++, +++ and ++++ indicates intensity of acute hepatitis E in patients and "-" indicates the degree of recovery The findings of the liver function tests are also illustrat ed for each individual patient as below : Table 3 : Patient No.1 (Table Removed) Normal values: SCOT = 10-35 lU/L : SGPT = 10-40 lU/L: S.Bilirubin = 0.3-1.0 mg/dl: Alk. Phosphatase = 60-170 lU/L. + = Positive, - = Negative. Table 4 : Patient No.2 (Table Removed) Normal values: SCOT = 10-35 lU/L : SGPT = 10-40 lU/L: S.Bilirubin = 0.3-1.0 mg/dl: Alk. Phosphatase = 60*170 lU/L. + = Positive, - = Negative. Table 5 : Patient No.3 (Table Removed) Normal values: SCOT = 10-35 lU/L : SGPT = 10-40 lU/L: S.Bilirubin = 0.3-1.0 mg/dl: Alk. Phosphatase - 60-170 lU/L. + = Positive, - = Negative. Table 6 : Patient No.4 (Table Removed) Normal values: SCOT = 10-35 lU/L : SGPT = 10-40 lU/L: S.Bilirubin = 0.3-1.0 mg/dl: Alk. Phosphatase = 60-170 lU/L. + = Positive, - = Negative. Table 7 : Patient No.5 (Table Removed) Normal values: SGOT = 10-35 lU/L : SGPT = 10-40 lU/L: S.Bilirubin = 0.3-1.0 mg/dl: Alk. Phosphatase = 60-170 lU/L. + = Positive, - = Negative. Table 8 : Patient No.6 (Table Removed) Normal values: SGOT = 10-35 lU/L : SGPT = 10-40 lU/L: S.Bilirubin = 0.3-1.0 mg/dl: Alk. Phosphatase = 60-170 lU/L. + = Positive, - = Negative. Table 9 : Patient No.7 (Table Removed) Normal values: SCOT = 10-35 lU/L : SGPT = 10-40 lU/L: S.Bilirubin = 0.3-1.0 mg/dl: Alk. Phosphatase = 50-170 lU/L. + = Positive, - = Negative. Table 10 : Patient No.8 (Table Removed) Normal values: SCOT = 10-35 lU/L : SGPT = 10-40 lU/L: S.Bilirubin = 0.3-1.0 mg/dl: Alk. Phosphatase = 60-170 lU/L. + = Positive, - == Negative. The present polyherbal pharmaceutical composition thus promotes a rapid rate of recovery in subjective symptoms and objective parameters supported by liver function tests in patients 'of acute Hepatitis E virus infection thereby grossly reducing the period of clinical convalescence. Example 3 : The usefulness of the present polyherbal pharmacqsu-tical composition in the therapy of hepatitis B virus carrier developing a super imposed acute hepatitis due to hepatitis E virus infection has been illustrated. A 45 year health male who has been a carrier of hepatitis B virus (as demonstrated by the presence of HBsAg at two different intervals of 3 months each) developed acute hepatitis E virus infection resulting in hepatitis. The Table 11 shows the details of the liver function tests at the time of presentation (before the start of therapy) and subsequently upto 16 weeks at the interval of 4 weeks. He received the polyherbal pharmaceutical composition in the doses of two tablets two times a day for a period of 12 weeks. There was a marked improvement in the liver function tests at 4 weeks interval with a complete recovery occurring at the end of 8 weeks therapy. Clearance of hepatitis B virus infection was observed at the end of 8 weeks therapy. The therapy with the polyherbal pharmaceutical composition was stopped after 12 weeks and the liver function tests were idane after 4 weeks, which were normal along with the absence nf hepa-titis B virus infection. HBV Carrier with Acute HEV Superinfection snows the findings of liver function tests, hepatitis B virus and hepatitis E vi\|i\|s. In a patient receiving polyherbal pharmaceutical composition- (Table Removed) Normal values: SCOT = 10-35 lU/L : SGPT = 10--in IU/L: S.Bilirubin = 0.3-1.0 mg/dl: AlK. Phosphatase = 60-170 lU/L. + = Positive, - = NFegative. The above example suggests that the polvherbal pharmaceutical composition brings about the clearance of hepatitis B virus infection and also is helpful in superadded hepatitis E virus infection. We claim: 1. A process for the preparation of a novel synergistic pharmaceutical herbal composition for treatment of acute and chronic viral hepatitis, hepatitis E virus infection, therapeutic effect of hepatitis B virus infection and as a hepatoprotective agent, said process comprising the steps of: a. preparing an extract of whole or parts of essential plants selected from Rheum emodi Wall, Phyllanthus amarus Linn., Eclipta alba Hassk, Androsraphis paniculate Nees and Picrorhiza kurroa Royle ex Be nth., and optionally adjuvants selected from Fumaria officinalis Linn., Tinospora cordifolia Pliers., Terminalia chebula Retz., Cichorium intybus Linn., Tephorosea purpurea Linn, and Boerhaavia 'diffusa with a solvent such as hereindescribed, wherein the extract per dose of the essential plants ranges from 25 to 250 mg and the extract per dose of the optional plants ranges from 5 to 50 mg, b. evaporating the extract under reduced pressure below 50°C to obtain a residue, c. mixing the residue with pharmaceutically acceptable neutral agents as hereindescribed, and preparing the herbal composition by methods known per se. 2. A process as claimed in claim 1 wherein the plant parts are selected from leaves and roots. 3. A process as claimed in claim 1 wherein the solvent is selected from ethanol, methanol, chloroform, hexane, ethyl acetate, methyl chloride, carbon tetrachloride, toleuene, acetone and water and mixtures thereof. 4. A process as claimed in claim 1 wherein the plant or parts thereof are used as whole or in powdered form. 5. A process as claimed in claim 1 wherein the pharmaceutically acceptable neutral agents are selected from starch microcrystalline cellulose powder, calcium carbonate and starch gelatin paste. 6. A process as claimed in claim 1 wherein the composition of plant extracts comprises the following ingredients: Ingredients Qty. of Herb (per kg) Rheum emodi Wall 170 mg Eclipta alba Hassk 300 mg Phyllanthus amarus Linn 300 mg Tephrosea purpurea Linn 180 mg Cichorium intybus Linn 180 mg Boerhaavia diffusa 100 mg Tinospora cordifolia Miers 72 mg Terminalia chebula Retz. 72 mg Andrographis peniculate Nees. 60 mg Picrorrhiza kurroa Royle ex Benth. 60 mg Fumaria officinalis Linn. 30 mg 7. A process for the preparation of a novel synergistic herbal composition for treatment of acute and chronic viral hepatitis, hepatitis E virus infection, therapeutic effect of hepatitis B virus infection and as a hepatoprotective agent substantially as hereindescribed with reference to the examples.

