Oral pharmaceutical compositions comprising vitamin e and phospholipid for use in liver health optimization

Abstract

The disclosure relates to an oral composition comprising an active ingredient consisting essentially of alpha tocotrienol, gamma tocotrienol, delta tocotrienol, alpha tocopherol and phospholipid in specific percentages for use in liver health optimization. The compositions are stable at room temperature & accelerated storage conditions.

Description

[0001] ORAL PHARMACEUTICAL COMPOSITIONS COMPRISING VITAMIN E AND PHOSPHOLIPID FOR USE IN LIVER HEALTH OPTIMIZATION

[0002] FIELD OF THE INVENTION

[0003] The present disclosure relates to an oral pharmaceutical compositions consisting of alpha tocotrienol, gamma tocotrienol, delta tocotrienol, alpha tocopherol and phospholipid for use in liver health optimization. The compositions are stable at room temperature and accelerated stability conditions.

[0004] BACKGROUND OF THE INVENTION

[0005] Fatty liver disease (FLD), both alcoholic fatty liver disease (AFLD) and non-alcoholic fatty liver disease (NAFLD), result in an unregulated lipid metabolism. The NAFLD is a prevalent metabolic disorder, often associated with obesity and insulin resistance, characterized by excessive fat accumulation in the liver. NAFLD can progress to nonalcoholic steatohepatitis (NASH), liver fibrosis, and eventually cirrhosis.

[0006] NAFLD is defined as the presence of hepatic steatosis, with or without inflammation and fibrosis, in the absence of alcohol history. NAFLD is subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). In NAFL, hepatic steatosis is present without evidence of significant inflammation, whereas in NASH, hepatic steatosis is associated with hepatic inflammation that may be histologically indistinguishable from alcoholic steatohepatitis. There are many approaches used to assess and evaluate whether a subject has NAFLD and if so, the severity of the disease, including differentiatingwhether the NAFLD is NAFL or NASH. The severity of NAFLD can be assessed using the NAFLD Activity Score (NAS).

[0007] Most people with NASH have no symptoms. Some may have right upper quadrant pain, hepatomegaly, or nonspecific symptoms such as abdominal discomfort, weakness, fatigue or malaise. A doctor or nurse may suspect the presence of NASH from the results of routine blood tests. In NAFLD, liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are often high. The current gold standard to confirm NASH is a histological evaluation of liver biopsy, which is expensive, invasive, and can cause pain, hemorrhage, or even death. A simple blood test that would identify and distinguish the various stages of both NAFLD and NASH (and thereby reduce the need for liver biopsy) would be highly desirable.

[0008] There are many pathways driving FLD but three of the important pathways for disease progression are reactive oxygen species (ROS), sterol regulatory element-binding protein-1 (SREBP-1), and peroxisome proliferator-activated receptors (PPAR). Modulation of each of these pathways has shown some benefit in abrogating FLD. Blocking ROS using vitamin E has demonstrated positive effects in animal models and there are some positive data in human trials. The role of oxidative stress and lipid dysregulation is central to NAFLD pathogenesis.

[0009] Vitamin E, a potent antioxidant, especially in the form of tocotri enols and tocopherols, has shown potential for protecting the liver against oxidative damage and may prevent liverinjury by protecting against mitochondrial toxicity and blocking intrinsic apoptotic pathways. Vitamin E may also down-regulate NF-kB-dependent inflammatory pathways. However, antioxidant therapies have not always been favorable and were shown to be associated with worsening pathology. Administration of high doses of Vitamin E improved NAS within two years, but often increases insulin resistance and plasma triglyceride levels. Indeed, concerns about long-term safety of high-dose Vitamin E exist, such as an increase in overall mortality, the incidence of hemorrhagic stroke, and even prostate cancer in males older than 50 years.

[0010] Phospholipid, key structural components of cell membranes, have also been studied for their hepatoprotective properties. Essential phospholipids have been administered to people with fatty liver since 1988 due to their antioxidant, anti-inflammatory, and apoptosis-modulating effects.

[0011] The European patent publication no. EP4161505 discloses a self-emulsifying composition comprising phospholipids, tocotrienols and tocopherols as active ingredients and a nonionic surfactant, a co-surfactant, vegetable oil as inactive ingredients. The EP4161505 also discloses that the composition provide an effectively delivered micronutrients and vitamins to the liver and also facilitate hepatic regeneration thereof to enhance the normalisation of fatty liver. Specifically, the EP4161505 discloses a composition containing, by weight of the composition, 4.5-20 % w / w of phospholipids, 10-35 % w / w of tocotrienols (preferably the tocotrienols comprise 3.5-9% w / w of alpha tocotrienol, 0.4-2.2 % w / w of betatocotrienol, 4.5-15.5 % w / w of gamma tocotrienol, 1-7.5 % w / w of delta tocotrienol) and 2-10 % w / w of tocopherol (preferably alpha tocopherol).

[0012] The PCT publication no. WO2019075277 discloses liposomal formulations containing phosphatidylcholine / phosphatidylcholine derivatives and vitamin E for the treatment of liver fibrosis and associated conditions such as fatty liver disease and NASH.

[0013] Thus, there remains a need in the art for oral compositions comprising vitamin E and phospholipids having improved efficacy for treatment or management of liver disease, preferably NAFLD. The inventors have surprisingly discovered that oral compositions comprising active ingredient consisting essentially of 8 % to 35 % of alpha tocotrienol, 16 % to 60 % of gamma tocotrienol, 2 % to 20 % of delta tocotrienol, 8 % to 30 % of alpha tocopherol and 3 % to 60 % of phospholipid based on the total weight of the active ingredients, wherein the compositions are useful in liver health optimization. Specifically, the compositions provide improved hepatoprotective effect, improved efficacy for the treatment or management of liver disease, preferably NAFLD and / or improving liver health.

