Nutraceuticals in Healthcare: Benefits, Challenge, and Future Directions

PROJECT WORK

(BP812PW)

Submitted to
DEPARTMENT OF PHARMACY
RADHA GOVIND UNIVERSITY
(Approved by PCI)

In partial fulfillment of degree of

BACHELOR OF PHARMACY (B. Pharm)

Submitted by​ Supervised by

Name: Pankaj Kumar Gupta Dr. Rahul Kumar
B.Pharm 8th Sem Assistant Professor
Roll No. 2125320037 Department of Pharmacy
Session: 2021-2025
 DEPARTMENT OF PHARMACY

RADHA GOVIND UNIVERSITY, RAMGARH, JHARKHAND

(Approved by P.C.I)

Certificate by The Principal

This is to certify that the content of this project “Nutraceuticals in Healthcare:
Benefits, Challenges, and Future Directions” by Pankaj Kumar Gupta is the
bonafide student of B. Pharma 8TH sem. has submitted to the Department of
Pharmacy, Radha Govind University, Ramgarh for consideration in the partial
fulfillment of the provision of subject PROJECT WORK (BP812PW) in the session
of 2021-2025.

DATE: 10/05/2025​ PRINCIPAL SIGNATURE

PLACE: RAMGARH
 DEPARTMENT OF PHARMACY

RADHA GOVIND UNIVERSITY, RAMGARH, JHARKHAND

(Approved by P.C.I)

Certificate by Guide
This is to certify that Pankaj kumar Gupta of B. Pharma 8th semester student of
Department of Pharmacy, Radha Govind University, Ramgarh has prepared the Project
on topic “Nutraceuticals in Healthcare: Benefits, Challenges, and Future Directions” for
consideration in the partial fulfillment of the provision of subject PROJECT WORK
(BP812PW) in the session of 2021-2025.
He/ she prepared the report under my guidance.

DATE: 10/05/2025​ GUIDE SIGNATURE

PLACE: RAMGARH
 DEPARTMENT OF PHARMACY

RADHA GOVIND UNIVERSITY, RAMGARH, JHARKHAND

(Approved by P.C.I)

Declaration by the Student

I, Pankaj Kumar Gupta, Hereby declare that this project report is the record or authentic
carried out by me during the period from 2021-2025 and has not been submitted to any
other university or institute for the award of any degree/diploma etc.

Date: 10/05/2025​ Student Signature

Place: Ramgarh
 ACKNOWLEDGEMENT

I would like to express my sincere gratitude to all those who contributed to the successful completion of
this project.

First and foremost, I thank Rahul Kumar Sir, my project guide, for their invaluable guidance, constant
support, and encouragement throughout the course of this work. Their insights and expertise greatly
helped in shaping the direction and quality of the project.

I am also thankful to the faculty and staff of the Department of Pharmacy, Radha Govind University,
for providing the resources and academic environment necessary to carry out this work.

A special thanks to my classmates and friends for their cooperation, constructive suggestions, and moral
support.

Finally, I am deeply grateful to my family, whose motivation, patience, and encouragement played a vital
role in the completion of this project.

This work would not have been possible without the support of all those mentioned above. Thank you all.
 INDEX

1.​ Introduction 01-06

2.​ Nutraceuticals in Cardiovascular Diseases 07-09
3.​ Nutraceuticals in Cancer Chemo- and Radiotherapy 10-11
4.​ Nutraceuticals for Skin Treatment 12-14
5.​ Nutraceuticals as Specialized Medical Products 15-17
6.​ Challenges in the Formulation of Nuraceuticals and 18-21
Dietary Supplement
7.​ Excipient Selection 22
8.​ Safety and Quality Control of Nutraceuticals 23-27
9.​ Conclusion 28
10.​Reference 29-31
 INTRODUCTION