Full Text

FIELD OF THE INVENTION :
The present invention relates to a method for the
preparation of a novel synergistic pharmaceutical herbal
composition, useful in the treatment acute viral Hepatitis
and therapeutic effects on (1) acute hepatitis due to
Hepatitis E Virus (HEV), (2) healthy Hepatitis B Virus
carrier state with a super infection (intercurrent) by
Hepatitis E Virus resulting in acute hepatitis. The
present novel herbal composition is derived essentially
from four plants namely (1) Phyllanthus amarus, (2) Eclipta
alba, (3) Andrographis paniculata, (4) Picrorhiza kurroa.
In addition, the present invention also provides a, novel
herbal composition comprising essentially extracts from
plants namely (1) Phyllanthus amarus, (2) Eclipta alba,
(3) andrographis paniculata, (4) Picrorhiza kurroa and (5) Rheum emodi. -
The present novel composition is the safe and effective herbal pharmaceutical preparation for the treatment of acute viral hepatitis caused by Hepatitis E virus infection, healthy Hepatitis B virus carrier who develop a superadded acute viral hepatitis due to Hepatitis E virus. Further, the said composition also acts as a hepatoprotective agent and improves the liver cell line functions. BACKGROUND OF THE INVENTION :
The Ayurvedic system of
Indian medicine provides many formulations for treating many disorders/diseases in human being. A
few of the plants have already been investigated for the beneficial medicinal properties.
Phyllanthus amarus : Phyllanthus amarus is a herbaceous plant which occurs as a winter weed throughout the hotter parts of India. The plant is bitter and astringent in taste and the extract of the roots and the leaves are used as a remedy for jaundice and other liver disorders.
Eclipta alba : Eclipta alba is a herbaceous plant which grows in moist conditions throughout India. The extracts of Eclipta alba are largely used for the treatment of the liver and the ga11 bladder. The plant juice and extracts are used in combination with other aromatics in the treatment of jaundice. Andrographis paniculata : Andrographis paniculata is an annual herb which is grown as a hedge plant throughout the plains of India. The plant is reputed in the Ayurvedic system of medicine to be useful in the treatment of sluggish liver and jaundice. Picrorrhiza kurroa : P. kurroa is a perennial herb found in the Alpine Himalayas from Kashmir to Sikkim. Its use in the Ayurvedic system of medicine is described as being used in the disease states of jaundice, liver disorders and urinary disor-ders.
Fuaaria officinalis : This plant, reputed to be useful in disor-ders of the liver, is found throughout India, from the Indo-gangetic plain to the Nilgiri Hills,
Tinospora cordifolia : This species is a succulent climbing shrub and it occurs in most districts of Southern India. The extracts of T cordifolia are effective in promoting the regenera-tion of liver tissue, and preventing fibrous changes in the incidence of hepatotoxicity. The crude drug itself, and the tincture prepared from it are now official in the Indian pharma-copea.
Terrainalia chebula : The fruits of this large deciduous tree are used for its purgative, tonic and carminative properties- In combination with Embellica myrobalans and Belleric mYroballan, under the Indian name TRIPHALA, these fruits are used as adjuncts to other medicines in the treatment of almost all disease state in the Ayurvedic system of medicine.
Cichorum intybus : This is a rough and glandular perennial herb found throughout northwest India. The root of the plant is known to be useful in the disease states of the enlargement of the liver and the spleen.
Tephrosia purpurea : The root of this branched herbaceous plaint has been found to be useful in the treatment of sluggish liver by improving its function and in enlarged spleen.
Rheum emodi : Rheum emodi is a plant grown in sub Himalayan regions of India and its neighbouring countries. The traditional preparation consists of dried rhizome of the plant and roots which are cut into pieces and dried.
Rhubarb root contains a large proportion of Chrysophanic acid, sometimes called Chrysophan, an allied substance Emodin, a glucoside rhapantiein, a tannin named Rheo tannic acid several resins, an albuminoid principle, mucilage, extractives, tannic and gallic acids, sugar, starch, pectin, lignan, calcium oxalate and various inorganic salts.
Acute hepatitis is usually viral in origin and it is a diffuse necro-inflammatory disease of the liver as a result of infection by primary seven hepatotropic viruses A {HAV), B .(HBV) parentral transmitted non-A non-B (HCV), Delta (HDV) and enteti-cally transmitted non-A non-B (HEV), F (HFV) and G (HGV). HEPATITIS E VIRUS (HEV) :
The absence of serological markers for either Hepatitis I A Virus (HAV) or Hepatitis B Virus (HBV) led to the recognition of a viral hepatitis agent (s) which were collectively grouped as non-A, non-B hepatitis (NANBH) virus. Two epidemiologically distinct forms of NANBH were identified which appeared to be transmitted by either (a) parenteral route or (b) fecal/oral route. The virus responsible for most cases of parenterally transmitted NANBH has been termed hepatitis C virus (HCV).
A second, epidemiologically distinct form of NANBH was referred to as enterically transmitted NANBH (ET-NANBH). Major outbreaks of ET-NANBH have occurred in Asia, the Soviet Union, North America and Africa. The etiological agent of ET-NANBH has been identified cloned and termed the hepatitis E virus (HEV).
The serological tests to diagnose acute HEV hepatitis as demon-strated by the presence of HEV-IgM/IgG have recently been commer-cially available and been useful in identifying the aetiological agent in patients of acute infection, healthy HBV carriers who develop a superadded (intercurrent) infection with HEV. Due to the commercial availability of the diagnostic tests for HEV infection (HEV IgM/IgG) a clear epidemiological data, natural history of the disease and drugs/natural plant products which might be useful in treating patients of acute HEV infection will emerge in future.