[0014] Additionally, the inventors discovered a method of treating a non-alcoholic fatty liver disease by orally administering an oral composition comprising:

[0015] a) an active ingredient consisting essentially of 8 % to 35 % w / w of alpha tocotrienol, 16 % to 60 % w / w of gamma tocotrienol,

[0016] 2 % to 20 % w / w of delta tocotrienol, 8 % to 30 % w / w of alpha tocopherol and 3 % to 60 % w / w of phospholipid based onthe weight of active ingredients, and

[0017] b) a pharmaceutically acceptable excipient.

[0018] wherein the method is characterized by achieving one or more of the following effects, reduces the biomarkers of the liver such as AST, ALT, SGPT, and SGOT,

[0019] increases the biomarker of the liver such as HDL,

[0020] provides hepatoprotective effect, which can be demonstrated by improvement in histopathology of liver cells, and

[0021] improves liver health.

[0022] SUMMARY OF THE INVENTION

[0023] One embodiment provides an oral composition for use in liver health optimization, wherein the composition comprises,

[0024] a) an active ingredient consisting essentially of 8 % to 35 % w / w of alpha tocotrienol, 16 % to 60 % w / w of gamma tocotrienol, 2 % to 20 % w / w of delta tocotrienol, 8 % to 30 % w / w of alpha tocopherol and 3 % to 60 % w / w of phospholipid based on the weight of active ingredients, and

[0025] b) a pharmaceutically acceptable excipient.

[0026] wherein the composition is characterized by achieving one or more of the following effects, reduces the biomarkers of the liver such as AST, ALT, SGPT, and SGOT,

[0027] increases the biomarker of the liver such as HDL,

[0028] provides hepatoprotective effect, which can be demonstrated by improvement in histopathology of liver cells, and

[0029] improves liver health.Another embodiment provides use of a composition for liver health optimization in a subject in need thereof by orally administering to the subject the composition comprising, a) an active ingredient consisting essentially of 8 % to 35 % w / w of alpha tocotrienol, 16 % to 60 % w / w of gamma tocotrienol, 2 % to 20 % w / w of delta tocotrienol, 8 % to 30 5 % w / w of alpha tocopherol and 3 % to 60 % w / w of phospholipid based on the weight of active ingredients, and

[0030] b) a pharmaceutically acceptable excipient.

[0031] The compositions disclosed in the embodiments are useful in liver health optimization, 0 which includes one or more of; improved hepatoprotective effect, improved efficacy for treatment or management of liver disease, or treating NAFLD and / or improving liver health in general.

[0032] Another embodiment provides a method of treating a non-alcoholic fatty liver disease by 5 orally administering a composition comprising:

[0033] a) an active ingredient consisting essentially of 8 % to 35 % w / w of alpha tocotrienol, 16 % to 60 % w / w of gamma tocotrienol, 2 % to 20 % w / w of delta tocotrienol, 8 % to 30 % w / w of alpha tocopherol and 3 % to 60 % w / w of phospholipid based on the weight of active ingredients, and

[0034] Cb) a pharmaceutically acceptable excipient.

[0035] wherein the method is characterized by achieving one or more of the following effects, 1. reduces the biomarkers of the liver such as AST, ALT, SGPT, and SGOT,

[0036] 2. increases the biomarker of the liver such as HDL,provides hepatoprotective effect, which can be demonstrated by improvement in histopathology of liver cells, and

[0037] improves liver health.

[0038] BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figures 1 shows changes in level of AST n assigned group during day 0, 28 and 56. All values represented are in Mean ± SEM (n=3), statistical evaluation was done using Two-way ANOVA by Graph pad prism 5.0. ###p<0.001 compared to Group I i.e. Normal Chow fed group and *p<0.05, ***p<0.001 compared to Group II i.e. High Fat diet.

[0040] Figures 2 shows changes in level of ALT in assigned group during day 0, 28 and 56. All values represented are in Mean ± SEM (n=3), statistical evaluation was done using Two-way ANOVA by Graph pad prism 5.0. ###p<0.001 compared to Group I i.e. Normal Chow fed group and **p<0.01, ***p<0.001 compared to Group II i.e. High Fat diet.

[0041] Figures 3 shows changes in level of Alkaline Phosphatase (ALP) in assigned group during day 0, 28 and 56. All values represented are in Mean ± SEM (n=3), statistical evaluation was done using Two-way ANOVA by Graph pad prism 5.0. ###p<0.001 compared to Group I i.e. Normal Chow fed group and **p<0.01, ***p<0.001 compared to Group II i.e. High Fat diet.

[0042] Figures 4 shows changes in level of total cholesterol in assigned group during day 0, 28 and 56. All values represented are in Mean ± SEM (n=3), statistical evaluation was doneusing Two-way ANOVA by Graph pad prism 5.0. ###p<0.001 compared to Group I i.e. Normal Chow fed group and ***p<0.001 compared to Group II i.e. High Fat diet.

[0043] Figures 5 shows changes in level of Triglycerides in assigned group during day 0, 28 and 56. All values represented are in Mean ± SEM (n=3), statistical evaluation was done using Two-way ANOVA by Graph pad prism 5.0. ###p<0.001 compared to Group I i.e. Normal Chow fed group and *p<0.05, ***p<0.001 compared to Group II i.e. High Fat diet.

[0044] Figures 6 shows changes in level of HDL in assigned group during day 0, 28 and 56. All values represented are in Mean ± SEM (n=3), statistical evaluation was done using Two-way ANOVA by Graph pad prism 5.0. #p<0.05, ###p<0.001 compared to Group I i.e. Normal Chow fed group and *p<0.05, **p<0.01, ***p<0.001 compared to Group II i.e. High Fat diet.

