WO2015177805A1

WO2015177805A1 - Combination of taurine and racemethionine for treatment of liver diseases

Info

Publication number: WO2015177805A1
Application number: PCT/IN2014/000510
Authority: WO
Inventors: Kamlesh Rajnikant Zota; Sanjay Agrawal; Ketan Chandulal Zota; Manukant Chandulal Zota; Himanshu Muktilal Zota
Original assignee: Zota Health Care Ltd
Priority date: 2014-05-19
Filing date: 2014-08-01
Publication date: 2015-11-26
Also published as: AP2016009662A0; EA201691599A1

Abstract

The present invention describes of a synergistic oral composition comprising of taurine and racemethionine, wherein the taurine being taken in the range of 250mg to 500mg and the racemethionine is taken in the range of lOOmg to 200mg by weight of the Composition, the active weight resulting into a therapeutically, synergisticaily effective oral composition, in order to provide safe and effective dosage form along with other pharmaceutical excipients. It provide different release drug profile such as Sustained or controlled or retard formulation available in oral formulation (capsule, tablet, granules and syrup thereof) and instant energy with hepatic disorders, active antioxidant properties, due to its synergisticaily effective amount of taurine and racemethionine in the formulation, the effective amount as above is taken along with suitable excipients, additives and releasing agents to make a formulation.

Description

COMBINATION OF TAURINE AND RACEMETHIONINE FOR

TREATMENT OF LIVER DISEASES

FIELD OF THE INVENTION

The present invention relates to a synergistic oral pharmaceutical composition for the effective treatment of liver diseases, the said composition comprises of main active ingredients such as Taurine and Racemethionine, along with pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION

The back ground and field of the invention related to a synergistic oral pharmaceutical composition for treatment of liver diseases, the formulation made by combination of taurine and recemethionine as active ingredients' whereas the none of the prior art related to the taurine and recemethionine combination not been disclosed

The liver is the heaviest and one of the largest organs in the body. Though this powerhouse organ is involved in over 500 different functions the major functions can be classified into two main categories:

- Metabolic functions: Liver plays a key role in maintaining body's chemical constitution and performs thousands of chemical reactions important in metabolism of major nutrients like carbohydrates, fats and proteins.

- Detoxification: Liver is the major organ responsible for the detoxification of internal as well as external toxic substances, infectious microbes, chemical substances, drugs, toxins as well alcoholic substances.

These important functions are possible due to of chemical reactions which are controlled by enzymes - the protein substances made up of amino acids. Certain amino acids are concentrated in liver and are responsible for major reactions in liver like methylation, sulfuration and so on. During stressed liver conditions like in alcoholism, fatty liver or in toxic liver diseases these

l amino acids are commonly found in reduced levels. This leads to acute or chronic hepatotoxic conditions, hepatopathies and abnormal liver function tests mainly raised levels of alanine aminotransferase (ALT or SGPT) and aspartate aminotransferase (AST or SGOT).

Supplementation of these important amino acids helps in maintaining the proper liver functions, protecting the liver Cells from toxic damages and in many cases in regeneration of liver cells in necrotic region. The prior published WO 2006/062273 Al, teaches to a health supplement food utilizing, in particular, branched amino acids from among essential amino acids. More specifically, the present invention relates to health supplement food comprising branched chain amino acids composed of leucine (L), isoleucine (I) and valine (V) which is made to have a composition similar to essential amino acids contained in naturally-occurring milk, eggs, soybeans, beef etc, and enhancing instant impact power under anaerobic conditions, via addition of L- glutamine and taurine which are essentially required when a person is exposed to excessive exercise, stress or overwork; a health supplement food for improving a weak constitution, comprising herbal materials such as ginseng, red ginseng and Acanthppanax; and a diet food or beverage further comprising dietary fibres such as insulin, polydextrose and crystalline cellulose, and carnitine and hydroxy citric acid.

United States Patent 5817695 which describes of a nutritional product is provided for cancer patients, in terms of calorie requirement, a low concentration of carbohydrate, a high concentration of fat and an imbalance of amino acids wherein L-phenylalanine, L-tyrosine and L-methionine are present in the below normal concentrations and L-leucine is present in substantial excess of normal concentrations to suppress cancer growth and as an adjunct to conventional cancer therapies.

Certain amino acids have found to play a promising role in preventing and treating a majority of these liver diseases due to their antitoxic, osmoregulatory effects and antioxidant properties. Glutathione and Taurine are vital amongst them.

Racemethionine and taurine are such two important amino acids found to have synergistic therapeutic effect in normal liver functions as well as during stressed or toxic liver conditions hence the combination of those two active drugs have not been described or suggested in any prior art published documents.

OBJECTS

The pharmaceutically effective combination of Taurine and Racemethionine in the disclosed amount would effectively remove toxic chemicals and metabolites.

A synergistic effective amount of present composition it enhances transport of important ions across hepatocytes thus improving their functions and recovery. A deficiency of taurine can lead to electrolyte imbalance due to impaired mineral transport across cell membranes and this reduces the ability of the liver to remove toxic substances.