The first direct evidence for a new viral agent of ET-NANBH came in 1983 from human volunteers and cynomolgns monkeys transmission studies. The feces inoculum was found by Immune Electfon Microscopy (lEM) to contain 27-30 nm virus like particles which reacted to serum from the human and cynomolgus monkeys during acute phase of the disease. Feces obtained during the course of the experimental infection were also found to contain 27-30 nm particles which reacted to acute phase sera from the monkeys, the human volunteer and the inoculum source individuals. The absence of a cell culture system lead to use of cyno or human specimens for molecular cloning of the HEV agent.
The first well characterized epidemic for HEV was in Delhi, India in 1955 in which 29300 individuals were involved.
Since then over 30 epidemics of ET-NANBH have been identi-fied in the last 10 years m 17 different countries all over the world.
Sporadic cases of HEV have been known to occur in the same geographic areas of epidemics. Sporadic cases have also been reported among persons from Europe and the U.S. traveling to areas endemic for HEV. Sporadic HEV accounts upto 50% of clini-cal hepatitis in areas endemic for the HEV disease. If all of these cases are due to HEV then this viral agent is the most common cause of acute viral hepatitis occurring in the developing world.
Large outbreaks of HEV infection generally occur in tropifral climates and are usually associated with fecal contamination of drinking water caused by flooding during the rainy reason.The disease seems to have its highest attack in young adults.
Epidemics appear to be cyclical, occurring every few years in areas endemic for the virus probably due to a short-lived immunity acquired after exposure HEV.
The incubation period of HEV has a mean of about 6 weeks. The disease appears to be self limiting without the development. of chronicity and long term sequelae. However, there is a much higher degree of mortality associated with HEV than with HAV. In epidemics it has been known to be as high as 1.2%. The preicter-ic stage lasts for 1-10 days and this includes gastrointestinal
symptoms such as pain, nausea, vomiting and loss of appetite. The icteric phase includes jaundice, dark urine and clay-coloured stools along with tender hepatomegaly. There is a gross altara-tion in liver function tests e.g. Serum Bilirubin, SGPT, SCOT and Alkaline Phosphatase along with the presence of anti HEV IgM which establishes the aetiological diagnosis of the disease This period usually lasts for about three to four weeks and complete recovery characterised by clinical improvement in sings and symptoms along with normalization of liver function tests usually occurs in approximately three months after onset of symptoms. Histopathological examination of needle biopsy specl-men obtained during the course of Hepatitis E have no features that distinguish this form from other forms of acute viral hepa-titis. There is a high rate of fulminant hepatitis associated with HEV, particularly among pregnant woman in the third trimes-ter with a fatality rate of between 10-40%. Immunity to HEV. i-s transient. There is a strong IgM response during the acute phase followed by a rise in IgG anti-HEV antibody, which begins to disappear after about 9 months post infection. HEV infection does not appear to lead to chronic liver disease but it aan aggravate the course of chronic hepatitis B virus infection or produce a superinfection (intercurrent) in a healthy hepatitis B virus carrier state thereby resulting in increased morbidity and mortality. The control measure for acute HEV hepatitis incli
provision of clean water supplies, safe disposal of human excreta
and sound personal and food hygiene practices. No specific
treatment for infection caused by Hepatitis E virus is curreritly
available.
HEPATITIS B VIRUS (HBV) :
Hepatitis B virus is partially double stranded DNA virus that replicates in part through an RNA intermediate. The com-plete virus is known as Dane particle and measures 42 nm in diameter. This consists of a 27 nm core of an incomplete dsDNA surrounded by a coat of surface material. Man is the natural source and reservoir of Hepatitis B virus infection. So far, no effective drug therapy against HBV has been available. Hepatit is B virus is endemic in some population and hyperendemic in many parts of world. Chronic infection occurs in less than 2% of population in North America, Western Europe, Australia, where as high prevalence rate is seen in Asia, the pacific islands, part of China and India. The only way of gradually eradicating the infection is by (1) active universal immunisation in childhood and/or (2) development of treatment modalities for persistently infected persons. The source of infection is HBV infected bloHod or transmission by sexxial route from infected mother to newborn (perinatal). All age groups and both sexes are susceptibly. Endemicity exists and high risk groups include blood recipients, haemophilics, dialysis patients, intravenous drug users, heterp-sexuals, health care workers and children born to HBV infect
mothers. The incubation period of acute HBV hepatitis is 4-18 weeks. The first marker appearing in blood is HbsAg followed by a high rise in transaminase levels. HBV infection may lead to both asymptomatic and sever form of liver diseases. Around 5-10% of acute HBV infected population be.come chronic carriers. HBV carrier stage is common if exposure occurs in early childhood. Most of the infections are acquired in early childhood, usually as mother to child transmission and results in a persistent HBV carrier stage. There are more than 200 Hepatitis B virus carriers in world, who besides .developing a chronic liver disease (chronic hepatitis, cirrhosis, hepatocellular carcinomal as a result of persistent HBV infection are also at a constant risk of acquiring a super infection with other hepatotropic viruses which might worsen their clinical condition. Infection with Hepatitis Delta Virus, hepatitis noh-A, non-B ' [both Hepatitis C virus (HCV) , Hepatitis E virus (HEV) and hepatitis A virus (HAV)] is hazardous to healthy carriers of hepatitis B virus. In developed countries e.g. Italy, France, England and United States, Hepatitis Delta or Hepatitis C virus have been found to be major aetiological factor's which usually lead to super infection in HBV carriers. In contrast, the high prevalence of HEV in the Indian continent and being the major aetiological agent responsible for acute hepatitis is postulated to present a big risk of intercur-
