Recent Patents-Nutraceuticals

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Recent Patents on Drug Delivery & Formulation 2019, 13, 105-156

REVIEW ARTICLE
ISSN: 1872-2113
eISSN: 2212-4039
Drug Delivery
& Formulation
Nutraceuticals’ Novel Formulations: The Good, the Bad, the Unknown and
Patents Involved
Nada A. Helal1,#, Heba A. Eassa2,#, Ahmed M. Amer3, Mohamed A. Eltokhy4, Ivan Edafiogho5 and
Recent Patents on Drug Delivery & Formulation
Mohamed I. Nounou5,*
1
Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt; 2Department of
Pharmaceutics and Industrial Pharmacy, College of Pharmacy for Girls, Al Azhar University, Cairo, 11651, Egypt;
3
Research and Development Department, Medizen Pharmaceutical Industries Company, Alexandria, Egypt;
4
Department of Microbiology, Faculty of Pharmacy, Misr International University, Cairo, 11757, Egypt; 5Department
of Pharmaceutical Sciences (DPS), School of Pharmacy and Physician Assistant Studies (SOPPAS), University of Saint
Joseph (USJ), Hartford, CT, 06103, USA
Abstract: Traditional nutraceuticals and cosmeceuticals hold pragmatic nature with respect to their
definitions, claims, purposes and marketing strategies. Their definitions are not well established
worldwide. They also have different regulatory definitions and registration regulatory processes in
different parts of the world. Global prevalence of nutraceuticals and cosmeceuticals is noticeably high
with large market share with minimal regulation compared to traditional drugs. The global market is
flooded with nutraceuticals and cosmeceuticals claiming to be of natural origin and sold with a thera-
peutic claim by major online retail stores such as Amazon and eBay. Apart from the traditional formu-
A R T I C L E H I S T O R Y
lations, many manufacturers and researchers use novel formulation technologies in nutraceutical and
Received: January 15, 2019
cosmeceutical formulations for different reasons and objectives. Manufacturers tend to differentiate
Revised: April 07, 2019 their products with novel formulations to increase market appeal and sales. On the other hand, re-
Accepted: April 10, 2019
searchers use novel strategies to enhance nutraceuticals and cosmeceuticals activity and safety.
DOI:
10.2174/1872211313666190503112040
The objective of this review is to assess the current patents and research adopting novel formulation
strategies in nutraceuticals and cosmeceuticals. Patents and research papers investigating nutraceutical
and cosmeceutical novel formulations were surveyed for the past 15 years. Various nanosystems and
advanced biotechnology systems have been introduced to improve the therapeutic efficacy, safety and
market appeal of nutraceuticals and cosmeceuticals, including liposomes, polymeric micelles, quantum
dots, nanoparticles, and dendrimers. This review provides an overview of nutraceuticals and cosmeceu-
ticals current technologies, highlighting their pros, cons, misconceptions, regulatory definitions and
market. This review also aims in separating the science from fiction in the nutraceuticals and cosme-
ceuticals development, research and marketing.
Keywords: Nutraceuticals, adulteration, counterfeiting, novel drug delivery, nanocarriers, fortified foods, toxicity, regulatory
affairs.
1. INTRODUCTION The oldest written document that included different 12 reci-

pes of herbal medications was discovered on Sumerian clay
The famous Hippocrates' quote (400 BC), “Let food be
tablet in Nagpur (around 5000 years ago) [3]. Dioscorides,
thy medicine and medicine be thy food”, represents that
the father of pharmacognosy, wrote “De Materia Medica”
there has been a great interest in herbal products since dec-
book in 77 AD, which included 657 plant originated medi-
ades [1]. There were many historical civilizations, such as
cines [3]. Hence, herbal products have been an interesting
ancient Egyptian, Greek, Roman and others that used herbal area along the human history.
products and plants in treating and preventing diseases [2].