SUMMARY OF THE INVENTION

The present invention describes of a synergistic composition comprising of Taurine and Recemethionine wherein the active Taurine is being taken in the range of 250mg to 500mg and the Racemethionine is taken in the range of l Omg to 200mg by weight of the composition, the active weight resulting into a therapeutically , synergistically effective oral composition, in order to provide safe and effective oral dosage form along with other excipients.

In one aspect, the invention is to provide different release drug profile such as sustained or controlled or retard formulation available in oral formulation (capsule, tablet, granules and syrup thereof)

In one aspect, it will provide instant energy with hepatic disorders and active antioxidant properties, due to its synergistically effective amount of taurine and recemethionine in the oral formulation, the effective amount as above is taken along with suitable excipients, additives and releasing agents to make a formulation. DETAILED DESCRIPTION OF THE INVENTION

The present inversion described in detail in connection with certain preferred ,and optional embodiments. Alleged composition surprisingly found the synergistic combination of active ingredients such as taurine and racemethionine in an effective amouilt for the treatment of liver diseases.

The present invention discloses an efficacious and synergistically effective pharmaceutical composition in oral dosage form. This comprises therapeutically effective amount of taurine taken in the range of 250mg to 500mg and the racemethionine is taken in the range of lOOmg to 200mg by weight of the composition along with recipients thereof unable to make the formulation stable, in the form of tablet, capsule, granules and syrup thereof.

Further embodiment of the invention, Liver is the main organ for taurine biosynthesis and also an important organ for taurine's many biological activities. Taurine a liver protecting amino acid, is essential for formation of bile acids and thus for detoxification processes. Further taurine contains sulfur and directly combines and removes of toxic chemicals and metabolites. The effective amount of Taurine reduces the secretion of apolipoprotein B100 and lipids in Hepatic G2 cells and is effective in removing fatty liver deposits, preventing liver disease, and reducing cirrhosis. Importantly taurine has protective and preventive role in portal hypertension, a detoxifying agent with antioxidant action that helps protect liver cells against various toxins. Taurine increases levels of antioxidant enzymes like glutathione peroxidase, superoxide dismutase and catalase in liver and thus protects hepatocytes from free radical and ROS induced damages. In the case of Taurine deficiency and liver injuries (study on mice) wherein Taurine deficiency can trigger hepatitis and liver fibrosis, probably due to a diminished antioxidant defence, increase in inflammatory reactions and mitochondrial dysfunction in hepatocytes.

The inclusion of taurine in combination of recemethionin in a liver supplementation is beneficial for the treatment of above complication.

Liver injuries (study on mice) wherein Taurine deficiency can trigger hepatitis and liver fibrosis, probably due to a diminished antioxidant defence, increase in inflammatory reactions and mitochondrial dysfunction in hepatocytes is being demonstrated and the deficiency is being recovered using the inventive composition. As the deficiency increases free radicals, ROS mediated oxidative damages and formation of toxic metabolites in liver cells. This can be seen as there is a 6-fold increase in the TNF plasma levels. Tissue necotising factor alpha is a marker for inflammatory processes that leads to cell death. The present invention supplementation prevents these damages and protects cells.

Severe toxicities cause death of more and more hepatocytes. These cells are replaced by formation of new cells. If the cell destruction is high, the newly formed cells are immature and abnormal in shape (oval shape). Development of these cells is associated with liver dysfunction, which can be protected and recovered by using the alleged composition.

This affectivity of the alleged composition is observed in a rat study which used carbon tetrachloride as toxicant. The alleged composition pre-treatment induced a marked beneficial effect regarding the prevention of hepatocellular necrosis and atrophy as demonstrated morphologically. In conclusion, these results suggest that pre-treatment prevents the morphologic damage caused by CC14 in the early stages.

In embodiment of the invention Racemethionine in combination of taurine at the effective amount, is anti-oxidant amino acid useful to treat liver diseases caused by alcoholism including cirrhosis. It protects hepatocytes and enhances their regeneration thus improving liver functions. It acts as important sulphur and methyl group donor in detoxification reactions in liver cells. Apart from direct beneficial actions Racemethionine is a major source of other liver detoxificants including glutathione and S-Adenosyl Methionine (SAMe).

The racemethionine is Sulphur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. Other commonly used names are methionine and DL -methionine.

The first indication of Racemethionine (race-e-me-THYE-oh_'-neen) is used to make the urine more acidic. Making the urine more acidic helps to relieve skin irritation in incontinent (loss of bladder control) adults and diaper rash in infants. This medicine also helps to control strong urine odor. Racemethionine produces ammonia-free urine by lowering the urinary pH.