rrent infection in HBV carrier and may lead to severe liver injury. At present there is no effective therapy is available for such a group of healthy hepatitis B virus carriers who are super infected with Hepatitis E virus and develop acute hepatitis.
SUMMARY OF INVENTION :
A process for the preparation of a novel synergistic pharmaceutical herbal composition for treatment of acute and chronic viral hepatitis, hepatitis E virus infection, therapeutic effect of hepatitis B virus infection and as a hepatoprotective agent, said process comprising the steps of:
a. preparing an extract of whole or parts of
essential plants selected from Rheum emodi Wall.,
Phyllanthus amarus Linn., Eclipta alba Hassk.,
Andrographis paniculate Nees and Picrorhiza kurxoa
Royle ex Benth., and optionally adjuvants selected
from Fumaria officinalis Linn., Tinospora cordifolia
Miers., Terminalia chehula Retz., Cichorium intybus
Linn., Tephorosea. purpurea Linn. and Boerhaavia
diffusa with a solvent such as hereindescribed,
wherein the extract per dose of the essential plants
ranges from 25 to 250 mg and the extract per dose of
the optional plants ranges from 5 to 50 mg,
b. evaporating the extract under reduced pressure
below 50°C to obtain a residue,
c. mixing the residue with pharmaceutically
acceptable neutral agents as hereindescribed, and
preparing the herbal composition by methods known per
se .
The invention provides a novel herbal composition
which is useful in the treatment of acute viral hepatitis,
the said composition consists essentially of extracts from
plants namely Phyllanthus amarus, Eclipta alba,
Andrographis paniculata and Picrorhiza kurroa.
The invention also provides a novel hepatoprotective composition comprising extracts of Phyllani nus amarus, Eclipta alba, Andrographis paniculata, Picrorhiza kurros and Rheum emodi, used for the treatment of acute viral hepatitis (Hepatitis E virus infection)-.
The invention further provides a novel hepatoprotective composition optionally includes one or more extracts of plants selected from Fumaria officinalis, tinospora cordifolia, Terminalia chebula, Cichorium intybus Tephrosea /purpurea and Boerhaavia diffusa.
The invention relates to a novel herbal composition which is useful in the treatment of acute viral hepatitis infection due to Hepatitis E virus, the composition consists essentially of aqueous extractable components of Phyllanthus amarus, Eclipta alba, Andrographis paniculata, Picrorrhiza kurroa and/or Rheum emodi.
In an embodiment, composition of plant extracts comprises the following ingredients (per kg) Rheum emodi Wall- 170 mg, Eclipta alba Hassk- 300 mg, Phyllanthus amarus Linn-300 mg, Tephrosea purpurea Linn-180 mg, Cichorium intybus Linn-180 mg, Boerhaavia diffusa-100 mg, Tinospora cordifolia Miers- 12 mg, Terminalia chebula Retz-12 mg, Andrographis peniculate Nees-60 mg, Picrorrhiza kurroa Royle ex Benth-60 mg, Fumaria officinalis LinnSO mg.
The Invention also provides a novel hepatoprotective compo-sition comprising extracts of Phyllanthus amarus, Eclipta alba, Andrographis paniculata, Picrorhiza kurroa and Rheum emodi. . As used herein the expression water extractable coBiponents of above plants includes extracts prepared from whole plants or parts thereof.
The invention also relates to a method of treating healthy carriers of Hepatitis B virus patients who develop acute Hepati-tis E virus superinfection (intercurrent) which comprises admip-istering to the patients the present novel herbal pharmaceutical preparation.
Further, the invention provides a novel composition uselful in the clinical treatment of acute viral hepatitis caused by hepatitis E virus infection which comprise of fractions of Phyl-lanthus amarus, Eclipta alba, Andrographis paniculata, Picrorhiza kurroa and/or Rheum emodi with optional extracts of plants such as Fumaria officinalis, Tinospora cordifolia, Terminalia chebula, Cichorium intybus, Tephrosea purpurea and Boerhaavia diffusa, said fractions contain aqueous extractable components of the above plants or parts thereof.
Moreover, the invention also relates to a process for the
preparation of a novel herbal composition by mixing in any known
manner the extracts of Phyllanthus amarus, Eclipta alba, Andro-
graphis paniculata, Picrorhiza kurroa and/or Rheum eaiodi. The
present novel composition is a synergistic mixture showing surprising
properties addition, the process includes adding optional ingredients such as extracts of plants namely Fumarla officinalis, Tinostpora cordifolia, Terminalia chebula, cichorium intybus Tephnispa purpurea and Boerhaavia diffusa. DETAILED DESCRIPTION OF THE INVENTION :
The invention describes (1) a novel herbal composition and a process foi' the preparation of aqueous extract of plants, its usefulness in (2) treatment of acute viral hepatitis caused by Hepatitis E virus infection, (3) therapeutic effects on Hepatitis B virus healthy carrier state who develop a superadded (intercurrent) infection due to Hepatitis E virus, ^he following description is given merely to illustrate the inventiion and this should not be
g
onstrudeto limit the scope of the invention. XAMPLE 1 : Describes the pnarmaceutical preparation of plant
extract.
Pharmaceutical preparation of plant extracts :
The plant extracts which are mixed together to obtain the present novel composition can be obtained by any known manner. All batches of plants used in the preparation the present movel composition were botanically authenticated. The solvent used in the extraction of the plants may be any suitable solvent such as ethanol, methanol, chloroform and water.
Preferably, the plants extract can be obtained by any known manner. Most preferably, the whole plants and parts thereof wert powdered and extracted with water. The extract was evaporatsed