[0045] Figures 7 shows changes in level of LDL in assigned group during day 0, 28 and 56. All values represented are in Mean ± SEM (n=3), statistical evaluation was done using Two-way ANOVA by Graph pad prism 5.0. ###p<0.001 compared to Group I i.e. Normal Chow fed group and ***p<0.001 compared to Group II i.e. High Fat diet.

[0046] Figures 8 shows changes in level of VLDL in assigned group during day 0, 28 and 56. All values represented are in Mean ± SEM (n=3), statistical evaluation was done using Two-way ANOVA by Graph pad prism 5.0. ###p<0.001 compared to Group I i.e. Normal Chow fed group and ***p<0.001 compared to Group II i.e. High Fat diet.Figures 9 shows histopathological examinations of the liver in the NAFLD rat model in the five groups after 56 days of induction of fatty liver (A) group I showed normal hepatic cells with distinct nuclei, cytoplasm, (B) group II showed numerous spherical vacuoles of fat droplets at the periphery of hepatic lobule that compressed the sinusoids. In contrast, (D, E, F) group III, IV and V showed a somewhat normal histological appearance with small fat droplets present compared to group 1.

[0047] DESCRIPTION OF THE INVENTION

[0048] The present invention will be better understood with reference to the following description taken in combination with the drawings. For the purpose of illustration, there are shown in the drawings certain embodiments of the present invention. In the drawings, like numerals indicate like elements throughout. It should be understood, however, that the invention is not limited to the precise arrangements, dimensions, and instruments shown:

[0049] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings.

[0050] The term “liver health optimization” as used herein refers to improved hepatoprotective effect, improved efficacy for treatment or management of liver disease, preferably NAFLD and / or improving liver health.The liver disease may be selected from fatty liver, nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated steatohepatitis (MASH), nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or metabolic dysfunction related disease.

[0051] Nonalcoholic Fatty Liver Disease (NAFLD) terminology updated to Metabolic dysfunction Associated Steatotic Liver Disease (MASLD).

[0052] Steatotic Liver Disease (SLD) is the primary term to encompass various causes of Steatotic as listed below. A new category, MetALD, describes individuals with MASLD who consume more than 140 g / week of alcohol for women and 210 g / week for men. If additional factors contributing to steatosis are discovered, then this aligns with a combined etiology. When it comes to alcohol, the condition is referred to as MetALD or ALD, depending on the severity of alcohol consumption. If no overt cardiometabolic criteria are present, other causes should be ruled out. If none are identified, this is called cryptogenic SLD. Depending on clinical judgment, it may also be considered possible MASLD and would benefit from periodic reassessment on a case-by-case basis.

[0053] i. Metabolic Associated Steatotic Liver Disease (MASLD) previously known as NAFLD a. Metabolic Dysfunction Associated Steatohepatitis (MASH) previously known as NASH b. Metabolic Dysfunction Associated Steatotic Liver (MASL)

[0054] c. Metabolic Dysfunction Associated Liver Diseaseii. Metabolic Associated Steatotic Liver Disease (MASLD) and increased alcohol intake (MetALD)*

[0055] iii. Alcoholic Associated Liver Disease (ALD)

[0056] iv. Specific aetiology SLD

[0057] 5a. Drug-Induced Liver Injury (DILI)

[0058] b. Monogenic Diseases **

[0059] c. Miscellaneous ***

[0060] v. Cryptogenic SLD

[0061] 0 *Weekly intake 140-350 g female, 210-420 gmale. **e.g.: lysosomal acid lipase deficiency (LALD), Wilson disease, hypobetalipoproteinemia, and inborn errors of metabolism. ***Hepatitis C virus, malnutrition, celiac disease, and human immunodeficiency virus.

[0062] NAFLD / MASLD associated health conditions

[0063] 5 Hepatocellular Carcinoma (HCC), hepatitis B. hepatitis C and Non-alcoholic Steatohepatitis

[0064] NAFLD / MAFLD is the common cause of HCC. Infection by hepatitis B, hepatitis C, and medical condition of Non-alcoholic Steatohepatitis further contributed towards HCC development.

[0065] 0

[0066] Oxidative Stress. Hepatic Lipotoxicity and Portal Hypertension

[0067] Development of NAFLD / MASLD promotes Oxidative Stress caused by excess fatty acid and Hepatic Lipotoxicity which leads to Portal Hypertension (PH).The term “improved hepatoprotective effect” refers to a greater ability of a drug, compound, or treatment to protect the liver from damage caused by toxic substances, infections, inflammation, or diseases. This enhancement could be due to:

[0068] Higher efficacy: The compound reduces liver damage more effectively than other treatments.

[0069] Broader protection: It works against multiple types of liver injuries, such as those caused by alcohol, drugs (e.g., paracetamol overdose), or viruses.

[0070] Faster recovery: It promotes quicker regeneration of liver tissue or improves liver function restoration.

[0071] Better safety profile: It achieves hepatoprotection with fewer side effects or at lower doses.

[0072] The improvement can be demonstrated by achieving one or more of following: (a) reducing the biomarkers of the liver such as AST, ALT, SGPT, and SGOT, (b) increasing the biomarker of the liver such as HDL and (c) improving histopathology of liver cells.

[0073] The term “improved efficacy for treatment or management of liver disease” refers to the enhanced effectiveness of a drug, compound, or therapeutic intervention in treating or managing liver diseases. Improved efficacy implies that the treatment achieves better clinical outcomes compared to existing therapies. This could manifest as:

[0074] Higher success rates in achieving disease remission or slowing disease progression.

[0075] Greater symptom relief (e.g., reduction in jaundice, fatigue, or pain).Better biochemical outcomes, such as normalization of liver enzymes (ALT, AST), reduced bilirubin levels, or improved markers of liver function (e.g., albumin, INR).

[0076] Slower fibrosis progression or enhanced reversal of liver damage in chronic liver conditions.

[0077] Improved survival rates or quality of life in patients with liver diseases like cirrhosis, hepatitis, or liver cancer.