But one more very important function which is exhibited by Racemethionine is for treating hepatic injury due to acetaminophen overdose. Mechanism of action

Racemethionine and Taurine protect against acetaminophen overdose-induced hepatotoxicity by maintaining or restoring hepatic concentrations of glutathione. Glutathione is required to inactivate an intermediate metabolite of acetaminophen, which is hepatotoxic. In acetaminophen overdose, excessive quantities of this metabolite are formed because the primary metabolic pathways (glucuronide and sulfate conjugation) become saturated. The excess metabolite binds irreversibly to essential hepatic proteins and enzymes, causing cell damage and death. Racemethionine serves as a precursor for the synthesis of glutathione and sulphate.

The Combined effect in hepatic disorders

Taurine, or 2-aminoethanesulfonic acid, is an organic acid. It is a major constituent of bile and can be found in the large intestine and in the tissues of many animals, including humans. Taurine is the most abundant free amino acid in the human body. It has a ubiquitous distribution and accounts for approximately 0.1% of total body weight. Taurine has many fundamental biological roles such as conjugation of bile acids, antioxidation, osmoregulation, membrane stabilization and modulation of calcium signaling.

Taurine is conjugated via its amino terminal group with chenodeoxycholic acid and cholic acid to form the bile salts sodium taurochenodeoxycholate and sodium taurocholate. The low pKa of taurine's sulfonic acid group ensures this moiety is negatively charged in the pH ranges normally found in the intestinal tract and, thus, improves the surfactant properties of the cholic acid conjugate, it has been shown to be effective in removing fatty liver deposits in rats, preventing liver disease, and reducing cirrhosis in tested animals.

Mode of action

The present invention and it's mode of action which demonstrated that taurine reacts with and neutralizes hypochlorous acid, which is generated during oxidative neutrophil burst. The result is a stable taurochloramine compound, as opposed to unstable aldehyde compounds formed in states of taurine deficiency. Individuals who are taurine deficient may become more susceptible to tissue damage by xenobiotic agents such as aldehydes, chlorine, and certain amines. Animal studies have also demonstrated taurine's ability to complex with and neutralize the xenobiotic effects of carbon tetrachloride and retinol. Research also suggests that translocation of bacterial endotoxins may be a factor in determining a person's response to xenobiotic insult. Even small amounts of endotoxin markedly enhance liver injury from hepatotoxic substances such as carbon tetrachloride, ethanol, and cadmium. Taurine was found to significantly inhibit intestinal endotoxin translocation and subsequently decrease hepatic injury from these substances.

The first indication of Racemethionine (race-e-me-THYE-oh-neen) is used to make the urine more acidic. Making the urine more acidic helps, to relieve skin irritation in incontinent (loss of bladder control) adults and diaper rash in infants. This medicine also helps to control strong urine odor. Racemethionine produces ammonia-free urine by lowering the urinary pH.

But one more very important function which is exhibited by Racemethionine is for treating hepatic injury due to acetaminophen overdose.

The present formulation containing the combination of taurine and racemethionine in an effective amount has prevented the above disclosed diseases effectively the said comprising an effective amount of taurine in the range of 250mg to 500mg, and recemethionine in the range of lOOmg to 200mg , excipients used in the present invention taken from maize starch 50 mg to 75mg, lactose 44mg to 66mg , microcrystalline cellulose taken in the range of 60mg to 90mg, colloidal silicone dioxide lOmg to 15mg, poly vinyl pyrrolidine 12mg to 18mg, isopropyl alcohol 90mg to 135mg, sodium starch glycolate 5mg to 7.5 mg , crosspovidene4mg to 6mg, magnesium stearate lOmg to I5mg, purified talc 5mg to 7,5mg, hydroxypropyl methyl cellulose l lmg , titanium dioxide 2, isopropyl alcohol 97mg, methylene chloride 146mg, and Sucrose 500mg to 750mg, Sorbitol 2000mg to 3250mg, Citric acid 5mg to 7.5mg, SMP 5mg to 7.5mg, SPP lrrig to 7.5mg, Bronopol 1.25mg to 2.50mg, Citric acid 1.25mg to 2.50mg, Sodium CMC lOmg to 35mg, Sodium benzoate lOmg to 35mg, Water, Colour & essence taken for preparing tablets, capsules, Granules & syrup. The above combination has been exemplified with working examples

A method for the preparation of above formulation comprising the following steps:

Dispensing:

• Taking all the raw materials to be used for the process must be approved prior to start of dispensing.

• Check the weighing balance calibrated or not and clean the dispensing utilities.

• Check temperature, relative humidity and pressure differential of dispensing area within the limits.

• Weigh the active and excipients as per requisition.

• All the raw materials are then packed in individual poly bags with dispensing Label and containers with proper status label.

• „ The dispensed materials to be transferred to the dispensing hold. • The raw material is then transferred to the processing area when required i.e., when batch manufacturing is undertaken.

Sifting:

• Sift separately required quantities of Taurine, Racemethionine, Maize Starch, Lactose, Microcrystalline Cellulose, Colloidal silicon Dioxide and collect each in a individual double lined polybag.