Nutraceuticals are characterized as ‘specially designed preparations’, formulated with the aim
of fulfilling specific dietary requirements and/or offer preventive health care. Nutraceuticals
are the formulation of nutrient/nutrients which helps in prevention and treatment of some
diseases, in addition to a supplement diet. Nutraceutical is a term given by Dr. Stephen De
Felice in 1989 and came from two words “nutrition” and “pharmaceutical”. These are foods or
a part of foods that are beneficial in providing various health benefits including the treatment
and/or prevention of the disease. Science of nutrition has increasingly achieved new horizons,
starting from the anticipation of deficiencies in nutrients to prominence on human health and
prevention and treatment of chronic ailments. Terms ‘nutraceuticals’, ‘food supplements’,
‘dietary supplements’ have evolved after the concept was originated by Dr. De Felice. There is
no sharp demarcation between food supplements and nutraceuticals given by regulatory
authorities. Literature of recent years emphasizes on redefining the concept of nutraceuticals,
taking into consideration the efficacy, safety and toxicity of these products. Food products are
nourishing substances that are eaten, drunk or otherwise taken to sustain life, provide energy
and promote growth. Currently, isolation of nutrients from these food products are well
recognized and used. The starting point to differentiate food/dietary supplements and
nutraceuticals is the identification of an epidemiological target, followed by safety and efficacy
studies that understand the mechanism of action. One approach to differentiate these two types
of formulations is describing ‘food supplements’ as agents to compensate deficiencies in micro-
or macronutrients; in addition, the use of a “nutraceutical” in the treatment of a pathological
disease must be supported by strong scientific evidence. With adequate clinical evidence,
nutritional supplements should have a strong safety profile with few undesirable side effects
and better bioavailability. There is a very fine line of demarcation between two types of
formulations: the same ingredients may work as a nutraceutical or food supplement but may
be demarcated on the basis of claims. Nutraceuticals include single or combinations of pro-
and pre-biotic foodstuff and food for special medical uses; and food supplements includes
single or combinations of mineral, vitamins, protein supplements, functional foods and herbal
products. By prolonging or eliminating the need for pharmaceuticals in subjects to fit for an
alternative nonpharmacological treatment to a pathological condition, the incorporation of
nutraceuticals into daily diet may aid in the prevention of pathological disorders. There are
claims that foods including spices and herbs possess the tendency to decrease the risk of many
diseases and can be highly beneficial in improving the quality of life. There is a plethora of
benefits that nutraceuticals have provided, including their promising results in the prevention
and treatment of complicated diseases. However, there is a need of administration and
prescription of nutraceuticals, and they should be strictly regulated in order to prevent their
uncontrollable use and side effects. Several researchers have studied drug compound-based
nutraceuticals to improve the efficacy as well as bioavailability. The safety and efficacy of
various statins have been used in the prevention of cardiovascular diseases even in pregnant
women. Nutraceuticals with an effective safety profile and well-established impact
nonpregnancy might be a suitable therapeutic option for preventing diabetes mellitus and
hypertensive disorders, or as an adjuvant to therapy with standard medications. Calcium,
omega-3 polyunsaturated fatty acids, vitamin D, folic acid, resveratrol, alpha-lipoic acid, zinc,
inositol, and probiotic supplements are potentially proven candidates as novel nutraceuticals.
Researchers have evaluated the nutraceutical associated with the drug compound ezetimibe for
patients at risk of elevations of statin level, which further leads to cardiovascular diseases. The
use of a novel nutraceutical in blend with non-steroidal anti-inflammatory drugs (NSAIDs) has
been proven a potential candidate for osteoarthritis, thus improving its efficacy and safety for
commercial use .The market remains robust and ever-growing for nutraceuticals such as
antioxidants; omega-3 fatty acids; plants such as algae, aloe vera, seaweed, and wheatgrass;
and teas and herbs such as ginseng and Echinacea. Detailed findings including clinical data on
nutraceuticals are shown in Table 1. A recent survey suggested that the nutraceutical market is
expanding globally and the probability states that it may reach up to $340 billion by 2024. The
compound annual growth rate (CAGR) of nutraceuticals is estimated to be 7.2% from 2016 to
2024. This increment in the growth of the nutraceuticals-based industry is associated with
various factors such as a rise in demand for nutraceuticals, an awareness among people of the
benefits of nutrition, and an incremental rate observed in the healthcare graph [9,10]. Currently,
Europe, the USA, and Japan account for ˃90% of the total global nutraceutical market and the
global market is supposed to reach $336 billion by 2023 from $247 billion in 2019 at a CAGR
of 8%. With this attainment of the maturity of global markets, now the focus of nutraceutical
players has been shifted towards developing economies, especially those across the Asia
Pacific, including India. The Indian market had only a 2% market share of the total global
nutraceutical market in 2017. It is estimated to reach $11 billion by 2023, increasing at a CAGR
of 21%. By 2023, India is also expected to hold at least 3.5% market share of the global market.
Table 1. Clinical data findings on nutraceuticals

Nutraceutic Bioactive Dosage Formulati Durati Action

als Molecule on on of Populatio
study n size
(voluntee
rs)
Omega-3 Eicosapentaen 60 Capsule 12 Cystic 15
oic acid (EPA) mg/kg/d months fibrosis
and ay
Docosahexaen
oic
acid (DHA)
Omega-3 Eicosapentaen 900 mg Capsule 15 days Reduction 61
oic acid (EPA) in the of
and omega-3 chemothera
Docosahexaen rich py
oic group y-related
acid (DHA) and 250 toxicities
mg in
the
omega-3
poor
group
Omega-3 Eicosapentaen 2000 Capsule 21 Appetite 72
oic acid (EPA) mg/day Days
and
Docosahexaen
oic
acid (DHA)
Aloe vera aloe-emodin, 2000 Capsule 21 days Appetite 72
aloin, aloesin, mg/day
emodin, and
acemannan
Aloe Vera aloe-emodin, - Gel 2 Acute 120
aloin, aloesin, months dermatitis
emodin, and
acemannan
Aloe Vera aloe-emodin, 60 ml juice 5 Irritable 110
aloin, aloesin, months bowel
emodin, and syndrome
acemannan
Seaweed polysaccharid 2000 Extract 12 High- 34
es proteins, mg/day weeks density
lipids, and lipoprotein
polyphenols (HDL)
cholesterol
Wheatgrass vitamins, (A, - cream 12 Plantar 134
B, weeks fasciitis
C, and E),
minerals such
as iron,
calcium,
magnesium,
benzo(a)pyre
ne, ferulic,
gallic, caffeic,
syringic, and
p-coumaric
acid
Wheatgrass vitamins, (A, 100 Juice 1 Active 23
B, cc/day month distal
C, and E), ulcerative
minerals such colitis
as iron,
calcium,
magnesium,
 benzo(a)pyre
ne, ferulic,
gallic, caffeic,
syringic, and
p-coumaric
acid
Ginseng ginsenosides 100 mg Capsule 12 Psychomot 16
twice a weeks or
day functions
Ginseng ginsenosides - Hydrogel 2 weeks Skin 20
homeostasi
s
Echinacea polysaccharid 20 mg or Powder 6 weeks Anti- 104
e 40 mg anxiety and
s, twice a anti-
glycoproteins, day depressant
alkamides,
cichoric acid,
caftaric acid,
and
chlorogenic
acids

The COVID-19 virus is having a knock-on effect on every industry. The long-term
repercussions are hard to predict as of yet. In a post-COVID-19 pandemic situation, the global
economy is still struggling and its impact on the global trade and nutraceuticals market is rising
with rapid deterioration in the supply of products irrespective of high demands. The
Nutraceutical industry is not able to bridge the gap between high demand and low supply as
75–80% of raw material used in nutraceuticals was sourced from China in North America,
Europe, and Asia Pacific. Due to China’s manufacturing shutdown, and the sudden recessive
conditions in native regions, nutraceutical production has been reduced. A sharp surge in
demand was observed for dietary supplements from consumers, as they provide a strong
immune function and decrease possible health threats. However, an officially shared and
accepted definition of nutraceuticals is missing; these are also referred to as ‘pharma food’—a
powerful toolbox that is beyond the diet but before the drugs. Various formulations containing
macronutrients (required in large amounts, e.g., omega-3 fatty acids, magnesium, potassium,
and calcium), micronutrients (required in lesser amounts, e.g., minerals or vitamins) and
phytochemicals that are present in the food source and are available at drug stores. Further,
probiotics, minerals, polyunsaturated fatty acids, carotenoids, amino acids and proteins,
vitamins, dietary fibres, spices and phytochemicals have also become part of these
formulations. Nutraceuticals exist in various types and may range from herbal products to
isolated nutrient diets and may go up to existing genetically modified foods. Plant foods such
as vegetables, whole grains, and vitamins are rich in dietary phytochemicals. Dietary
supplements are consumed as such, or as isolated active ingredients. These phytochemicals are
immensely diverse and these include carotenoids, phenolics, alkaloids, organosulfur, and
nitrogen-containing compounds. However, these products may not be substantiated by
scientific data on their safety, efficacy, and effect on health and/or pathological conditions. In
the pharmaceutical industry, it is mandatory to do clinical tests on animals or in vitro for the
verification of a compound’s effects. On the contrary, in nutrition, there was no such method
in the past for the verification of the effects of foods in preventing or treating diseases. In recent
years, however, food composition has been scientifically tested and verified as people are
becoming more and more aware of health-related issues and how food can directly or indirectly
be responsible for maintaining proper health and preventing diseases (Figure 1).