[0078] The term “improving liver health” as used herein refers to to actions, interventions, or treatments aimed at enhancing the liver's functional capacity, preventing damage, or promoting its recovery from existing injuries. This may involve restoring normal liver function, reducing inflammation, detoxifying harmful substances, or preventing the progression of liver-related diseases.

[0079] The term "pharmaceutically acceptable" refers to a substance (e.g., an active ingredient or an excipient) that is suitable for use in contact with the tissues and organs of a subject without excessive irritation, allergic response, immunogenicity and toxicity, is commensurate with a reasonable benefit / risk ratio, and is effective for its intended use. A "pharmaceutically acceptable" excipient or carrier of a pharmaceutical composition is also compatible with the other ingredients of the composition.

[0080] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject, is sufficient to prevent, reduce the risk of developing, delay the onset of, slow the progression of or cause regression of the medical condition being treated,or to alleviate to some extent the medical condition or one or more symptoms or complications of that condition, at least in some fraction of the subjects taking that compound. The term "therapeutically effective amount" also refers to an amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, organ or human which is sought by a medical doctor or clinician.

[0081] The terms "treat," "treating", "treatment" “managing” and “management” include alleviating, ameliorating, inhibiting the progress of, reversing or abrogating a medical condition or one or more symptoms or complications associated with the condition, and alleviating, ameliorating or eradicating one or more causes of the condition. Reference to "treatment" of a medical condition includes prevention of the condition. The terms "prevent", "preventing" and "prevention" include precluding, reducing the risk of developing and delaying the onset of a medical condition or one or more symptoms or complications associated with the condition.

[0082] The term “dosage form,” as used herein, is the form in which the dose is to be administered to the subject or patient in need thereof. The dosage form may have unique physical and pharmaceutical characteristics. Dosage forms, for example, may be solid, liquid or gaseous. “Dosage forms,” may include for example, a capsule, tablet, caplet, gel caplet (gelcap), syrup, a liquid composition, a powder, a concentrated powder, a concentrated powder admixed with a liquid, a chewable form, a swallowable form, a dissolvable form, an effervescent, a granulated form, and an oral liquid solution. In a specific embodiment, the dosage form may be a soft gelatin capsule.The term "stable" refers to the formulation that retains potency of active ingredient at least 95 %, 96 %, 97 %, 98 % or 99 % as compared to initial value of the active ingredient in the formulation.

[0083] One embodiment discloses an oral composition for use in treating non-alcoholic fatty liver disease, wherein the composition comprises:

[0084] a) an active ingredient consisting essentially of 8 % to 35 % w / w of alpha tocotrienol, 16 % to 60 % w / w of gamma tocotrienol, 2 % to 20 % w / w of delta tocotrienol, 8 % to 30 % w / w of alpha tocopherol and 3 % to 60 % w / w of phospholipid based on the weight of active ingredients, and

[0085] b) a pharmaceutically acceptable excipient.

[0086] Another embodiment discloses a pharmaceutical composition characterized by achieving one or more of the following effects,

[0087] a) reduces the biomarkers of the liver such as AST, ALT, SGPT, and SGOT,

[0088] b) increases the biomarker of the liver such as HDL, and

[0089] c) provides hepatoprotective effect, which can be demonstrated by improvement in histopathology of liver cells.

[0090] Another embodiment provides that the liver disease is selected from fatty liver, nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated steatohepatitis (MASH), nonalcoholic steatohepatitis with liver fibrosis, nonalcoholicsteatohepatitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or metabolic dysfunction related disease.

[0091] Another embodiment discloses a method of treating a non-alcoholic fatty liver disease by orally administering a composition consisting essentially of vitamin E and phospholipids as active ingredients, wherein the active ingredients comprise:

[0092] a) about 26 % w / w to 40 % w / w of tocotrienol,

[0093] b) about 8 % w / w to 30 % w / w of tocopherol, and

[0094] c) about 3 % w / w to 60 % w / w of lecithin.

[0095] Another embodiment discloses a method of treating a non-alcoholic fatty liver disease by orally administering a composition consisting essentially of vitamin E and phospholipids as active ingredients, wherein the active ingredients comprise:

[0096] a) 72.69 % w / w of tocotrienol,

[0097] b) 22.30 % w / w of tocopherol, and

[0098] c) 5 % w / w of lecithin.

[0099] Another embodiment discloses a method of treating a non-alcoholic fatty liver disease by orally administering a composition consisting essentially of vitamin E and phospholipids as active ingredients, wherein the active ingredients comprise:

[0100] a) 38.24 % w / w of tocotrienol,

[0101] b) 11.74 % w / w of tocopherol, and

[0102] c) 50 % w / w of lecithin.In another embodiment, the present disclosure provides an oral composition for use in liver health optimization, wherein the composition comprises,

[0103] a) 60 % to 90 % w / w of an active ingredient consisting of alpha tocotrienol, gamma tocotrienol, delta tocotrienol, alpha tocopherol and phospholipid, based on the total weight of the composition,

[0104] b) 1 % to 12 % w / w of palm olein,

[0105] c) 5 % to 15 % w / w of poly oxy-35 castor oil, and

[0106] d) 2 % to 8 % w / w of caprylocaproyl maerogol-8-glycerides.