Dry Mixing

• Load the sifted Materials in Rapid Mixer Granulator (RMG) and mix for 15 minutes at

100 RPM.

Binder Preparation

• In a Clean S.S. vessel, prepare binder solution with Polyvinyl Pyrrolidone (PVPK-30) and Isopropyl Alcohol by continuous stirring to get uniform Paste.

Granulation

• After Completion of dry mixing, start to add binder solution in RMG with impeller at 75 RPM and chopper off for 5 minute. Stop RMG and rake the stick material on RMG inner wall and Impeller.

• Close the lid of RMG and start mixing speed at 75 RP^{^}M and chopper off for 05 minutes to make lumps of resulting materials. Then allow mixing by running impeller at 75 RPM and chopper on for 2 minute to prepare granules.

Drying

• Air dry the wet mass in fluidized bed dryer for 05 minutes.

• Dry material at an inlet air temperature of 60°C ± 5°C.

• Rake the material after completion of each drying cycle.

• Continue dry the granules till LOD of the granules achieved between NMT 5.0 % w/w at 105°C.

Sifting and Milling

• Sift the dried granules through sieve 16 # (SS) and collect the granules in cleaned container lined with polybag. • Mill the oversized Granules retained on sieve through 1.2 mm SS screen with forward direction at 1500 RPM. Collect the milled granules in cleaned container line with polybag.

Blending and Lubrication:

• Sift separately Purified Talc, Magnesium Stearate, Sodium Starch Glycolate, and Crossprovidone and through Sieve 60 # and collect in a double lined polybag.

• Transfer the dried sifted and milled granules of above stage in to Octagonal Blender and add above sifted lubricant materials (Sodium Starch Glycolate & Purified Talc, Crossprovidone, Magnesium Stearate) in to octagonal blender. Close the lid of blender and run it for 15 min at 15 RPM.

• Add sifted Magnesium Stearate of above stage to octagonal blender. Close the lid of blender and run 3 minutes at 15 RPM.

Compression:

• Compress the lubricated blend using tablet shaped punches by compression machine. Coating:

(A) Preparation Of Coating Solution

• In S.S. vessel transfer required quantities of Hydroxy Propyl Methyl Cellulose, Titanium Dioxide adds Isopropyl Alcohol, Methylene Chloride with continuous stirring to prepare the slurry.

• Transfer the solution to solution tank and use for coating purpose.

(B) Coating Instruction And Operation

• Load the tablets into Pearl Coater Switch on the hot air blower. Adjust the temperature of incoming air to 50°C- 55°C. Start rotation of coating pan and spray the dispersion.

• Continue coating until entire coating dispersion is used.

• Store the coated Tablets in double Polylined Container with tight fitting lids; label the Containers with all relevant Batch details.

The method for preparation of tablet comprising the following steps- 1. Take taurine shift it 40 # then add in mass mixture.

2. Take racemethionine shift it 40 # then add in mass mixture.

3. Take lactose shift it 40 # then add in mass mixture.

4. Take starch shift it 40 # then add in mass mixture.

5. Take LP. A then add in mass mixture mix it for 30 minutes.

6. Take P.V.P.K30 8with contains stirring till (clear soon)

7. Add step (5) solution slowly in mass mixture with mixing till proper mass obtain.

8. Shift above mass through 8# in multi mill.

9. Keep it in tray drayer.

10. Adjust temp at 40 c for 4 hours till LP. A complete remove then heat it 60 c for two hours.

11. Shift it at 16 # through shifter.

12. Pass magnesium stearate and talcum mix it and shift it through 100#

13. Mix step 11 & 12 in mass mixture for 5 minutes.

14. Compress the tablet.

In process

1. Check D.T. limit.

2. Check thickness limit.

3. Check weight individual tab for every two hours.

The method for preparation of capsule comprising the following steps-

1. Take 5 kg and taurine shift it 40 # through shifter.

2. Take 2 kg racemethionine shift it 40 # through shifter.

3. Take Magnesium Stearate 0.030 kg shift it 100 # through shifter. 4. Take talcum 0.020 kg shift it 100 # through shifter.

5. Mix it add material and mixture it for 30 minutes

6. Check cap filling machine.

7. Fill 300 cap plates with cap.

8. Fill it with powder 223gms for 300 cap. In process

1. Check 300 filled capsule

a) Proper sealing

b) Denting

c) Locking

2. 20 cap individual cap weight limit +/- 3%

3. 20 cap weight limit +/- 2%

4. DT not more than 10 minutes.

5. Polishing

6. Striping

The method for preparation of Granules comprising the following steps- Dispensing:

• Weigh the active and excipients as per requisition.

• The dispensed materials to be transferred to the dispensing hold.

• The raw material is then transferred to the processing area when required i.e., when batch manufacturing is undertaken. Sifting:

• Sift separately required quantities of Taurine, Racemethionine, Maize Starch, Lactose, Microcrystalline Cellulose, Colloidal silicon Dioxide and collect each in an individual double lined polybag.