Fig 1: Potential roles of nutraceuticals

 NUTRACEUTICALS IN CARDIOVASCULAR DISEASES

Among all other diseases, cardiovascular diseases reveal significant risk-related factors
acquiescent to nutraceutical intervention. There is significant evidence indicating that
nutraceuticals can be used in cardiovascular diseases. Cardiovascular diseases (CVDs) mainly
affect the blood vessels and the functioning of the heart. CVDs are one of the biggest causes of
mortality, as they account for about 30% of deaths all over the world annually. Dietary
supplements have been proven to be beneficial in risk management and prevention of
cardiovascular diseases and can be classified broadly into the ones used in the treatment of
arrhythmias, Congestive heart failure, angina, hypertension and hyperlipidaemias. Some of the
nutraceuticals and dietary supplements that are used for the treatment and prevention of CVDs
are discussed below.

Allicin and Alliin

Ischemic heart disease and atherosclerosis are associated with elevated levels of plasma
triglycerides and blood-cholesterol are associated with. Allium sativum is antihyperlipidemic
in nature and it exerts its effects by the elimination of cholesterol and its end-products in high
amounts in the feces and by decreasing the cholesterol synthesis endogenously. This helps in
producing more favorable ratio of HDL and LDL. Allicin and alliin can affect cholesterol
levels, if these can be protected by gastric acids. Garlic supplementation on serum cholesterol
was assessed using thirteen placebo-controlled trials concerning 781 patients. Garlic also has
some inherent antihypertensive effect, apart from being antihyperlipidemic.

Omega-3Fatty Acids

Omega-3 fatty acids are derived from marine sources and are called polyunsaturated fatty acids
(PUFAs). Docosahexaenoic acid (DHA) and Marine omega-3 eicosapentaenoic acid (EPA)
plays a critical role in the treatment and prevention of cardiovascular diseases. In one study, it
has been reported that intake of fish oil supplements reduced mortality rate by 29% for over a
period of 2 years in the diet and reinfarction trial (DART), which was a randomized trial
involving 2033 men post-myocardial infarction. Consumption of fish oil led to a noteworthy
reduction in unexpected demises by 45%, cardiovascular diseases deceased by 30% and a 20%
decrease in overall mortality. According to the recent clinical trial studies, it has been found
that the risk of cardiac arrhythmias is decreased with the help of omega-3 fatty acids, and they
also improve the health of the patients suffering from plaque formation caused by
atherosclerosis. Omega-3 fatty acids period and helping treat arrhythmias.

Soy Isoflavones

Soy proteins and soy isoflavones are important nutrients with potentially medicinal benefits
such as antihyperlipidemic, antihypertensive, anti-hyperglycaemic, antioxidant, anticancer,
anti-inflammatory, anti-obesity and neuroprotective activities that support the biological
plausibility for observational associations. It is evident from clinical study reports that
consumption of soy protein reduces serum cholesterol levels in humans. In addition, USFDA
has evidenced that 25g of soy proteins or isoflavone per day intake showed a lowering of blood
pressure in postmenopausal women. Moreover, soy proteins exert favourable effects on the
serum lipid concentrations, especially in hypercholesterolemic patients. In a study, subjects fed
with a diet low in saturated fat leads to the decrease in risk of coronary heart disease. Soy
isoflavone had no effects on the lipid profiles. Further a study reported significant reduction of
the ratio of LDL to HDL after intake of new soy products, having high levels of isoflavones,
cotyledon soy fibre and soy phospholipids (Abaco and Abalon).

Proteins, Peptides and Amino Acids

Hypertension is associated with cardiovascular diseases. ACE (angiotensin converting enzyme)

inhibitors have been a chief line of therapy to treat the condition, but these drugs lead to side
effects such as hypotension, elevated levels of potassium, impaired renal function, coughing
and skin rashes. Natural, ACE inhibitors are found in casein and whey protein derived from
milk. It is also evidenced from animal studies that these milk-derived proteins exert
antihypertensive effects. The same has been reported in clinical studies where a statistically
significant hypotensive effect has been observed.
Antioxidant Vitamins

Antioxidants have been used as potential supplements in chronic diseases such as

cardiovascular diseases and cancer. They reduce LDL-cholesterol oxidation by counteracting
the damaging effects of free radicals. Vegetables, fruits, fish and fixed oils contain antioxidant
vitamins in large volumes, which works by preventing the formation of oxygen free radicals or
by entrapping them. It has been evidenced in some epidemiologic studies of CHD patients on
a diet of large quantities of antioxidants that they result in fewer incidences of morbidity and
mortality. Supplements having antioxidant vitamins C and E help in preventing CHD.
However, supplementation with ß-carotene can produce adverse effects and, thus, is not
recommended. The National Health and Nutrition Examination Survey-I cohort study observed
that risk of CHDs decreases in vitamin C intake, which was found in the observation of over
10 years in American men and women of age group of 25–74 years, in which subjects were
randomized with diverse combinations of 10 nutritional supplements for over five years.
 NUTRACEUTICALS IN CANCER CHEMO- AND RADIOTHERAPY