[0107] In another embodiment, the present disclosure provides an oral composition for use in liver health optimization, wherein the composition comprises,

[0108] a) 80.9 % w / w of an active ingredient consisting of alpha tocotrienol, gamma tocotrienol, delta tocotrienol, alpha tocopherol and phospholipid, based on the total weight of the composition,

[0109] b) 4.10 % w / w of palm olein,

[0110] c) 12 % w / w of poly oxy-35 castor oil, and

[0111] d) 3 % w / w of caprylocaproyl maerogol-8-glycerides

[0112] In another embodiment, the present disclosure provides an oral composition for use in liver health optimization, wherein the composition comprises,

[0113] a) 82.34 % w / w of an active ingredient consisting of alpha tocotrienol, gamma tocotrienol, delta tocotrienol, alpha tocopherol and phospholipid, based on the total weight of the composition,b) 4.10 % w / w of palm olein,

[0114] c) 12 % w / w of poly oxy-35 castor oil, and

[0115] d) 3 % w / w of caprylocaproyl maerogol-8-glycerides

[0116] In another embodiment, the present disclosure provides a method of treating a nonalcoholic fatty liver disease by orally administering to the subject from 150 to 250 mg of tocotrienol, 50-80 mg of tocopherol and 250-300 mg of lecithin for at least 12 weeks.

[0117] The administration of the composition of the embodiments ameliorates one or more symptoms of NAFLD, including but not limited to, fat content of liver, increased hepatic aminotransferase levels, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), increased serum ferritin, elevated levels of gamma-glutamyl transferase (gamma-GT), and elevated levels of plasma insulin, cholesterol and triglyceride.

[0118] The composition may comprise based on the total weight of the active ingredients about 20 %, 25 %, 30 %, 35 %, or 40 % w / w of alpha tocotrienol; about 40 %, 45 %, 50 %, 55 %, or 60 % w / w of gamma tocotrienol; about 8 %, 10 %, 12 %, 14 %, 16 %, 18 %, or 20 % w / w of delta tocotrienol; about 11 %, 12 %, 13 %, 14 %, or 15 % w / w of alpha tocopherol and about 30%, 35%, 40%, 45%, 50 %, 55 %, or 60 % w / w of phospholipid.

[0119] The phospholipids used as an active ingredient in the composition may be a plant-based phospholipid. Amongst others, the phospholipids used is phophatidylcholine,phosphatidylethanolamine, phosphatidic acid, phosphoinositides or phosphatidylserine. The phospholipid may be derived from soy bean, such as soy bean lecithin.

[0120] In another embodiment, the oral compositions of the invention are stable at for at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months and 24 months.

[0121] In another embodiment, the oral compositions are stable at room temperature or at 25°C / 60 % relative humidity (RH) for at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months and 24 months.

[0122] In another embodiment, the oral compositions of the invention are stable at 30°C / 75 % RH for at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months and 18 months.

[0123] In another embodiment, the oral compositions of the invention are stable at 40°C / 75 % RH for at least 6 months.

[0124] The compositions disclosed in the embodiments are useful in liver health optimization, which includes one or more of; improved hepatoprotective effect, improved efficacy for treatment or management of liver disease, or treating NAFLD and / or improving liver healthin general. The improvement can be demonstrated by achieving one or more of following: (a) reducing the biomarkers of the liver such as AST, ALT, SGPT, and SGOT, (b) increasing the biomarker of the liver such as HDL and (c) improving histopathology of liver cells.

[0125] In another embodiment, an oral composition provides hepatoprotective effect, which can be demonstrated by improvement in histopathology of liver cells as shown in Figure 9.

[0126] The pharmaceutically accepted excipients are listed below without. The list is non exhaustive and only for illustrative purposes.

[0127] Gelatin Shell Components

[0128] These excipients form the capsule's outer shell:

[0129] • Gelatin: The main structural component, sourced from animal collagen.

[0130] • Plasticizers:

[0131] o Glycerin, Sorbitol, Polyethylene glycol (PEG)

[0132] « Water: Ensures proper gel formation and flexibility.

[0133] • Colorants: For aesthetics and identification:

[0134] o FD& C dyes, Iron oxide pigments, Titanium dioxide (opacifier)

[0135] • Preservatives (optional): Prevent microbial growth:

[0136] o Methylparaben, Propylparaben, Potassium sorbate

[0137] Fill Formulation Excipients

[0138] These excipients are used to prepare the capsule fill material:

[0139] a. Solvents and Vehicles (for liquid or semi-solid fills)• Medium-chain triglycerides (MCT oil), Sesame oil, soybean oil, or other vegetable oils, Polyethylene glycol (PEG 400, PEG 600), Propylene glycol, Ethanol (as a co-solvent, if needed)

[0140] b. Surfactants and Emulsifiers (to enhance solubility or dispersion)

[0141] « Polysorbates (e.g., Polysorbate 80), Sorbitan monooleate, Cremophor (e.g., Cremophor EL or RH)

[0142] c. Antioxidants (to stabilize oils and prevent oxidation)

[0143] • Butylated hydroxytoluene (BHT), Butylated hydroxyanisole (BHA), Tocopherols (Vitamin E)

[0144] d. Chelating Agents (to enhance stability)

[0145] • Disodium EDTA, Citric acid

[0146] e. Viscosity Modifiers (to adjust flow properties)

[0147] • Beeswax, Paraffin wax, Hydrogenated vegetable oils

[0148] 3. Functional Excipients

[0149] « Sweeteners (for chewable softgels): Sorbitol, Maltitol, Flavoring Agents: Natural or synthetic flavors for palatability.

[0150] • Absorption Enhancers: Glyceryl monostearate, Labrasol.

[0151] The compositions discloses in various embodiments may be prepared in various dosage forms like tablet, capsule, sachet, chewable dosage forms, orally disintegrating dosage forms, emulsion, suspension, solution, gels etc.

[0152] The composition may be administered once daily, two more times a day. In another embodiment, the composition is in the form of tablet which comprises one or moreexcipients including microcrystalline cellulose, lactose, sodium starch glycolate, croscarmellose sodium, magnesium stearate.

[0153] In another embodiment, an oral pharmaceutical composition is in the form of a soft gel capsule or liquid emulsion.