Dry Mixing

• Load the sifted Materials in Rapid Mixer Granulator (RMG) and mix for 15 minute at

100 RPM.

Binder Preparation

Granulation

• Close the lid of RMG and start mixing speed at 75 RPM and chopper off for 05 minutes to make lumps of resulting materials. Then allow mixing by running impeller at 75 RPM and chopper on for 2 minute to prepare granules.

Drying

• Air dry the wet mass in fluidized bed dryer for 05 minutes.

• Dry material at an inlet air temperature of 60°C ± 5°C

• Rake the material after completion of each drying cycle.

• Continue dry the granules till LOD of the granules achieved between NMT 5.0 %

w/w at 105°C.

Sifting and Milling

• Sift the dried granules through sieve 16 # (SS) and collect the granules in cleaned container lined with polybag, • Mill the oversized Granules retained on sieve through 1.2 mm SS screen with forward direction at 1500 RPM. Collect the milled granules in cleaned container line with polybag.

Blending and Lubrication:

• Sift separately Purified Talc, Magnesium Stearate, Sodium Starch Glycolate^ and Crossprovidone and through Sieve 60 # and collect in a double lined polybag.

• Transfer the dried sifted and milled granules of above stage iii to Octagonal Blender and add above sifted lubricant materials (Sodium Starch Glycolate & Purified Talc, Crossprovidone, Magnesium Stearate) in to octagonal blender. Close the lid of blender and run it for 15 min at 15 RPM,

The method for preparation of syrup comprising the following steps-

1. Take 20 litres D. M. water heat at 20° C than add sucrose with continuous stirring till complete sucrose dissolve.

2. Add SMP 0.100 kg, SPP 0.020 kg, sodium banzoate 0.100 kg bronopol, 0.025kg with continuous CMC sodium 0.200 kg and citric acid 0.100 kg.

3. Then heat it to boil.

4. Add sorbitol 20 litters with stirring.

5. Fill it then keep it at room temperature.

6. Dissolve L- Taurine 6.750kg in DM water stirring till complete dissolve then filter it and add it in main tank.

7. Dissolve racemethionine 2.500kg in 10 litter DM water stirring till complete dissolve then filter it and add it in main tank. 8. Dissolve colour tetrazine yellow 10 gm in 5 litter DM water stirring till complete dissolve then filter it and add it in main tank.

9. Dissolve essence chocolate bourbon 300 ml and essence vanilla 30 ml and essence honey 20 ml mix it and add in main tank.

10. Complete volume 100 litter by adding DM water.

11. Adjust pH 4.00 to 5.00.

12. Filter complete volume and keep it With label. Ready for filling

Demonstration with regard to synergism, and affectivity of the composition

Apart from metabolic functions liver performs the important function of detoxification of externally introduced toxic substances as well as internally produced toxic waste substances. These functions are carried out either physically by filtering the blood and removing the Waste substances or by neutralizing them chemically. The process involves the formation and utilization of thousands of chemicals including enzymes and the stepwise detoxification where the substances are converted into less harmful and more soluble substrates which are easily excreted out of body via urine or other excretory organs. These functions require continuous administration of amino acids including racemethionine and taurine.

While doing these important function, Liver itself is under the danger of severe toxicities and damages due to harmful toxins, waste products, viruses, bacteria or alcohol. In normal circumstances the liver is protected from their harmful effects due to following two ways:

1. Directly acting and neutralizing the toxic substances: This process involves the transfer of methyl or sulfur group to the toxic substance or its metabolite making them less harmful, racemethionine and taurine both are the excellent sources of methyl group whereas taurine is the richest source of sulfur group in detoxification processes. Further taurine is the most abundant amino acid present in bile which has important role in fat metabolism and detoxification process. 2. The presence of antioxidants which destroy the harmful free radicals and neutralize then! before they could cause serious damage. Glutathione formed from racemethionine is the major antioxidant in the liver.

When body's detoxification process is weakened or the burden of waste and toxic substances increases, the normal detoxification process is insufficient making liver more prone for physical and chemical damages which include:

- Increase in liver size (enlarged liver)

- Accumulation of fats in liver (fatty liver)

- Liver structure damage which can be confirmed by increased blood, levels of liver enzymes like SCOT (AST) or SGPT (ALT)

- Replacement of normal liver cells with abnormal liver cells and liver fibrosis

- Reduced liver function causing increased toxicities to liver itself, rising levels of these toxicants in blood damages Other organs like kidneys, brain or heart.

Alcohol is a major liver toxicant and its chronic consumption may cause following types of liver damages:

• Fat accumulation (fatty liver or steatosis): In some people, the liver is enlarged, tender, or both.

• Inflammation (alcoholic hepatitis): People may have a fever, jaundice, fatigue, under nutrition, and a tender, painful, enlarged liver.

• Liver fibrosis

• Cirrhosis

Viruses are also the major culprits for liver diseases including hepatitis. Racemethionine and taurine formulation in Hepatoprotection :

The best way to protect the liver is to provide the basic building blocks to support its functions or to increase the antioxidant defence that protects the liver cells against toxic damages. Certain amino acids have found to play important role in these vital functions, racemethionine and Taurine are the two major amongst them.