Radiotherapy and chemotherapy are conventional therapies for cancer therapy but have serious
side effects and various complications (e.g., pain, fatigue, diarrhea, vomiting, nausea, and hair
loss). Some cancers are highly resistant to chemo- and radiotherapy and, because of this,
systemic cytotoxic chemotherapy and radiotherapy are not very operative at cultivating patient
subsistence. In this situation, various combination therapies overlay an efficient means to treat
cancer. Likewise, there are a variety of plants and natural supplements that are observed to
reduce the side effects of radiotherapy and chemotherapy. Thus, these should be used in
combination with radio-or chemotherapy for the reduction of side effects and to augment
treatment effectiveness. The proliferation of cells leading to cancer results in the need to treat,
and the nutraceutical industry is evolving to treat the needs of the consumers. The evolution of
the nutraceutical industry can be recognized as it has now reached disease prevention after it
started from health promotion. A plethora of currently used herbs and phytochemicals are safe
pharmacologically and have been proven to be potent nutraceuticals in suppressing tumor
progression, alleviating the disadvantages of radio-and chemotherapy, and increasing the
sensitivity of these therapies. Caponio and his team evaluated the effects of the phenolic
compounds found in Aglianico Grape pomace (GP) on colorectal cancer cell lines at varying
stages of development after subjecting them to an in vitro digesting model. Aglianico GP
extract was found to have strong effects on cell proliferation and apoptosis, as well as on other
cellular processes. Substantial upregulation of Bax, as well as the Bax/Bcl-2 ratio and caspase-
3, was observed in both HT29 and SW480 cells. UHPLC-DAD analysis revealed that
anthocyanins, phenolic acids, and flavonoids were the primary components responsible for the
elevated (total phenolic content) TPC and antioxidant activity in the Aglianico GP digested
extract. In 2021, Zhang and his co-workers studied the combined effect of chrysin and apigenin
by suppressing the activity of the P38-MAPK/AKT pathway in colorectal cancer. Apigenin and
chrysin, both at 25 µM, substantially inhibited clone number, migration, and invasion, while
increasing apoptosis in both colorectal cancer (CRC) cell lines. Additionally, chrysin and
apigenin significantly suppressed p-P38 and p-AKT. Anisomycin, a P38 agonist, effectively
mitigated the tumor-inhibiting action of apigenin and chrysin. Together, apigenin (25 µM) and
chrysin (25 µM) had a synergistic impact in limiting the proliferation and metastasis of CRC
cells by suppressing the P38-MAPK/AKT pathway.

Curcumin (Diferuloyl-Methane) from Turmeric (Curcuma Longa)

Curcumin has been classified as a commanding nutraceutical for cancer treatment. Pre-clinical
studies with curcumin suggest that it inhibits carcinogenesis in different types of cancers, such
as pancreatic, colorectal, prostate, gastric, and hepatic cancer; in addition, it has been able to
suppress it at every step, that is, angiogenesis, metastasis, and proliferation. It is much more
effective when it is in combination with chemo- and radiotherapies for cancer treatment.

Ginger
Ginger is an antimutagenic, antioxidant, and anti-inflammatory nutraceutical and is known to
diminish the side effects of radio and chemotherapy. It is these properties of ginger that provide
helpful radio-protector activity. A reported loss in the doses of morphine in cancer patients is
seen with the help of Ginsenoside Rf and Ginseng and its polysaccharides help reduce the side
effects of cancer treatment therapies, which have been reported to cause a 50% less risk of the
recurrence of cancer.

Genistein

Genistein is a potent isoflavone and has promising anti-carcinogenic properties. In vitro studies
have shown that there are a few components that exert their antitumor effects only at higher
concentrations that are not possible to achieve at normal dietary consumption. Thus, it is
difficult to achieve the desired effect at the tumor site, which leads us to think that the mode of
delivery is a very important factor that needs to be considered in in-vivo studies and clinical
trials. For a therapy to be formulated, the non-toxicity of the natural components is a very
important factor. Nevertheless, it has been found that some compounds are more potent if
administered early in life and Genistein is one of them.
 NUTRACEUTICALS FOR SKIN TREATMENT

The skin is known to be the body’s largest organ, and it offers protection against all sorts of
microorganisms, ultraviolet radiations, and chemicals also participating in sensitivity. As a
result of having a major role in protecting the body, the skin may face alterations, such as
immune dysfunction, photo-aging, and inflammation, which may result in harm to human
health. A potential strategy for delaying or diminishing pre-mature agingof the skin and
alleviation of skin-related disorders can be found with the help of nutraceuticals. These
nutraceuticals can be bioactive peptides, bioactive polysaccharides, botanical extracts,
carotenoids, etc. Supplementation with these products in several human trials have evidenced
fewer signs of aging and also protection against UV-radiation aging.

Bio-Active Peptides

Peptide moieties are the combination of two or more amino acids and are short sized with low
molecular weight (<3 kDa), and some may perform important biological actions that are termed
bioactive peptides. Bioactive peptides have been isolated from a wide variety of dietary
proteins, including plants and animals. Eggs, milk (casein and whey), and meat proteins are the
most common sources of animal protein. Soy, oats, pulses (chickpea, bean, pea, and lentils),
canola, wheat, flaxseed, and hemp seed are common plant sources for bioactive peptides.
Peptides that are used for cosmetic purposes are usually derived from collagen and typically
serve as nutraceutical formulations because of their increased bioavailability and solubility. It
has typically been observed in a controlled study of VERISOL®, which contains bioactive
collagen peptide (BCP). In this study VERISOL® and a placebo were given to subjects for 8
weeks and skin wrinkles were measured before the treatment and after 8 weeks. It was observed
that BCP promoted a significant decrease in the eye-wrinkle volume in comparison to placebo
after 8 weeks of treatment. Not only this, BCP intake showed an increase in the content of
elastin and procollagen type1 along with an increase in the fibrillin content. Thus, this treatment
reduces wrinkles and has encouraging effects on skin matrix synthesis. Peptan F and porcine
origin Peptan P are some other nutraceuticals of fish origin containing collagen peptides used
to slow aging by effectively maintaining the moisture content within skin layers. Recently, a
study indicated improved skin properties without risk of oxidative damage by use of a
nutraceutical product Celergen®, proving it a safe and effective supplement. This nutraceutical
is based on a marine collagen peptide derived from deep-sea fish, grape skin, coenzyme Q10,
and serotonin.