under reduced pressure below 50°C leaving a residue. For human administration, the residue is mixed with pharmaceutically acceptable neutral excepients and converted into suitable oral dosage form.
Alternatively, the method of preparing the novel composi-tions comprising blending and extracting in any known ratio of all the plants or plant materials together by any known manner..
The hepatoprotective herbs used for the formulation of the present composition contains the extracts, preferably aquetous extracts of the following :
Common Name Botanical Name Range of Extract
in mg per dose
Bhumyama Laki Phyllanthus amarxus 25-250
Bringraj Eclipta alba 25-250
Kalmegh Andrographis paniculata 25-250
Kutki Picrorhiza kurroa 25-250
What is unexpected in the present invention is that earlier, the above four plant extracts were combined in the range of 10 to 20 mg individually, the hepatoprotective property of this comlli'-nation is identified only when the amounts of these ingredients are enhanced to the rage of 25 to 250 mg per dose. In otrter words, the applicants for the first time noticed the hitherfto unknown hepatoprotective property of the composition comprising
extracts of plants namely Phyllanthus amari»s, Ecllpta alba Andrographis paniculata and Picrorhiza kurroa when the amounts of these plant extracts are enhanced to the range of 25 to 250 :. mg per dose.
The present invention also provides a hepatoprotective in the liver disease resulting from acute Hepatitis E virus infec-tion and anti hepatitis B virus composition comprising the fol-lowlng plant extracts :
Coanon Name Botanical Name Range of Extract
in rag per dose
Bhumyama Laki Phvllanthus amarus 25-250
Bringraj Eclipta alba 25-250
Kalmegh Andrographis paniculata 25-250
Kutki Picrorhiza kurroa 25-250
Rheum emodi Rheum emodi Wall 25-250
The above novel compositions also comprising optional ingre-dients such as extracts, preferably aqueous extracts of the following plants :
CoiRBion Name Botanical Name Range of Extract
in rog per dose
Pitpapra Fumaria officinalis 5-50
Gilo Tinospora cordifolia 5-50
Haritaki Terminalia chebula 5-50
Kasni Cichoriumiinlybus 10-50
Sarphunka Tephrosea purpurrea 10-50
Punarnava Boerhaavia diffusa 10-50