H

-C—N

HO

CH₂

?H₂

S

j

CH₃

Racemethionine:

The role of racemethionine, sulfur containing lipotropic amino acid in hepatoprotection has been amply supported. It is a potent methyl donor, powerful antioxidant and a major source of other liver detoxificants including glutathione and S-Adenosyl Methionine (SAMe). Further methionine is the precursor for the synthesis of cysteine and taurine required in large quantities for liver functions.

Racemethionine has following important functions:

- Lipotropic action- This encourages the export of fat from the liver and thus reduces the chances of fatty liver and liver cirrhosis.

- Liver detoxification-

Methionine acts as a chelator, binding to heavy metals such as lead and others and removing them from the body before they can build up and cause damage to tissues. Methionine also protects liver from the damaging effects of drugs like acetaminophen, nimesulide and other hapatotoxic drugs.

Antioxidant Methionine reconstitutes an important antioxidant defence mechanism. It neutralizes a variety of oxidants by forming methionine sulfoxide and thus scavenges free radicals like H₂0_2, superoxide, ozone, hypochlorous acid, and chloramines,

Methionine in Alcoholic liver disorders -

Alcohol is a major cause of liver disease that disrupts methionine and oxidative balance. Methionine supplementation was found to improve the alcohol-induced histological changes in the liver. Triglyceride content of the liver was found to decrease in a dose-dependent manner with increasing methionine ingestion. Hepatic adenosine triphosphate content increased significantly with higher methionine consumption. These results underscore the impairment of the transmethylation/transsulfuration pathway in the development of alcohol-induced liver diseases and the protective role of racemethionine against alcohol induced hepatotoxicities.

Methionine is the major precursor for other important antioxidant substances like SAMe, cysteine and glutathione.

S-adenosyl-L-methiottine (SAM, or SAMe) in liver protection -

SAMe improves and normalizes liver function. In Europe, SAMe is used in the treatment of cirrhosis and liver damage caused by alcohol.

Through methylation, SAMe increases membrane fluidity, restoring several factors that promote bile flow.

Treatment with SAMe helps decrease serum bilirubin (pigment in the blood that can cause jaundice) in patients with elevated serum bilirubin level.

SAMe was also shown to be useful for opposing the oxidative stress and the alcohol-induced liver injury.

Glutathione (GSH) - The Master Antioxidant in liver: Glutathione is an antioxidant often referred to as the body's "master antioxidant" due to its central role in protecting the body's cells from free radical damage. Glutathione is composed of the amino acids cysteine (formed from methionine), glutamine and glycine and is concentrated in the liver.

Due to its -SH group, glutathione controls many redox reactions. In liver cells, glutathione protects hepatOcytes from the damaging effects of free radicals, toxins, heavy metals and hepatotoxic drugs.

The effect of glutathione depletion in liver is associated with abnormal and elevated liver enzyme like SGOT and SGPT.

Glutathione is important in the management of patients with alcoholic liver disease and viral hepatitis, particularly those with hepatitis C.

Glutathione protects cells in several ways. It neutralizes oxygen molecules before tney can harm cells. It forms the enzyme glutathione peroxidase which neutralizes hydrogen peroxide. It is also a component of another antioxidant enzyme, glutathione-S-transferase which is a broad-spectrum liver-detoxifying enzyme.

Taurine:

Taurine (2-aminoethanesulfonic acid) is a sulfur-containing conditionally-essential amino acid. Derived from methionine and cysteine metabolism, taurine is known to play an important role in numerous physiological functions. Apart from conjugation of bile acids, other metabolic actions of taurine include: detoxification, membrane stabilization, osmoregulation, and modulation of cellular calcium levels. It is found in high concentrations in skeletal muscles, central nervous system as well as in the heart muscles and liver. Taurine is incorporated into one of the most abundant bile acids, chenodeoxychloic acid. Studies have shown that taurine deficiency results in reduced bile acid secretion, reduced fat absorption and reduced liver function, all of which can be reversed by supplementing the diet with taurine.

Detoxifying effects -Taurine directly combines with toxic molecules and removes them from blood circulation. Thus it helps in blood purification that protects important organs including liver from damages.

Taurine in inflammatory liver cells has cytoprotective action. Taurine increases the activities of antioxidant enzymes like superoxide dismutase, glutathione peroxidase and catalase. Taurine reduces Reactive Oxygen Species (ROS) levels by increasing the levels of the antioxidant enzymes.

Taurine is effective in removing fatty liver deposits, preventing liver disease, and reducing cirrhosis. Importantly taurine has protective and preventive role in portal hypertension, the major cause of death in cirrhotic liver conditions.

During hepatitis, taurine supplementation has been shown to reduce bilirubin, total bile acids, and biliary glycine taurine ratio which are important indicators of liver toxicities.