[0154] In another embodiment, the liquid emulsion comprises a combination of oil, surfactant and co-surfactant. Particularly, palm olein is used as a carrier. Further, non-ionic surfactant is used due to its self- emulsifying capability. Further, the non-ionic surfactant used is nontoxic and non- reactive to produce a chemically stable system. Further, the co-surfactant used is caprylocaproyl maerogol-8-glycerides. Together with the active ingredients aforementioned, the combination provides a stable emulsion upon slight agitation.

[0155] In another embodiment, the soft gel capsule comprises one or more excipients including beeswax, palm olein, caprylocaproyl maerogol-8-glycerides, poly oxy-35 castor oil, soyabean oil. Fatty materials that may be included in the present invention include, by way of example and without limitation, vegetable oils (including palm oil, palm hydrogenated oil, com germ hydrogenated oil, castor hydrogenated oil, cotton-seed oil, olive oil, peanut oil, palm olein oil, and palm stearin oil), animal oils (including refined oil and refined lard whose melting point ranges from 30° to 42° C ), Cacao fat, margarine, butter, and shortening.The dosage form may be administered to the subject in need thereof either once, twice or more times a day. The dosage form may be administered in unit dosage form or divided

[0156] into multiple units before administration to the subject in need thereof.

[0157] Table 1: Active ingredient of the composition of the invention & comparative example.

[0158] SN Ingredients Group I Group II Group III Group IV Group V (normal chow (HFD) (HFD) (HFD) (HFD) feed) (no (Vitamin E) (Vitamin E +5% (Vitamin E +50% (no treatment) treatment) w / w phospholipid) w / w phospholipid) 1 Alpha NA NA 25.53 % w / w 22.36 % w / w 11.76 % w / w tocotrienol

[0159] 2 Gamma NA NA 43.15 % w / w 41.00 % w / w 21.57 % w / w tocotrienol

[0160] 3 Delta NA NA 9.82 % w / w 9.33 % w / w 4.91 % w / w tocotrienol

[0161] 4 Alpha NA NA 23.48 % w / w 22.30 % w / w 11.74 % w / w tocopherol

[0162] 5 Lecithin NA NA NA 5 % w / w 50 % w / w

[0163]

[0164] Note: w / w as mentioned in Table 1 above refers to w / w of the total weight of the five active ingredients.

[0165] Process of preparation of formulations:

[0166] The formulation is preferably prepared in Soft Gelatin Capsule. Fine oil in water emulsion

[0167] is formed upon a mild agitation by dilution in aqueous media, eg gastrointestinal (GI)

[0168] fluids. The preparation of formulation involves a mixing of Palm Olein RBD, Tocotrienol

[0169] and Tocopherol 50% Suspension, Polyoxyl 35 Castor Oil, Caprylocaproyl Macrogolglycerides and Lecithin Soya Bean Oil all together for homogeneity and ready

[0170] for encapsulation. The specific oil (Palm Olein RBD) to Surfactant (Polyoxyl 35 Castor

[0171] Oil and Caprylocaproyl Macrogolglycerides) % w / w was included. Such ratio was able toself-emulsify upon gentle agitation in aqueous medium along with determined Lecithin

[0172] Soya Bean Oil concentration. In vivo, the formulation disperse readily in GI tract and mechanical action of GI tract provides a necessary agitation.

[0173] Table 2: Active ingredient composition of the invention & examples.

[0174] Example 1 Example 2 Example 3 Example 4 Example 5 Composition % % mg / cap % % % mg / cap mg / cap mg / cap mg / cap w / w w / w P w / w w / w w / w #Tocotrienol &

[0175] Tocopherol

[0176] 594.59 54.05 594.59 54.05 594.59 59.45 594.59 59.45 594.59 54.99 Complex 50 %

[0177] Suspension

[0178] Lecithin Soya Bean 214.5 19.50 214.5 19.50 214.5 21.45 214.5 21.45 295.75 27.35 Palm Olein RBD 101 9.18 141 12.82 41 4.10 41 4.10 31 2.87 Polyoxyl 35 Castor

[0179] 140 12.73 100 9.09 100 10.00 120 12.00 120 11.10 Oil

[0180] Caprylocaproyl

[0181] 50 4.55 50 4.55 50 5.00 30 3.00 40 3.70 Macrogolglycerides

[0182]

[0183] # Contains combination of active ingredients Alpha tocotrienol; Gamma tocotrienol; Delta tocotrienol and Alpha tocopherol.

[0184] The above example are subjected to initial evaluation and stability for physical testing as per the commonly used methods in the art & the results are listed in tablet below.

[0185] Table 3. Physical evaluation of the formulations.

[0186] The compositions in Table 2 above were subjected to initial evaluation and stability for physical testing & the results are listed below.Condition Test Example 1 Example 2 Example 3 Example 4 Example 5

[0187] Reddish brown Reddish brown Reddish brown Reddish brown Reddish brown Physical appearance

[0188] oil oil oil oil oil Initial Physical test for

[0189] Satisfactory Satisfactory Satisfactory Desirable Desirable emulsification

[0190] Moisture content NA NA NA NA NA Reddish brown Reddish brown Reddish brown Reddish brown Reddish brown Physical appearance

[0191] oil oil oil oil oil 25°C / 60%RH

[0192] Physical test for

[0193] 6 Month NA NA NA NA NA emulsification

[0194] Moisture content NA NA NA NA 10.2%

[0195] Reddish brown Reddish brown Reddish brown Reddish brown Reddish brown Physical appearance

[0196] oil oil oil oil oil 30°C / 75%RH

[0197] Physical test for

[0198] 6 Month NA NA NA NA NA emulsification

[0199] Moisture content NA NA NA NA 10.6%

[0200] Reddish brown Reddish brown Reddish brown Reddish brown Reddish brown 40°C / 75%RH Physical appearance

[0201] oil oil oil oil oil

[0202] 6 Month

[0203] Physical test for

[0204] NA NA NA NA NA

[0205] emulsification

[0206]