The present composition is a synergistic composition exhib-iting surprising properties such as enhanced hepatoprotective activity in the liver disease caused by Hepatitis E virus infec-tion and anti hepatitis B viral properties. The present inven-tion is illustrated with reference to the following examples and such examples should not be construed at any extent to limit the scope of the invention.
The most preferred method of preparing the polyherbal compo-
sition in tablet form is given below :
COMPOSITION :
Ingredients Qty of crude Qty of crude
Herb/Tablet Herbs for 20
lac tablets
Bhringraj (Eclipta alba) 300 mg 60 kg
Bhumyamalaki (Phyllanthus amarus) 300 mg 60 kg
Sarpaunkha (Tephrosea purpurea) 180 mg 36 kg
Kasni (Cichorium intybus) 180 mg 36 kg
Revand chini {Rheum emodi) 170 mg 34 kg
Punarnava (Boerhaavia diffusa) 100 mg 20 kg
Glio (Tinospora cordifolia) 72 mg 14.4 kg
Haritaki (Terminalia chebula) 72 mg 14.4 kg
Kalmegh (Andrographis paniculata) 60 mg 12 kg
Kutki (Picrorrhiza kurroa) 60 mg 12 kg
Pitpapra (Fumaria officinalis) 30 mg 6 kg
Total 304.8 kg

1. EXTRACTION :
The above mentioned herbs were weighed accurately and re-duced to moderately coarse powder. The herbs (304. fl kg) were extracted in a steam jacketed boiling pan using 8-9 times puri-fied water for 3.0 hours and filtered. The aiarc was again subjected to extraction as earlier using 6-7 tiaes purified water for three more hours and filtered and both the filtrates were combined together.
2. CONCENTRATION, DRYING AND PULVERISATION OF HERBAL EXTRACT
The combined filtrate was concentrated and dried by spray drying method where no excipient is used. Sometimes it is dried by tray drying method also where the combined filtrate is concentrated to a semisolid consistency and was poured on to, a thin bed of Starch-Microcrystalline cellulose powder (each 10% of herbal extract) over trays of electric tray drier and dried at 70-80°C.
The dried extract was pulverised through micro-pulverifer and sieved through No.40 sieve. 3- GRANULATION :
Powdered herbal extract was mixed with inert diluents like Microcrystalline cellulose. Calcium carbonate and granulated using starch-gelatin paste. 4. DRYING AND SIZING OF GRANULES :
The granules were dried in electric tray drier at 60°C and the entire quantity of granules were passed through No.16 sievei
5. COMPRESSION ;
The granules were mixed with lubricants like Starch, Talc and Magnesium stearate and compressed on Rotary Tablet Compres-sion Machine using circular deep concave punches.
EXAMPLE 2 : describes the controlled clinical trial of the present composition (with Rheum emodi) in the treatment of acute viral hepatitis caused by Hepatitis E virus infection. MATERIAL & METHOD :
Nine (9) patients (6 males, 3 females) of a mean age of 11.5 years (range 18 to 45 years) presenting within one week of the onset of the clinical symptoms suggestive of classical acute viral hepatitis (AVH) were included in the study. The diagnosis of AVH was established by the clinical symptoms (acute onset orf jaundice, gastrointestinal symptoms p.g. abdominal pain, anorexia, vomiting along with tender hepatomegaly). The diagnosis was supplemented by abnormal liver function tests e.g. estimation [of Serum Bilirubin, ALT (SGPT), AST (SCOT), and Alkaline Phospa-
J-
tase. The diagnosis of the etiological agents (hepatitis viruses A, B, C, D and E) were done by the following parameters : hepatitis B virus - presence of HBcIgM with or without HBsAg, hepatitis A virus - presence of HAV IgM, hepatitis C virus - presence ©f anti HBc, hepatitis D virus - presence of anti HDV IgM, hepatitis E virus - presence of anti HEV IgM. All the serological tests were done by Enzyme Immune Assay (Elisa) at the time of clinical presentation and the subsequent intervals during therapy. In all
the 9 patients the serological markers of hepatitis A, B, C and D were absent and only anti HEV IgM was present. Further, the other possible causes which might have led to a similar clinical presentation e.g. surgical jaundice, drug mdaced cholestasis, herpes and cytomegalo virus infection were also excluded in all the 9 patients. A prior consent of all the patients were ob-tained and they were explained about the treatment protocol. The preparation of polyhedral pharmaceutical preparation in the tablet form for clinical use in the above 9 patients has been described in example 1. Each patient was given 2 tablets of polyhedral pharmaceutical preparation, two times a day for a period of 4 weeks. The clinical assessment and the liver fund-tion tests along with the anti HEV IgM (Elisa) was done at two weekly interval, also if required at weekly interval (m pateent No.9). RESULTS :
Table 1 - shows the mean values of liver function tests eft the time of diagnosis and at subsequent period of polyher^j^ pharmaceutical composition therapy.
Table 2 - summarises the effects of the polyherbal pharita-ceutical composition therapy.
Tables 3 to 8 - show the details of liver function tests ^at the time of presentation (prior to start of therapy) and at 2 a^iB 4 week interval of the polyherbal pharmaceutical composit:^» therapy.
In all the nine Acute E virus hepatitis patients a clinical as well as biochemical recovery was noted from second week onward. A complete clinical recovery occurred in all the patients by four weeks of therapy. No side effect of the therapy was observed in any of the nine patients.
Table 1: Summary of Biochemical Investigations (mean values) from Clinical Trial Data on the Polyherbal Pharmaceutical composition in the patients of Classical Acute E virus Hepatitis.
(Table Removed)
Normal values: SCOT =10-35 lU/L: SGPT = 10-40 lU/L;
S.Bilirubin = 0.3-1.0 mg/dl : Alk. Phosphatase = 60-170 lU/L
Table 2 - demonstrates the effects on physical sign and symptoms of the patients of classical Acute E virus hepatitis receiving polyherbal pharmaceutical composition therapy (9 patients).
(Table Removed)
+, ++, +++ and ++++ indicates intensity of acute hepatitis E in patients and "-" indicates the degree of recovery
The findings of the liver function tests are also illustrat ed for each individual patient as below : Table 3 : Patient No.1
(Table Removed)