Taurine plays important role in alcoholic liver disorders. Taurine reverses the hepatic steatosis (deposition of fat) and lipid peroxidation caused by chronic alcohol consumption.

Racemethionine + Taurine: A synergistic combination -

Both Racemethionine and Taurine are concentrated in liver and play important role in liver function, detoxification of harmful substances and hepatocyte protection. Many of their functions are independent of each other.

When taurine is used up for metabolic reactions, it is biosynthesized from methionine. Thus methionine is used up in this process and can become deficient in cells during increased workload. Supplementation of taurine reduces the need for conversion of methionine to taurine thus allowing Methionine for its other important functions of liver protection. Further, in some patients excess methionine has been reported to increase homocysteine levels. It is found that taurine causes excretion of homocysteine via kidney and thus balances the effect on homocysteine, if any.

Thus the combination of racemethionine and Taurine is a synergistic combination useful in various liver diseases and others.

Conclusion:

Few patients have responded well with formulation in hepatic disorders of various etiologists. Clinically and pathologically liver function tests were in normal range after the drug administration.

Claims

1. A synergistic combination of taurine and racemethionine an effective amount for treating liver diseases comprising, taurine taken in the range of 250mg to 500mg, and recemethionine taken in the range of lOOmg to 200mg, along with excipients selected from maize starch 50 mg to 75mg, lactose 44mg to 66mg, microcrystalline cellulose 60mg to 90mg, colloidal silicone dioxide lOmg to 15mg, poly vinyl pyrrolidine 12mg to 18mg, isopropyl alcohol 90mg to 135mg, sodium starch glycolate 5mg to 7.5 mg , crosspovidene4mg to 6mg, magnesium stearate lOmg to 15mg, purified talc 5 mg to 7. 5mg, hydroxypropyl methyl cellulose l lmg , titanium dioxide 2, isopropyl alcohol 97mg, methylene chloride 146mg, Sucrose SOOrrtg to 750mg, Sorbitol 2000mg to 3250mg, Citric acid 5mg to 7.5mg, SMP 5mg to 7.5mg, SPP lmg to 7.5mg, Bronopol 1.25mg to 2.50mg, Citric acid 1.25mg to 2.50mg, Sodium CMC lOmg to 35mg, Sodium benzoate lOmg to 35mg, Water, Colour & essence.

2. A pharmaceutical process as claimed in claim 1, wherein the pharmaceutical composition for the tablet is that taurine taken in amount of 450mg, and recemethionine taken I80mg, excipients taken in an amount of maize starch 55mg, lactose 48.5mg, microcrystalline cellulose 66mgj colloidal silicone dioxidel lmg, poly vinyl pyrrolidine I3.2mg, isopropyl alcohol 99mg, sodium starch glycolate 5,5 mg , Crossprovidone 4.4mg, magnesium stearate l lmg, purified talc5.5mg, hydroxypropyl methyl cellulose l lmg , titanium dioxide 2, isopropyl alcohol 97mg, methylene chloride taken at 146mg,

3. A pharmaceutical process as claimed in claim I, wherein oral formulation comprising the following steps,

a) Dispensing,

• Weigh the active and excipients in a desired quantity.

• All the raw materials are then packed in individual poly bags with dispensing Label The dispensed materials to be transferred to the dispensing hold followed by transferring to processing area

b) Sifting

Sift separately required quantities of taurine, racemethionine, Maize Starch, Lactose, Microcrystalline Cellulose, Colloidal silicon Dioxide and collect each in a individual double lined polybag. c) Dry mixing

Load the sifted Materials in Rapid Mixer Granulator (RMG) and mix for 15 minutes at 100 RPM. d) Binder preparation

In a Clean S.S. vessel, prepare binder solution with Polyvinyl Pyrrolidone (PVPK-30) and isopropyl Alcohol by continuous stirring until to get uniform Paste. e) Granulation

After Completion of dry mixing, add binder solution in RMG with impeller at 75 RPM and chopper off for 5 minute to prepare granules f) Drying

Air dries the wet mass in fluidized bed dryer for 05 minutes.

Dry material at an inlet air temperature of 60°C ± 5°C.

Rake the material after completion of each drying cycle.

Continue dry the granules till LOD of the granules achieved between NMT 5.0 % w/w at l05°C. g) Sifting and Milling

• Sift the dried granules through sieve 16 # (SS) and collect the granules in cleaned container lined with polybag.

• Mill the oversized Granules retained on sieve through 1.2 mm SS screen with forward direction at 1500 RPM. Collect the milled granules in cleaned container line with polybag. h) blending and lubricating

• Sift separately Purified Talc, Magnesium Stearate, Sodium Starch Glycolate* and Crossprovidone and through Sieve 60 # and collect in a double lined polybag.

i) Compression

• Compress the lubricated blend using tablet shaped punches by compression machine, j) Coating

Preparation of coating solution

• Transfer the solution to solution tank and use for coating purpose.