There were many plants that were famous for their heal-
ing properties over the last millennia. For instance, ginseng
*Address correspondence to this author at the Department of Pharmaceuti-
cal Sciences (DPS), School of Pharmacy and Physician Assistant Studies
had been used in China for treating and preventing different
(SOPPAS), University of Saint Joseph (USJ), Hartford, CT, 06103, USA; health problems [4]. Moreover, ancient Egyptians used many
E-mail: nounou@usj.edu plants, including garlic, turmeric, thyme, cumin, juniper and
#
Both authors contributed equality to this manuscript others in medicine [3]. Cinnamon represented a great value
2212-4039/19 $58.00+.00 © 2019 Bentham Science Publishers

106 Recent Patents on Drug Delivery & Formulation, 2019, Vol. 13, No. 2 Helal et al.
in both Roman and antient Egyptian civilizations [2]. The ing to FDA, cosmetics were defined as "articles intended to
Indian culture also used natural products in treating and pre- be rubbed, poured, sprinkled, or sprayed on, introduced into,
venting several diseases, such as Ayurveda [5]. Finally, or otherwise applied to the human body...for cleansing,
honey was considered as one of the most well-known reme- beautifying, promoting attractiveness, or altering the ap-
dies in many ancient civilizations and was mentioned in re- pearance" [13]. The terminology “Cosmeceuticals” has not
ligious books, such as the Holy Quran and Bible [2]. These been acknowledged yet under the law, according to The Fed-
findings have triggered a series of studies in nutraceuticals eral Food, Drug, and Cosmetic Act (FD&C Act) [14]. Cos-
field [2]. meceutical products are marketed as a drug, a cosmetic or
mixture of both [14]. According to the FD&C Act, the ter-
There is a controversy over a specific definition and set
minology for pharmaceutical drug was defined as “articles
of regulations to define the nutraceutical compounds [6]. The
definition of nutraceuticals may not be well established intended for use in the diagnosis, cure, mitigation, treatment,
or prevention of disease" and "articles (other than food)
worldwide [7]. However, nutraceutical compounds are health
intended to affect the structure or any function of the body of
enhancing products that improve mental and physical activi-
man or other animals” [13].
ties of the body. They are commercialized to minimize the
risk factors of various diseases [8]. Nutraceutical products Nutraceuticals have many beneficial effects; hence, they
are simply a hybrid between drug and food [9]. On the other have been used for treating and prevent many health prob-
hand, this terminology is a broader term that includes miner- lems, such as cancer, inflammation, hypertension, cardiovas-
als, vitamins, amino-acids, botanicals or herbs [10]. There- cular diseases, atherosclerosis, obesity, diabetes and others
fore, both dietary supplements and fortified foods can be [6]. Some nutraceuticals, such as silymarin, curcumin, vita-
classified as nutraceuticals [11]. The terminology of nu- min E, docosahexaenoic acid, choline and phosphatidylcho-
traceutical was defined by the foundation for innovation in line are used in treating and preventing steatosis [15]. Addi-
medicine in (New York, USA) in 1989 [9]. Defelice's defini- tionally, many nutraceutical products, such as gallic acid,
tion in 1995 was: “A food or parts of food that provide medi- caffeine, curcumin and others act as anti-aging and antioxi-
1
cal or health benefits, including the prevention and/or treat- dant agents [16, 17]. PUFA -rich fish oils reduce the risk of
ment of disease [12]”. This term was originated from two coronary cardiovascular diseases and enhance the brain func-
terminologies: "nutrition" and "pharmaceutical" [9]. tions [18]. Nutraceuticals are famous for their anticancer
efficacy; hence, many nutraceutical ingredients, such as epi-
There were many trials to distinguish the differences be-
tween dietary supplements, fortified foods and nutraceuticals gallocatechin gallate, curcumin, pomegranate and others,
treat different types of cancer, such as breast cancer, prostate
definitions because there is still a grey area between these
cancer and other types of cancer [19-21].