Bio-Active Polysaccharides

These are sugar-based polymers that have energy storage and structural functions. They are
present in life forms such as plants, fungi, animals, and prokaryote organisms having diverse
monosaccharide combinations, physicochemical properties, and structures. The most useful of
them for the nutraceutical formulations is the Glycosaminoglycans from the marine origin. The
basic unit of these are- an un-branched disaccharide (repeating) unit of amino sugar called N-
acetylglucosamine or N-acetyl galactosamine and a uronic acid called glucuronic or iduronic
acid. A human trial of the formulations containing these was conducted using Imedeen®
DermOne®, these contain some protein fractions as well along with the glycosaminoglycans
and serve as dietary supplements for skin care. In addition to the protein, the supplement
contained zinc gluconate and vitamin C which are relevant for skin care. In the trial conducted,
10 women were treated with an amount of 500 mg of Imedeen® for 90 days. Parameters
evaluated were dryness, brittleness of hair and nails, wrinkles, and mottles. It was seen that
after 90 days, all these signs were improved, and observations established skin thickness and
elasticity.

Bio-Active Botanical Extracts

These extracts are multifaceted mixtures of various compounds having diverse structures and
origin. Since a long time, they are being used and reviewed. Polyphenols are one of the key
natural compounds with cosmetic applications with a plethora of families and structures. These
are plant-based micronutrients available from diet. These are beneficial as support therapy in
the prevention of diseases and also improved the outcome of diseases. Various polyphenols
have significantly different bioavailability and the most abundant polyphenols in our diet
possess the maximum concentration of active metabolites in target tissues. Their composition
and proportion vary depending on the procedure of extraction and families. Pycnogenol® is a
formulation being made with the help of these and is rich in catechins, flavonoids and
procyanidins (B1, B2, B3, B7 C1 and C2), also, they contain phenolic acids such asferulic acid
and caffeic acids. It is also confirmed to have several effects such as cholesterol lowering and
cardiovascular benefits because of its antidiabetic, anti-inflammatory and antioxidant
properties.

Carotenoids

These are naturally occurring pigments found in algae, photo-synthetic bacteria and various
plants. These have linear tetra terpenoid structure. These are found in natural sources such as
fruits, vegetables etc. α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene
are the most commonly used dietary carotenoids. These carotenoids are used for skin health
such as anti-ageing and photo protection of skin. The probiotics and carotenoids are reported
for decreasing the skin damage due to UV-exposure and also in modulating early skin
biomarkers of UV effects. A Carotenoid mixture supplement of α-carotene, β-carotene and
lutein are proved effective in photo protection. Similarly, a mixture of beta-carotene, lutein and
lycopene carotenoids is reported for protection against erythema. The vitamin C and E is
studied for the photoprotective effect and found to be effective in skin health care. Vitamin C
is a hydrophilic vitamin, commonly taken in large doses via consuming various food products
with the intent of inhibiting the formation of carcinogenic nitrous metabolites. It acts as a
cofactor for the synthesis of collagen fibers and inhibits the biosynthesis of elastin in fibroblasts
thereby preventing its accumulation, which is highly present in photo-damaged skin. In
combination with vitamin E, it acts synergistically working with its mechanism of
transformation. Vitamin E is the main lipophilic antioxidant and is found in the form of
tocopherols. It binds with peroxyl radicals, thereby preventing lipid peroxidation of
polyunsaturated fatty acids. In addition, itsuse for preventing photodamage, sunburn, atopic
dermatitis, etc., is clearly evidenced.
 NUTRACEUTICALS AS SPECIALIZED MEDICAL PRODUCTS

According to the legal basis, dietary foods and enhancements for distinct medical purposes are
specialized medical products. These dietary supplements should be regulated according to the
regulatory agencies such as ‘European Food Safety Authority’ and the ‘U.S. Food and Drug
Administration’, in addition to numerous national protocols issued most often by the ‘Ministry
of Agriculture’ and/or ‘Ministry of Health’ of various countries around the world Nutraceuticals
are non-specific biological therapies used to promote wellness, prevent malignant processes,
and control symptoms. Figure 2 shows a flow chart indicating the role of nutraceuticals in
health promotion and disease prevention. Various nutraceuticals in health promotion are
summarized in Table 2.

Fig 2: Role of nutraceuticals in disease prevention and health promotion.

Table 2: List of nutraceuticals with health benefits

Nutraceuticals/ Dietary Nutrients Health Benefits

Supplements
Water Soluble Vitamins Vitamin c, Vitamin B1, Wound healing, Antioxidant
Vitamin B2, Vitamin B6, Carbohydrate metabolism,
Vitamin B12, Folic acid, Neurological
Pantothenic acid function
Energy metabolism, Nerve
function
Brain function
Convert proteins to energy
Formation of RBCs,
Synthesis of amino acids
Metabolism of fat, protein,
and carbohydrate
Folic acid Formation of
RBCs, Formation
of genetic material of cells
Pantothenic acid
Intraneuronal synthesis of
acetylcholine
Synthesis of cholesterol,
steroids, and fatty
acids
Fat Soluble Vitamins Vitamin A, Vitamin D, Cancer, Skin disorder,
Vitamin E, Vitamin K Healthy vision
Antioxidant
Absorption of calcium,
Formation of bones
and teeth
Boost immune system,
Antioxidant
Blood clotting
Minerals Calcium, Iron, Magnesium, Maintaining bone strength,
Phosphorous, Iodine, blood clotting
Chromium, Selenium, Zinc Oxygen transport, Energy
production. Healthy nerve
and muscle function and
bone
function
Phosphorylation process,
Genetic material
Heart functioning, Iron
absorption
Functioning of the thyroid
gland
Diabetes
 Antioxidant
Sperm production, wound
healing
Herbals Aloe vera Anti-inflammatory, Wound
Evening, primrose healing
oil Treatment of atopic eczema
Garlic Anti-bacterial, Anti-fungal
Ginger Carminative, Anti-emetic
Ginseng Adaptogen
Green tea Cell-mediated immunity,
Antioxidant
CHALLENGES IN THE FORMULATION OF NUTRACEUTICALS AND
DIETARY SUPPLEMENT