Coatng instruction and operation

• Load the tablets into Pearl Cpater Switch on the hot air blower. Adjust the temperature of incoming air to 50°C- 55°C. Start rotation of coating pan and spray the dispersion.

• Continue coating until entire coating dispersion is used.

4. A pharmaceutical process as claimed in claim 1, wherein tablet formulation comprising the following steps,

a) Take 450mg taurine shift it 40 # then add in mass mixture. b) Take 180 racemethionine shift it 40 # then add in mass mixture.

c) Take lactose 48mg shift it 40 # then add in mass mixture.

d) Take starch 5.5mg shift it 40 # then add in mass mixture.

e) Take 99mg I.P.A then adds in mass mixture mix it for 30 minutes.

f) Take P.V.P.K 13.2mg with contains stirring till until clear solution

g) Add step (5) solution slowly in mass mixture with mixing till proper mass obtain. h) Shift above mass through 8# in multi mill.

i) Keep it in tray drayer.

j) Adjust temp at 40° c for 4 hours till I.P.A complete remove then heat it 60° c for two hours.

k) Shift it at 16 # through shifter.

1) Pass magnesium stearate 150 gm and talcum 100 gm mix it and shift it through 100# m) Mix step 11 & 12 in mass mixture for 5 minutes.

5. A pharmaceutical process as claimed in claim 1, wherein capsule formulation comprising the following steps,

a) Take 5 kg and taurine shift it 40 # through shifter.

b) Take 2 kg racemethionine shift it 40 # through shifter.

c) Take Magnesium Stearate 0.030 kg shift it 100 # through shifter.

d) Take talcum 0.020 kg shift it 100 # through shifter.

e) Mix it add material and mixture it for 30 minutes

f) Check cap filling machine.

g) Fill 300 cap plates with cap.

h) Fill it with powder 223gms for 300 cap.

i) In process - Check 300 filled capsule

Proper sealing Denting

Locking

j) 20 cap individual cap weight limit +/- 3%

k) 20 cap weight limit +/- 2%

1) DT not more than 10 minutes,

m) Polishing

n) Striping

6 A pharmaceutical process as claimed in claim 1, wherein granules formulation comprising the following steps

a) Dispensing

• Weigh the active and excipients-as per requisition.

• The dispensed materials to be transferred to the dispensing hold.

• The raw material is then transferred to the processing area when required i.e., when batch manufacturing is undertaken.

b) Sifting:

• Sift separately required quantities of Taurine, Racemethionine, Maize Starch, Lactose, Microcrystalline Cellulose, Colloidal silicon Dioxide and collect each in a individual double lined polybag. c) Dry Mixing

• Load the sifted Materials in Rapid Mixer Granulatof (RMG) and mix for 15 minute at 100 RPM.

d) Binder Preparation

e) Granulation • After Completion of dry mixing, start to add binder solution in RMG with impeller at 75 RPM and chopper off for 5 minute. Stop RMG and rake the stick material on RMG inner wall and Impeller.

f) Drying

• Air dry the wet mass in fluidized bed dryer for 05 minutes.

• Dry material at an inlet air temperature of 60°C ± 5°C.

• Rake the material after completion of each drying cycle.

g) Sifting and Milling

• Mill the oversized Granules retained on sieve through 1.2 mm SS screen with forward direction at 1500 RPM. Collect the milled granules in cleaned container line with polybag.

h) Blending and Lubrication:

• Transfer the dried sifted and milled granules of above stage in to Octagonal Blender and add above sifted lubricant materials (Sodium Starch Glycolate & Purified Talc, Crossprovidone, Magnesium Stearate) in to octagonal blender. Close the lid of blender and run it for 1 min at 15 RPM.

7 A pharmaceutical process as claimed in claim 1, wherein syrup formulation comprising the following steps

a) Take 20 litres D. M. water heat at 20° C than add sucrose with continuous stirring till complete sucrose dissolve. b) Add SMP 0 .100 kg, SPP 0.020 kg, sodium banzoate 0.100 kg bfonopol, 0.025kg with continuous CMC sodium 0.200 kg and citric acid 0.100 kg.

c) Then heat it to boil.

d) Add sorbitol 20 litters with stirring.

e) Fill it then keep it at room temperature.

f) Dissolve L- Taurine 6.750kg in DM water stirring till complete dissolve then filter it and add it in main tank.

g) Dissolve racemethionine 2.500kg in 10 litter DM water stirring till complete dissolve then filter it and add it in main tank.

h) Dissolve colour tetrazine yellow 10 gm in 5 litter DM water stirring till complete dissolve then filter it and add it in main tank.

i) Dissolve essence chocolate bourbon 300 ml and essence vanilla 30 ml and essence honey 20 ml mix it and add in main tank.

j) Complete volume 100 litter by adding DM water,

k) Adjust pH 4.00 to 5.00.

1) Filter Complete volume and keep it with label. Ready for filling.

8 A pharmaceutical composition as claimed in claim 1 wherein it is available in various oral dosages forms such as tablet, capsule, granules and syrup thereof.