terminologies [13]. It was claimed that the main difference
between both fortified foods and nutraceuticals is the pur- The global spread of nutraceutical products has dramati-
pose of use [7]. The fortified foods are the foods that supply cally increased recently. The main factor that lead to inflat-
the body with essential amount of vitamins, minerals, carbo- ing the market share of these products, is that nutraceuticals
hydrates, proteins and other required nutritional elements to have no strict regulations to control them [22]. On the other
improve the health status or treat and/or prevent anemia only hand, pharmaceutical products are controlled by strict regu-
while nutraceuticals are used to treat or/and prevent diseases lations and are closely monitored. Pharmaceutical products
except anemia [7]. are also strictly regulated and have a governmental sanction
[6]. Moreover, nutraceuticals have been advertised under the
Dietary supplement terminology was defined by The Die-
tary Supplement Health and Education Act (DSHEA) in claim of being safe, effective and being a drug substitute.
Additionally, it has been claimed that these products can be
1994. The definition of DSHEA was: “a product (other than
used in preventing and treating many health problems with-
tobacco) that is intended to supplement the diet that bears or
out any side effects [23]. The patients also have been con-
contains one or more of the following dietary ingredients: A
cerned about the use of pharmaceutical products because of
vitamin, a mineral, an herb or other botanical, an amino
their high price and several side effects [22]. Therefore, the
acid, a dietary substance for use by man to supplement the
diet by increasing the total daily intake, or a concentrate, market share of nutraceuticals has been tremendously ex-
panded [13]. Approximately 80% of global population pre-
metabolite, constituent, extract, or combinations of these
ferred using dietary supplements and nutraceuticals [23].
ingredients”. Furthermore, DSHEA specified the supple-
Nutraceutical products now are the fastest growing market
ments by different, main criteria. Firstly, the dietary supple-
with an estimated worth of USD 117 billion globally in 2017
ments are represented by dosage formulas, such as tablets,
[24].
capsules and liquid dosage forms. Secondly, dietary supple-
ments could not be used as conventional foods or dietary The extensive usage of these products should be super-
sole items. Lastly, they should be labeled as a (dietary sup- vised closely and regulated [25]. Some countries developed
plement) [7]. It was also proposed that there are two main new regulatory bodies for monitoring these products. In the
distinguished differences between nutraceuticals and dietary USA, nutraceuticals are regulated as “drugs, food ingredients
supplements. First, nutraceuticals must treat or/and prevent and dietary supplements” due to the lack of a definite defini-
health problems. Secondly, nutraceuticals could be used as tion [6]. In contrast, in Europe, the European Food Safety
conventional foods or dietary items [7]. Authority (EFSA) acknowledged the nutraceuticals termi-
The Food and Drug Administration (FDA) outlined some
definitions to resolve the confusion between cosmetics, 1 Polyunsaturated fatty acid
pharmaceutical products and herbal products terms. Accord-
Nutraceuticals’ Novel Formulations Recent Patents on Drug Delivery & Formulation, 2019, Vol. 13, No. 2 107
nology and outlined regulations to ensure their safety [25]. 2. CLASSIFICATION OF NUTRACEUTICALS
Moreover, DSHEA and Drug Administration Modernization
The variability of nutraceuticals and their different com-
Act are responsible for confirming the safety of nutraceuti-
plex structures resulted in various categorizations [2]. The
cals before commercializing them [25, 26]. According to
most common, recent classification of nutraceuticals is based
FDA, the label of any nutraceuticals or dietary supplement
products should state that “This statement has not been on their novelty [34]:
evaluated by the FDA. This product is not intended to pre- 1. Traditional Nutraceuticals
vent, cure or treat any disease” [10].
i. Chemical constituents
There are many approaches that have been adopted to
a. Nutrients
classify nutraceuticals according to different parameters.