A quality nutraceutical formulation with physical and chemical stability, adequate safety,
technological feasibility and still cost-effective entails many challenges. When compared with
drug molecules that are well defined chemical entities, botanicals are complex ingredients
containing multiple chemical constituents and usually several classes of compounds are present
in a single product. Most of these botanicals are susceptible to heat, light, oxygen, alkaline pH
and elevated humidity. These are usually having poor flow, bulk density and variable particle
size distribution. Thus, successful development of nutraceutical formulation requires
knowledge of the fundamental aspects of the physicochemical properties of the different types
of ingredients, the use of adequate techniques of manufacturing, selection of the right
excipients and the addition of suitable manufacturing overages based on critical stability
studies. Here, emphasis is given on:

• Challenges with various dosage forms.

• Approaches to deal with formulation challenges.
• Excipients selection.

Challenges in the Formulation of Nutraceuticals and Dietary Supplement

While formulating nutraceuticals, the poor aqueous solubility, high melting point of
nutraceuticals and chemical instability of active constituents pose difficulties. For example,
omega-3 fatty acids, carotenoids, oil soluble vitamins, curcumin possess high nutritional value
but are poorly soluble. Therefore, the possible approach is to formulate these as novel delivery
systems. These novel delivery systems make them costly. Thus, efforts are needed to make
these formulations cost effective. Another challenge in formulating nutraceuticals is their high
melting point. For example, phytosterols, fatty alcohols and carotenoids all have high melting
points that may cause instability to formulation. Therefore, the possible approach is to prepare
solid dispersion/dissolve in suitable grade solvent and introduce in food as suspended
nanocrystals. However, the challenge is again that it leads to deteriorated stability and shelf
life, disagreeable appearance, and obnoxious odour and mouthfeel, which affect market value
and customer demand. Therefore, there is need to develop cost-effective. Chemical instability
is another challenge. For example, omega-3 fatty acid rich oils, such as fish oils, flaxseed oil,
cod liver oils; carotenoids; lycopene or curcumin all have stability issues. The extent of the
chemical degradation is completely dependent on the composition of the bioactive product, the
environmental conditions such as temperature, pH, pressure, etc., or the presence of metals or
other such oxidation-promoting agents. For such compounds, the development of nanoscale
products is essential to protect them from degradation. Further, in the case of the development
of probiotics, special, selective bacterial strains are necessary. A current challenge is the
selection of the proper strain followed by their incorporation in foods. Application of any
mismatching bacterial or toxic cultures, in addition to their negligent handling, can cause
disastrous consequences. Apart from these challenges, other considerations are solid dosage
formulation and process design for drug products and nutrition products that are similar, but
the purpose and regulatory requirements may differ. Finally, there is a challenge in the
formulation of nutraceuticals and dietary supplement dosage forms that are suitable for
different groups of the aging population, especially older adults and children. This is because
this group of people has limitations in solid dosage from (tablets or capsules) swallowing
(dysphagia). Therefore, advanced dosage forms such as or dispersible tablets, fast dissolving
films and easy-swallowing gels, which are normally used in pharmaceutical applications, must
be considered in nutraceutical and dietary supplement administration.

Approaches to Deal with Formulation Challenges

One of the most widely used approaches is isolation or preparation of concentrates of

nutraceuticals from natural sources. It is advantageous as most of herbal nutraceuticals are to
be administered in a large dose per daily serving. Further, multiple “active ingredients” are
present in different sources. There is significant variation in active ingredient compression and
flow characteristics within one dosage form. There are large variations in heat and moisture
sensitivity of ingredients within one formula. Significant stability challenges are there with
multiple opportunities for interaction. Different extraction processes involve microwave-
assisted extraction, counter current extraction, maceration, percolation and Soxhlet extraction.
Natural bioactive compounds are plant extracts; herbal concentrates; fruit, vegetable and
specialty concentrates; and fungal and microbial materials, which are included in feedstock to
produce concentrates (bio-fermentation process). Concentrates may include excipients used in
production (such as spray dried carriers). Systems have been used to modify the properties of
various compounds to produce new generations of drug compounds. They also play a role in
the food industry and in various kinds of nutritional supplements. Various formulations of
supplements prepared by nanotechnology, called nano formulations, that have increased
bioavailability, reduced side effects and protect the active ingredients against the process of
degradation, have been reported. The polyphenols obtained as nutraceuticals in the form of
dietary sources have proved greatly advantageous in improving diseased symptoms as observed
in preclinical and clinical studies. One of the most encountered disadvantages is its lower
bioavailability due to the lesser gastrointestinal absorption in the upper tract attributable to
hydrophobicity, presence in the polymeric or glycosylated form in foods, and they bound
tightly with the food matrices. All these factors lead to the minimum bio-accessibility of
polyphenols inside the body. Therefore, food processing-based research and development
techniques along with nano formulation, enzymatic treatment, probiotics combination
therapies, among others, have proved advantageous to overcome this challenge.

Liposomes and Nano emulsions

Liposomes and Nano emulsions are also termed as bilayer phospholipid vesicles and possess
greater potential for the industry of nutraceuticals as they can simultaneously encapsulate both
hydrophilic and lipophilic materials. This ensures a synergistic effect and is also helpful in the
protection of bioactive compounds that are highly sensitive, ensuring enhanced bioavailability,
sustainable release and storage stability. As the nanoliposomes have unique properties, they
can be effectively used in operative prevention against diseases and for health promotion. One
of the latest examples is lipid-based nanocarriers, nano phytosomes, which help in enabling the
delivery of botanical nutraceuticals. They have the potential to be used in various food products
for the design of novel functional beverages and food products. A study indicates increased
chemical and physical stability of rutin when rutin complexes were formed in the form of
phytosomes. These phytosomes complexes of rutin were formed with the help of
phosphatidylcholine (PC) with the molar ratio of (rutin: PC) being (1:3) with a particle size of
less than one hundred nm and 99% encapsulation efficiency, as it was able to mask the
undesirable properties of rutin. These were termed as phytosomes, phosphatidylcholine (PC)—
rutin complexes.
Lipid-Based Carriers

Lipid formulations in the form of nano capsules, and micronized carriers are potential
candidates to be used to effectively enhance the controlled release, solubility, and
bioavailability of phenolic compounds. As an example, β-Car nano capsules (>300 nm), due to
their physical stability showed only negligible variations during storage, which suggested that
they can be widely used as functional foods and beverages along with being nutraceutical
products.