Normal values: SCOT = 10-35 lU/L : SGPT = 10-40 lU/L:
S.Bilirubin = 0.3-1.0 mg/dl: Alk. Phosphatase = 60-170 lU/L.
+ = Positive, - = Negative.
Table 4 : Patient No.2
(Table Removed)

Normal values: SCOT = 10-35 lU/L : SGPT = 10-40 lU/L:
S.Bilirubin = 0.3-1.0 mg/dl: Alk. Phosphatase = 60*170 lU/L.
+ = Positive, - = Negative.
Table 5 : Patient No.3
(Table Removed)
Normal values: SCOT = 10-35 lU/L : SGPT = 10-40 lU/L:
S.Bilirubin = 0.3-1.0 mg/dl: Alk. Phosphatase - 60-170 lU/L.
+ = Positive, - = Negative.
Table 6 : Patient No.4
(Table Removed)
Normal values: SCOT = 10-35 lU/L : SGPT = 10-40 lU/L:
S.Bilirubin = 0.3-1.0 mg/dl: Alk. Phosphatase = 60-170 lU/L.
+ = Positive, - = Negative.
Table 7 : Patient No.5
(Table Removed)

Normal values: SGOT = 10-35 lU/L : SGPT = 10-40 lU/L:
S.Bilirubin = 0.3-1.0 mg/dl: Alk. Phosphatase = 60-170 lU/L.
+ = Positive, - = Negative.
Table 8 : Patient No.6
(Table Removed)

Normal values: SGOT = 10-35 lU/L : SGPT = 10-40 lU/L:
S.Bilirubin = 0.3-1.0 mg/dl: Alk. Phosphatase = 60-170 lU/L.
+ = Positive, - = Negative.
Table 9 : Patient No.7
(Table Removed)

Normal values: SCOT = 10-35 lU/L : SGPT = 10-40 lU/L:
S.Bilirubin = 0.3-1.0 mg/dl: Alk. Phosphatase = 50-170 lU/L.
+ = Positive, - = Negative.
Table 10 : Patient No.8
(Table Removed)