[0207] Moisture content NA NA NA NA 10.8%

[0208] 0Condition Assay Example 5 (%) d- Alpha-Tocopherol 126.1 d- Alpha-Tocotrienol 121.2 Initial d-Gamma-Tocotrienol 143.7

[0209] d-Delta-Tocotrienol 116.5 Phosphatidylcholine 137.6 d- Alpha-Tocopherol 112.8 d- Alpha-Tocotrienol 108.8 25°C / 60%RH

[0210] d-Gamma-Tocotrienol 128.8

[0211] 6 Month

[0212] d-Delta-Tocotrienol 104.4 Phosphatidylcholine 123.6 d- Alpha-Tocopherol 116.7 d- Alpha-Tocotrienol 112.3 30°C / 75%RH

[0213] d-Gamma-Tocotrienol 132.8

[0214] 6 Month

[0215] d-Delta-Tocotrienol 107.7 Phosphatidylcholine 112.0 d- Alpha-Tocopherol 117.5 d- Alpha-Tocotrienol 112.5 40°C / 75%RH

[0216] d-Gamma-Tocotrienol 132.3

[0217] 6 Month

[0218] d-Delta-Tocotrienol 107.4

[0219] 100.8

[0220]

[0221] PhosphatidylcholineBased on the above physical evaluation, Example 5 batch subjected for assay testing at initial and on stability condition.

[0222] 5 Experimental details of animal studies:

[0223] Effect of vitamin E (tocotrienols and tocopherol mixture) in mitigating NAFLD in a rat model.

[0224] A total of 35 healthy Sprague Dawley rats (230-250 g) of either sex and about 9-12 weeks 10 of age will be taken for study. The rats were housed in standard polypropylene cages (four rats per cage) under appropriate conditions of temperature (25°C ± 2°C), humidity (60%- 70%), and light (12-h dark / light cycles). They were provided ad libitum with a prepared high fat diet as per literature and RO water. All procedures were carried out according to the guidelines of institutional policies on animal experimental handling, designed to 15 minimize suffering and limit the number of animals used and were approved by Institutional Animal Ethical Committee. Induction group animals were fed with high fat diet (HFD) ad libitum for 8 weeks i.e.56 days instead of regular chow feed.

[0225] • Group I (Normal Group): (n=3) Normal Chow fed group: animals were fed with normal chow feed ad libitum also animals were handled daily for 8 weeks.

[0226] •20 Group II (High Fat Diet Group): (n=8) NAFLD induction group: animals were fed with high fat diet feed ad libitum also animals were handled daily for 8 weeks.Group III (High-fat diet + Vitamin E): (n=8) NAFLD induction by high fat diet and treated with Vitamin E.. Animals were fed with high fat diet feed ad libitum also animals were administered with Vitamin E by oral route daily for 8 weeks.

[0227] • Group IV (High-fat diet + Vitamin E + Lecithin 5% w / w): (n=8) NAFLD induction by high fat diet and treated with Vitamin E with added phospholipid (5% w / w each), animals were fed with high fat diet feed ad libitum and animals were treated with Vitamin E with added phospholipid by oral route daily for 8 weeks.

[0228] • Group V (High-fat diet + Vitamin E + Lecithin 50% w / w): (n=8) NAFLD induction by high fat diet and treated with Vitamin E with added phospholipid (50% w / w each). Animals were fed with high fat diet feed ad libitum and animals were treated with Vitamin E with added phospholipid by oral route daily for 8 weeks.

[0229] • Duration: Treatments of phospholipid and Vitamin E were administered orally from Day 0 until Day 56.

[0230] • Treatment Regimen:

[0231] Results: Biochemical Assessment:

[0232] 1. Liver Function Test Parameters:

[0233] Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are crucial enzymes in the liver that play significant roles in amino acid metabolism. Their levels in the blood are commonly used as biomarkers to assess liver health. Elevated ALT and AST levels are common in NAFLD patients and are used to screen for liver damage. The liver synthesizes most of the proteins found in the blood. Abnormal total protein levels can indicate liverdysfunction, malnutrition, or other health issues. Their levels in the blood are commonly used as biomarkers to assess liver health. Decrease level of albumin and total protein are common in NAFLD patients and are used to screen for liver damage.

[0234] Following markers were assessed to outline liver function changes

[0235] ■ Alanine transaminase (ALT)

[0236] ■ Aspartate transaminase (AST)

[0237] ■ Alkaline phosphatase (ALP)

[0238] ■ Bilirubin

[0239] ■ Albumin

[0240] ■ Total protein

[0241] . Group I (Normal chow feed):

[0242] Liver function parameters were within normal ranges, establishing a baseline for comparison.

[0243] . Group II (High-fat diet):

[0244] Significantly elevated liver enzymes, indicative of liver dysfunction. This group served as the NAFLD model, showing clear signs of liver stress and damage.

[0245] Markers like ALT, AST, ALP and total bilirubin were notably higher also level of total protein and albumin decrease compared to the control group (Group I), reflecting impaired liver function.

[0246] Interday comparison outline the progression of NAFLD in 56 days.

[0247] . Group III (High-fat diet + Vitamin E):• Liver function improved compared to Group II. A moderate decrease in liver enzymes (ALT, AST, ALP), Total Bilirubin as well as globulin and increase in levels of albumin and total protein was observed indicating that Vitamin E provided some protection against liver damage induced by the high-fat diet.

[0248] • Interday comparison outline gradual improvement from day 28 to day 56.

[0249] 5. Group IV (High-fat diet + Vitamin E + Lecithin 5% w / w):

[0250] • Further improvement in liver function compared to Group II and Group III

[0251] • Liver enzyme levels showed a more significant reduction in liver enzymes (ALT, AST, ALP), Total Bilirubin as well as globulin and increase in levels of albumin and total protein, suggesting that the addition of lecithin (at 5% concentration) alongside Vitamin E provided a synergistic protective effect against NAFLD progression.