Polysaccharide Matrices

These are the kind of matrices that have numerous enzymatic exposures that guarantee
degradation at specific points in the large and small intestine. When being used as a
nanoparticle coating, they can effectively retard the nonspecific release of bioactive
components encapsulated within until the coating is exposed in the intended environment
where it was intended to be released. These coated nanoparticles can potentially be used to
target various diverse organs of the GI tract to help improve the oral bioavailability.
 EXCIPIENT SELECTION

Next, the approach to deal with formulation challenges of nutraceuticals is the modification in
formulation parameters by appropriate selection of excipients. For nutrition, the final formula
must be robust to accommodate the variable physical characteristics of natural ingredients in a
complex formula. Materials and manufacturers must meet internal quality and safety,
specifications, and performance requirements. One formulation’s functionality can be another
formulation’s dysfunctionality. Excipient functionality can only be properly assessed in the
context of a particular formulation and manufacturing process. For natural product formulation,
excipient functionality in a particular formula is heavily influenced by the complex
combination of multiple active ingredient characteristics. Occasionally, seemingly equivalent
excipients are not equivalent in functionality.
 SAFETY AND QUALITY CONTROL OF NUTRACEUTICALS

Nutraceuticals are taken as supplements by users and are available as over-the-counter

products. Therefore, their safety is of prime concern, or else it may lead to lethal effects. The
most observed issues are contamination, adulteration (inadvertent or intentional), or misleading
labels. To demonstrate adulteration, three different detection strategies may be adopted (1) the
presence of an undeclared substance, (2) that a component is deviated from its normal level
(content) and (3) that a profile is unlikely to occur. Adulteration may be inadvertent adulteration
or intentional adulteration. Inadvertent adulteration may exist due to different conditions. For
example, during the different stages of plant growth, the formulation and manufacturing of
nutraceuticals, or during storage, contamination with fertilizers, heavy metals, fertilizers or
microbial agents may take place. Adulteration may also take place with synthetic drugs,
substitute species, dust, pollens, insects, rodents, parasites, microbes, fungi, mold, toxins, and
heavy metals. Any of this type of contamination may lead to infections or even serious illnesses
such as gastritis and associated complications, liver injury, and even life-threatening
conditions. Therefore, raw-material and finished-product quality control is required and may
be determined by specifications outlined in certain monographs, along with the stability of
active compound(s) and microbiological control. Serious harmful effects may result from the
intentional adulteration of supplements or herbal remedies. It usually occurs with synthetic
compounds, mostly undeclared. It usually occurs to alter the pharmacological response and
earn economic benefits. The sourcing of nutraceuticals from plants is often very limited, and
extract preparation is time- and cost-consuming. Therefore, these adulterations are not allowed
by regulatory authorities. Some examples of adulterations are quoted in the below sections.

• (a) Ibutramine hydrochloride monohydrate is a drug molecule that works by inhibiting

serotonergic and noradrenergic reuptake and shows effects as an anti-obesity drug and
is a common adulterant. In a study conducted with twenty-two samples of dietary
supplements in China, eleven were found to be contaminated with phenolphthalein, N-
mono-desmethyl sibutramine, and sibutramine. In another similar study performed on
fifteen samples in China, four of them contained sibutramine and N-di-
desmethylsibutramine. Further, it has also been reported that two pregnant women in
 Turkey lost their wombs due to the consumption of adulterated Chinese herbal
medicine “militant”. Sibutramine has also been reported as a solvent in slimming
preparations. It has led to mania-like psychosis in two women in Hong Kong.

• (b) Fenfluramine is another drug that was used as an adulterant in Chinese traditional
medicines and found in many slimming preparations. It caused primary pulmonary
hypertension and valvular heart disease. This drug was withdrawn from the market in
1997.

• (c) In some weight control programs using orexigens, diuretics, stimulants, and
laxative agents, it has been demonstrated that these products contain adulterants such
as ephedrine, norephedrine, caffeine, and furosemide.

• (d) Morphological substitute usage is another common example of adulteration that

may cause serious health issues. For example, Panax ginseng (Araliaceae), also known
as “Asian or Korean ginseng”, is used as traditional medicine. It is adulterated with
roots of Panax quinquefolius L. (American ginseng) and Eleutherococcus
senticosusmaxim (Siberian ginseng), which may cause health problems. Another
similar example is Panax ginseng being used as an adulterant in the roots of
Mandragora officinarum L. (Solanaceae) because they are morphologically similar but
have completely different pharmacological effects and phytochemistry [166]. Further,
the roots of Pfaffia panaculata (Mart.) Kuntze (Amaranthaceae), also known as
“Brazilian ginseng or suma root”, morphologically resembles P. ginseng roots, but the
phytochemical content is different, and, hence, pharmacological action is also
different.

• (e) Some other examples of physical similarity between species include the flower
Anthemisnobilis L. and the chamomile, Matricaria chamomilla L. (Asteraceae), both
of which are listed in the European Pharmacopoeia as therapeutic plants, as well as
several other species in the family Asteraceae, such as Tanacetum parthenium (L.) Sch.
Bip., Tanacetum cinerariifolium (Trevir.) Schultz Bip., Tripleurospermum callosum
(Boiss. et Heldr.) E. Hossain, Bellis perennis and Leucanthemum vulgare L.
Furthermore, the pharmacological activity differs depending on the phytoconstituents.
• (f) One of the serious intentional adulterations is the use of peanut skin extract in
different grape products. Grape seed-containing drugs are said to have very high
bioactive polyphenols content and are used in the prevention of cardiovascular and
neurodegenerative disorders. Peanut skin is used as it is widely available, is a high-
volume byproduct, and is very cheap compared to grape products. However, it is a
potential allergen, which may cause serious concerns when used as an adulterant,
which has been reported in a study where tested products contained no detectable
quantities of grape seed extract, but only peanut skin as an adulterant.