Normal values: SCOT = 10-35 lU/L : SGPT = 10-40 lU/L:
S.Bilirubin = 0.3-1.0 mg/dl: Alk. Phosphatase = 60-170 lU/L.
+ = Positive, - == Negative.
The present polyherbal pharmaceutical composition thus promotes a rapid rate of recovery in subjective symptoms and objective parameters supported by liver function tests in patients 'of acute Hepatitis E virus infection thereby grossly reducing the period of clinical convalescence.
Example 3 : The usefulness of the present polyherbal pharmacqsu-tical composition in the therapy of hepatitis B virus carrier developing a super imposed acute hepatitis due to hepatitis E virus infection has been illustrated.
A 45 year health male who has been a carrier of hepatitis B virus (as demonstrated by the presence of HBsAg at two different intervals of 3 months each) developed acute hepatitis E virus infection resulting in hepatitis. The Table 11 shows the details of the liver function tests at the time of presentation (before the start of therapy) and subsequently upto 16 weeks at the interval of 4 weeks. He received the polyherbal pharmaceutical composition in the doses of two tablets two times a day for a period of 12 weeks. There was a marked improvement in the liver function tests at 4 weeks interval with a complete recovery occurring at the end of 8 weeks therapy. Clearance of hepatitis B virus infection was observed at the end of 8 weeks therapy. The therapy with the polyherbal pharmaceutical composition was
stopped after 12 weeks and the liver function tests were idane after 4 weeks, which were normal along with the absence nf hepa-titis B virus infection.
HBV Carrier with Acute HEV Superinfection snows the findings of liver function tests, hepatitis B virus and hepatitis E vi|i|s. In a patient receiving polyherbal pharmaceutical composition-
(Table Removed)
Normal values: SCOT = 10-35 lU/L : SGPT = 10--in IU/L: S.Bilirubin = 0.3-1.0 mg/dl: AlK. Phosphatase = 60-170 lU/L. + = Positive, - = NFegative.
The above example suggests that the polvherbal pharmaceutical composition brings about the clearance of hepatitis B virus infection and also is helpful in superadded hepatitis E virus infection.

We claim:
1. A process for the preparation of a novel synergistic pharmaceutical herbal
composition for treatment of acute and chronic viral hepatitis, hepatitis E virus
infection, therapeutic effect of hepatitis B virus infection and as a hepatoprotective
agent, said process comprising the steps of:
a. preparing an extract of whole or parts of essential plants selected from Rheum
emodi Wall, Phyllanthus amarus Linn., Eclipta alba Hassk, Androsraphis
paniculate Nees and Picrorhiza kurroa Royle ex Be nth., and optionally adjuvants
selected from Fumaria officinalis Linn., Tinospora cordifolia Pliers., Terminalia
chebula Retz., Cichorium intybus Linn., Tephorosea purpurea Linn, and
Boerhaavia 'diffusa with a solvent such as hereindescribed, wherein the extract per
dose of the essential plants ranges from 25 to 250 mg and the extract per dose of
the optional plants ranges from 5 to 50 mg,
b. evaporating the extract under reduced pressure below 50°C to obtain a residue,
c. mixing the residue with pharmaceutically acceptable neutral agents as
hereindescribed, and preparing the herbal composition by methods known per se.
2. A process as claimed in claim 1 wherein the plant parts are selected from leaves and roots.
3. A process as claimed in claim 1 wherein the solvent is selected from ethanol, methanol, chloroform, hexane, ethyl acetate, methyl chloride, carbon tetrachloride, toleuene, acetone and water and mixtures thereof.
4. A process as claimed in claim 1 wherein the plant or parts thereof are used as whole or in powdered form.
5. A process as claimed in claim 1 wherein the pharmaceutically acceptable neutral agents are selected from starch microcrystalline cellulose powder, calcium carbonate and starch gelatin paste.

6. A process as claimed in claim 1 wherein the composition of plant extracts comprises
the following ingredients:
Ingredients Qty. of Herb (per kg)
Rheum emodi Wall 170 mg
Eclipta alba Hassk 300 mg
Phyllanthus amarus Linn 300 mg
Tephrosea purpurea Linn 180 mg
Cichorium intybus Linn 180 mg
Boerhaavia diffusa 100 mg
Tinospora cordifolia Miers 72 mg
Terminalia chebula Retz. 72 mg
Andrographis peniculate Nees. 60 mg
Picrorrhiza kurroa Royle ex Benth. 60 mg
Fumaria officinalis Linn. 30 mg
7. A process for the preparation of a novel synergistic herbal composition for treatment
of acute and chronic viral hepatitis, hepatitis E virus infection, therapeutic effect of
hepatitis B virus infection and as a hepatoprotective agent substantially as
hereindescribed with reference to the examples.

Documents:

1403-del-1998-abstract.pdf

1403-del-1998-claims.pdf

1403-del-1998-complete specification (granted).pdf

1403-del-1998-correspondence-others.pdf

1403-del-1998-correspondence-po.pdf

1403-del-1998-description (complete).pdf

1403-del-1998-form-1.pdf

1403-del-1998-form-2.pdf

1403-del-1998-form-26.pdf

1403-del-1998-form-4.pdf

1403-del-1998-form-5.pdf

1403-del-1998-form-9.pdf

1403-del-1998-petition-123.pdf

1403-del-1998-petition-124.pdf

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Patent Number

189316

Indian Patent Application Number

1403/DEL/1998

PG Journal Number

6/2003

Publication Date

08-Jan-2003

Grant Date

24-Feb-2004

Date of Filing

25-May-1998

Name of Patentee

DABUR RESEARCH FOUNDATION

Applicant Address

22, SITE IV, DAHIBABAD, GHAZIABAD 201 010,INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	RAJ MEHROTRA	9, SHAMIMA ROAD, LUCKNOW 226003,INDIA.

PCT International Classification Number

A61K 35/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA