Clinical Application of Palm-Tocotrienols:

Challenges and Opportunities

Dr. Fu Ju Yen

Ms. Puvaneswari Meganathan

Ms. Doryn Tan Meam Yee

Dr. Zaida Zainal

fujuyen@mpob.gov.my / fujuyen@gmail.com

mailto:fujuyen@mpob.gov.mymailto:fujuyen@gmail.com

WHY FUNCTIONAL INGREDIENTS?

(Department of Statistics, Malaysia)

ROLE OF FUNCTIONAL INGREDIENTS

TYPES OF FUNCTIONAL INGREDIENTS

TOCOTRIENOLS

Tocotrienol

Tocopherol

R1 R2

α CH3 CH3

β CH3 H

γ H CH3

δ H H

Vitamin E

VITAMIN E CONTENT

(Aggarwal et al., Biochem Pharmacol. , 2010)

TOCOTRIENOL COMPOSITION

Tocopherols

α + β Tocotrienols

γ + δ Tocotrienols

Tocotrienol is now intended for use in the following foods:

▪ Margarines and spreads▪ Designer fats and oils▪ Salad dressing and Mayonnaise▪ Potato chips and salty snacks▪ Bakery products▪ Cookies & crackers▪ Ready To Eat (RTE) cereals, cereal bars, granola bars, protein bars and

power bars

▪ Meal replacement and other functional beverage products and mixes▪ Meatless meat products (soy-based)

GRAS STATUS FROM FDA FOR TOCOTRIENOLS (APRIL 2010)

TOCOTRIENOLS AND INFLAMMATION

TOCOTRIENOLS AND INFLAMMATION

Mangialasche et al. 2010, 2012, 2013

Higher tocotrienol levels in blood had lower risk of

developing Alzheimer’s disease.

Higher gamma-tocotrienol levels in their blood had

lower risk of developing cognitive impairment.

2 years supplementation

of T3 suppressed mean

volume change in white

matter lesion.

Gopalan et al., Stroke. 2014

ALZHEIMER’S DISEASE

WHITE MATTER LESION

PERIPHERAL NEUROPATHY1 year supplementation

of T3 reduced

lancinating pain in

diabetic patients with

peripheral neuropathy.

The Vitamin E in Neuroprotection

Study (VENUS) Investigators, JAMA

Neurology. 2018

NEUROPROTECTION

Khanna et al., J. Neurochem.

2010

T3 supplementation reduced occlusion-induced

brain injury.Park et al., Stroke, 2011

NEURAL CELL DAMAGE

INFARC SIZEARTERIOGENESIS

T3 improved cerebrovascular circulation and fiber

connectivity after ischemic stroke Rink et al., J Cereb Blood Flow Metab. 2011

Nanomolar of tocotrienol

prevented glutamate

induced damage neural

cells.

STROKE

MECHANISM

METABOLIC DISEASES

(Zhao et al., Int. J. Obesity. 2014)

OBESITY

INSULIN SENSITIVITY

• Rat study showed lower weight gain

and weight of adipose tissue with T3

supplementation

• Normalised fasting glucose and

insulin with T3 supplementation

HF: high fat; LF: low fat; T3: tocotrienol; Epi:

epididymal; Peri: perirenal; Mes: mesenteric (Mes)

fat.

MECHANISM

HF: high fat; LF: low fat; T3:

tocotrienol.

(Zhao et al., Int. J. Obesity. 2014)

• Reduced gene expression for

macrophage recruitment in

adipose tissue.

MECHANISM

CANCER PREVENTION

CANCER PREVENTION

• Breast

• Lung

• Liver

• Ovarian

• Colon

• Cell cycle

arrest

• Apoptosis

• VEGF

• IL24

• EMT

• MMP-9

MECHANISM

(Kanchi et al., Drug Discovery Today, 2017)

PULMONARY DISEASES SMOKE-INDUCED COPD

Peh et al., Free Rad Biology and Medicine, 2017

ASTHMA

Zainal et al., IJMS, 2019

CHALLENGE

1. Bioavailability

2. Epidemiology study

3. Clinical trials

4. Adjuvant / Combination

(Meganathan et al., 2015. Sci. Reports.)

Gamma-tocotrienol from TRF 300 mg

(Yap et al., 2001. Journal of Pharm and Pharmacol.)

Oral

bioavailability in

rat

α-Tocotrienol: 27.7 ± 9.2%

γ-Tocotrienol: 9.1 ± 2.4%

δ-Tocotrienol: 8.5 ± 3.5%

Affected

by

• Dose

• Formulation

• Population

(Yap et al., 2003) (Fu et al., 2014)

Gamma-tocotrienol from TRF 800 mg

CHALLENGE 1: BIOAVAILABILITY

Solubility: Low

• Insoluble in water/ aqueous environment

• Soluble in ethanol but limited solubility in

DMSO

Permeability: High

• A drug can be assumed to have high

permeability across epithelium cell

membranes if its log P value is greater

than 1.

• Tocotrienol Log P: 8.2

• The fraction of an ingested compound that is absorbed and available for physiological functions,

reaches the systemic circulation in an active form.

• Unfortunately, like most nutraceutical ingredients, tocotrienols suffer from low bioavailability.

CHALLENGE: BIOAVAILABILITY

FORMULATION OF TOCOTRIENOLS

FORMULATION OF TOCOTRIENOLS

Lipid bilayer

Hydrophilic

polymer

Tocotrienols

VESICLE-BASED NANOCARRIERS

• Vesicular system with lipid bilayer

• Encapsulate tocotrienols at 40% efficiency

• Non-ionic vesicles using GRAS non-ionic surfactants

• Available in powder or suspension form

• Higher stability compared to nanoemulsion

• Storage stability tested for 2 months

207

nm PDI

< 0.3

(Maniam et al., Front. Pharmacol. 2018; Tan et al., Nanomedicine. 2017)

(Fu et al., J Controlled Release. 2009)

• Tumour suppression up to 10

days

• Prolonged survival of 19 days

Tumour-targeted nano T3

Non-targeted nano T3

Free T3

Untreated

A431 xenograft models

Free T3

Non-targeted nano-T3

Targeted nano-T3

Untreated

MDA-MB-231 breast cancer models

Day 11 Day 20• Lower tumour volume in groups

treated with nano-T3

• Significant improvement at day

20

(Tan et al., Nanomedicine. 2017)

CHALLENGE 2: EPIDEMIOLOGY STUDYFrancesca Mangialasche and team, Karolinska Institutet, Stockholm, Sweden

Year Subject / Cohort Findings

2010 Kungsholmen Project

232 advance-aged subjects

High plasma total vitamin E content reduced the risk of

developing Alzheimer’s disease

2012 AddNeuroMed-Project

168 Alzheimer disease

166 mild cognitive impairement

187 cognitively normal people

AD and MCI had lower levels of total tocopherols, total

tocotrienols, and total vitamin E.

Low plasma tocopherols and tocotrienols levels are

associated with increased odds of MCI and AD.

2013 AddNeuroMed-Project

81 Alzheimer disease

86 mild cognitive impairement

86 cognitively normal people

Plasma tocopherol and tocotrienol levels + MRI are

sensitive indicators of Alzheimer’s disease.

2013 Cardiovascular Risk Factors, Aging, and

Dementia (CAIDE) study

140 elderly subjects

High levels of serum tocopherol and tocotrienol are

associated with reduced risk of cognitive impairment.

2019 Finnish Geriatric Intervention Study to Prevent

Cognitive Impairment and Disability (FINGER)

Database of 2654 elderly subjects

On-going

CHALLENGE 3: CLINICAL TRIALS

Study Site:

• MPOB Nutrition Unit

• UPM Medical Faculty

• UM Medical Faculty

Anti-inflammatory effect of Tocotrienol supplementation in subjects with moderately

elevated inflammation (INTOC)

CHALLENGE 4: ADJUVANT / COMBINATION THERAPY

Tocotrienols Conventional

Medicine

• Natural• Multi-targeted

• Powerful• Established

mechanism

• Hard to achieve therapeutic level in tissues

• High dose toxicity

• Resistance

FUTURE PROSPECTS

FUTURE PROSPECTS

(Meganathan and Fu, IJMS, 2016)

TAKE HOME MESSAGE

PALM-TOCOTRIENOLS

Poster

Puvaneswari Meganathan

Health Properties of Tocotrienols: Evidence in

Human Studies

ACKNOWLEDGMENT • Dr. Tee E Siong, Chair of Organizing Committee

• Nutrition Society of Malaysia

• MPOB

• Dr. Ahmad Parveez, Deputy Director-General, MPOB

• Ms. Rosidah Radzian, Director of PDAS, MPOB

• Dr. Kanga Rani Selvaduray, Head of Nutrition, MPOB

• Co-researchers

• Industrial partners

• Colleagues, research assistants and students