• (g) One of the most important categories affected by adulteration is species containing
essential oils (spices). As these spices are of high economic value and are export-
oriented commodities, they are widely adulterated with natural and synthetic
adulterants. One of the most commonly reported examples is the adulteration of pure
Lavandula angustifolia Mill. (Lamiaceae) oil with other species of the same genus,
which are almost six times cheaper. Essential oils from citrus are usually adulterated
with sweet orange essential oil. Another quoted case is the use of citronella oil
(Cymbopogon winterianus), which is quite cheap, as an adulterant in very high
economic value essential oil from Melissa officinalis herb (balm oil). Melissa
officinalis herb contains citronellal as the main constituent whereas citronella oil
contains enantiomeric mixtures of citronellal.

• (h) Another intention of adulteration is to add to the industrial value of the product.
For example, synthetic α-iron and β-iron are added to the iris (Iris sp., Iridaceae) oil to
enhance the commercial value of the product, linalyl acetate or linalool, as the olfactory
quality of bergamot or lavender oil becomes improved. Other similar cases are when
vegetable oils are added to increase the weight of other products—for example,
lemongrass oil is diluted with coconut oil and sandalwood oil with polyethylene glycol.
Leaf cinnamon essential oil contains a lesser quantity of cinnamaldehyde but has the
same olfactory notes as those of cinnamon bark essential oil, and, therefore, it has been
reported as an adulterant. Cheaper petit-grain oil made from leaves is used as an
adulterant in Neroli oil made from the flowers of Citrus aurantium L. spp. amara L.
var. pumilia (Rutaceae). Another case study reports that samples of the dietary
supplements containing the leaf extract of G. biloba, used for cerebrovascular diseases,
tinnitus, and Alzheimer’s type of dementia, were demonstrated to be adulterated with free
flavonols and glycones (such as quercetin and kaempferol, respectively) as well as
genistein, the isoflavone derivative. In another case, abietic acid has been reported as an
adulterant in a herbal preparation used for the treatment of psoriasis.

• (i) One potential hazardous adulteration that has harmful effects on human health is
adulteration with allopathic drugs. The commonly used molecules in such types of
adulterations are non-steroid anti-inflammatory drugs (NSAIDs), steroids, anti-
diabetics, and analgesics. For example, glibenclamide and metformin are reported in
anti-diabetic herbal/botanical supplements. In addition, it has been reported that herbal
anti-diabetic remedies contain chlorpropamide, gliclazide, glimepiride, glipizide,
pioglitazone, tolazamide and tolbutamide. Many analgesic compounds, including
codeine, indomethacin, ketoprofen, morphine, oxyphenbutazone, paracetamol,
phenylbutazone, diclofenac, dipyrone, ibuprofen, mefenamic acid, salicylamide, and
salicylic acid, are found in adulterated dietary supplements. It has been reported that
herbal preparations contain anabolic steroids and hormones, such as rotenone,
betamethasone valerate, betamethasone, clenbuterol, dexamethasone, flumethasone,
hydrocortisone, prednisolone, prednisone, testosterone propionate, testosterone
isocaproate, testosterone phenylpropionate and testosterone decanoate. Another
significant case that has been reported is adulteration with phosphodiesterase type-5
(PDE-5) inhibitor analogs, such as sildenafil citrate (Viagra®, Pfizer, New York, NY,
USA), vardenafil hydrochloride (Levitra®, Bayer, Leverkusen, Germany), and tadalafil
(Cialis®, Elli Lilly, Indianapolis, IN, USA), have been found in dietary supplements
containing well-known natural constituents such as Panax ginseng L., Astragalus
membranaceous (Fisch.) Bunge, Schizandra chinensis (Turcz.) Baill., Ginkgo biloba
L., and many others. One of the possible consequences of such adulteration with
prescription-only drugs such as phosphodiesterase type-5 (PDE-5) inhibitor analogs,
which are contraindicated in men taking nitrates, may lead to unsafe drop in blood
pressure. Such reported adulterations are homosildenafil in a food beverage;
acetildenafil and hydroxyhomosildenafil in some other herbal products; vardenafil,
sildenafil, tadalafil, and vardenafil in an herbal product sold in Hong Kong;
benzamidenafil in herbal products; and this sildenafil, a thioketone analog of sildenafil,
in herbal aphrodisiac supplements; nitroso-vardenafil, a prodrug of sildenafil, is also a
reported adulterant, which is as carcinogenic as nitroso derivatives. Researchers
examined 91 herbal items for the presence of PDE-5 inhibitors and found that 74 of
them contained the PDE-5 inhibitor analogues, even though none of the labels
mentioned the presence of a synthetic inhibitor. Eighteen of twenty-three herbal dietary
supplements on the Dutch market tested positive for sildenafil or a comparable PDE-5
inhibitor in a similar investigation.
 CONCLUSION

To conclude, nutraceuticals are a potentially growing sector and are engaged in both fields,
either medical treatment or nutrition to ensure integrated medical assistance. These act as
potential dietary supplements, prevention of diseases such as CVD, the support and treatment
of various types of cancer, and other healthcare benefits. Therefore, nutraceutical industries
now understand and perceive extensively the potential success of nutrients that affect people
in healthcare. At present, medical care is assessed to be the domain of drugs. On the contrary,
nutrition is only appraised to be a product for healthy living. In the forthcoming years, it is
anticipated that work will be performed, as they both interact and complement each other. The
implementation of newer technologies such as the application of genetically modified
technology in the food industry, nanotechnology-based nutraceuticals, etc., leads to better
medical treatment and healthcare benefits, which further extended the increase in the
nutraceuticals revenue market. The scientific research ratifies that the improved safety and
potential effects of newly developed nutraceutical products will further stimulate investments
in newer technologies, such as nutrigenomics, converging techniques, varied imaging
technologies, and its applications in nutrition development and healthcare.
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