[0252] • Interday Comparison outline significant improvement from day 28 to 56.

[0253] 6. Group V (High-fat diet + Vitamin E + Lecithin 50% w / w):

[0254] • This group showed the most promising results.

[0255] • Liver enzyme levels were the lowest among all high-fat diet groups, suggesting a strong protective and restorative effect with the higher concentration of lecithin (50%) combined with Vitamin E. The liver function parameters approached near-normal levels, similar to Group I.

Claims

CLAIMS:

1. An oral composition for use in liver health optimization, wherein the composition comprising,a) an active ingredient consisting essentially of 8 % to 35 % w / w of alpha tocotrienol, 16 % to 60 % w / w of gamma tocotrienol, 2 % to 20 % w / w of delta tocotrienol, 8 % to 30 % w / w of alpha tocopherol and 3 % to 60 % w / w of phospholipid based on the weight of active ingredients, andb) a pharmaceutically acceptable excipient.

2. An oral composition according to claim 1, wherein the composition is characterized by achieving one or more of the following effects,a) reduces the biomarkers of the liver such as AST, ALT, SGPT, and SGOT,b) increases the biomarker of the liver such as HDL,c) provides hepatoprotective effect, which can be demonstrated by improvement in histopathology of liver cells, andd) improves liver health.

3. Use of an oral composition for liver health optimization in a subject in need thereof by orally administering to the subject in need thereof the composition comprising, a) an active ingredient consisting essentially of 8 % to 35 % w / w of alpha tocotrienol, 16 % to 60 % w / w of gamma tocotrienol, 2 % to 20 % w / w of delta tocotrienol, 8 % to 30 % w / wof alpha tocopherol and 3 % to 60 % w / w of phospholipid based on the weight of active ingredients, andb) a pharmaceutically acceptable excipient.

4. The use according to claim 3, wherein the liver health optimization is selected from improved hepatoprotective effect, improved efficacy for treatment or management of a liver disease, preferably NAFLD and / or improving liver health.

5. The use according to claim 4, wherein the liver disease is selected from the group consisting of fatty liver, nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction- associated steatohepatitis (MASH), nonalcoholic steatohepatitis with liver fibrosis, nonalcoholic steatohepatitis with cirrhosis, and nonalcoholic steatohepatitis with cirrhosis and with hepatocellular carcinoma or metabolic dysfunction related disease.

6. A method of treating a non-alcoholic fatty liver disease by orally administering an oral pharmaceutical composition comprising: an active ingredient consisting essentially of 8 % to 35 % w / w of alpha tocotrienol, 16 % to 60 % w / w of gamma tocotrienol, 2 % to 20 % w / w of delta tocotrienol, 8 % to 30 % w / w of alpha tocopherol and 3 % to 60 % w / w of phospholipid based on the weight of active ingredients, and a pharmaceutically acceptable excipient;wherein the method is characterized by achieving one or more of the following effects,a) reduces the biomarkers of the liver such as AST, ALT, SGPT, and SGOT,b) increases the biomarker of the liver such as HDL,c) provides hepatoprotective effect, which can be demonstrated by improvement in histopathology of liver cells, andd) improves liver health.

7. The method according to claim 6 wherein the composition is administered as once or twice daily.

8. The composition according to claim 1 wherein the pharmaceutically acceptable excipients are selected from gelatin, preservative, plasticizer, surfactant, emulsifier, colorant, antioxidant, chelating agent, viscosity modifiers, sweetener, flavoring agent or water.

9. The composition according to claim 1 wherein the composition is prepared in the form of dosage forms selected from tablet, capsule, sachet, chewable dosage form, orally disintegrating dosage form, emulsion, suspension, solution or gel.

10. The composition according to claim 9 wherein the composition is in the form of a soft gel capsule.

11. The composition according to claim 10 wherein the soft gel capsule comprises one or more excipients selected from the group consisting of beeswax, palm olein, caprylocaproyl maerogol-8-glycerides, polyoxy-35 castor oil and soyabean oil.

12. The composition according to the preceding claims wherein the compositions are stable at 25 °C / 60% RH for at least 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months and 24 months.

13. The composition according to claim 1, wherein the composition comprising:a) an active ingredient consisting essentially of 11.76 % w / w of alpha tocotrienol, 21.57 % w / w of gamma tocotrienol, 4.91 w / w % of delta tocotrienol, 11.74 % w / w of alpha tocopherol and 50 % w / w of phospholipid based on the weight of active ingredients, and b) a pharmaceutically acceptable excipient.

14. An oral composition for use in liver health optimization, wherein the composition comprising:a) 60 % to 90 % w / w of an active ingredient consisting of alpha tocotrienol, gamma tocotrienol, delta tocotrienol, alpha tocopherol and phospholipid, based on the total weight of the composition,b) 1 % to 12 % w / w of palm olein,c) 5 % to 15 % w / w of poly oxy-35 castor oil, andd) 2 % to 8 % w / w of caprylocaproyl maerogol-8-glycerides.

15. An oral composition for use in liver health optimization, wherein the composition comprising:a) 80.9 % w / w of an active ingredient consisting of alpha tocotrienol, gamma tocotrienol, delta tocotrienol, alpha tocopherol and phospholipid, based on the total weight of the composition,b) 4.10 % w / w of palm olein,c) 12 % w / w of polyoxy-35 castor oil, andd) 3 % w / w of caprylocaproyl maerogol-8-glycerides.

16. An oral composition for use in liver health optimization, wherein the composition comprises,a) 82.34 % w / w of an active ingredient consisting of alpha tocotrienol, gamma tocotrienol, delta tocotrienol, alpha tocopherol and phospholipid, based on the total weight of the composition,b) 4.10 % w / w of palm olein,c) 12 % w / w of polyoxy-35 castor oil, and,d) 3 % w / w of caprylocaproyl maerogol-8-glycerides.

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