First, it was classified based on their novelty into traditional b. Herbals
and nontraditional nutraceuticals [24]. Secondly, nutraceuti- c. Phytochemicals
cals can also be categorized according to their chemical con-
stituents into nutrients, herbals, dietary supplements, medical d. Polyunsaturated Fatty Acids (PUFAs)
food and functional food [2, 24]. Thirdly, nutraceuticals were ii. Probiotics and prebiotics
categorized into potential and established nutraceuticals
based on their established efficacy and safety [2]. Fourthly, iii. Nutraceutical enzymes
nutraceuticals were classified based on their structures into 2. Non-traditional Nutraceuticals
phytochemicals and herbals. Finally, there are other classifi-
cations that are based on other parameters, such as bioavail- a. Fortified nutraceuticals
ability, uses and others [2, 27]. b. Recombinant nutraceuticals
Unfortunately, nutraceuticals are herbal products that
suffer from different drawbacks and many limitations [28]. 2.1. Traditional Nutraceuticals
For example, nutraceuticals could suffer from ineffective
Traditional nutraceuticals are the foods that are not sub-
targeting, poor solubility, low permeability, fast metabolism
jected to any manual change [2]. They include three subcate-
and other limitations [28, 29]. Hence, those drawbacks
gories [34]. Both lycopene in tomatoes and omega 3 fatty
pushed researchers to discover and develop better methods
for improving the bioavailability, pharmacokinetics and effi- acids in salmon are examples of traditional nutraceuticals
[24].
cacy of these products [28]. Moreover, the Novel Drug De-
livery Systems (NDDS) achieve many advantages. They 2.1.1. Chemical Constituents
enhance the stability of nutraceuticals by preventing physical
2.1.1.1. Nutrients
and chemical degradation and prevent plasma concentration
fluctuation. NDDS also provide sustained release formula- They were defined in 1996 by The Association of Ameri-
tions and prevent toxicity by targeting the active constituents can Feed Control Officials “AAFCO”. The definition of
to the site of action [30, 31]. AAFCO is “a feed constituent in a form and at a level that
Furthermore, NDDS introduce new strategies to enhance will help support the life of an animal [24, 35]”. There are
pharmacokinetics, pharmacodynamics, nonspecific toxicity, many available nutrients, such as minerals, amino acids and
immunogenicity, biorecognition and efficacy of nutraceutical fatty acids, but the most commonly used nutrients are vita-
products [30]. NDDS can be administrated through different mins and antioxidants [35, 36].
routes of administration, such as oral, sublingual, transder- In 2018, Witham et al. [37] conducted a study to evaluate
mal, transmucosal and others [30]. There are various novel the use of omega-3 fatty acids or esters and maqui berry ex-
systems, including liposomes, phytosomes, nanoparticles, tract in the treatment of ocular disorders by using traditional
emulsions, nanoemulsion, microspheres, dendrimers, conju- and non-traditional systems (Table 1). The active ingredients
gate systems, chitosan-based delivery systems, micelle-based were loaded into soft gelatin capsules at different concentra-
delivery systems, nanoencapsulation, nanofibers and others, tions to evaluate their therapeutic effect [37]. It was claimed
which have been used extensively in nutraceutical formula- that this system was used in treating ocular diseases and
tions [28, 30-32]. other diseases, such as cancer, inflammation and heart disor-
There are many challenges and concerns associated with ders [37]. A clinical study was conducted on a group of vol-
nutraceuticals that should be taken into consideration. First, unteers who suffer from allergies, glaucoma, cataract, cor-
the presumed safety and efficacy of nutraceuticals need more neal disease and other ocular impairments to assess different
study [25]. Secondly, The difficulty of establishing regula- parameters. First, tear osmolarity value was evaluated via
tions to control nutraceuticals, is a big challenge due to the conducting TearLab® Osmolarity System. Secondly, Matrix
lack of globally shared regulations [25]. Thirdly, the in-vivo Metalloproteinase-9 (MMP-9) level was assessed by In-
and in-vitro studies that prove the nutraceutical products flammaDry test. Thirdly, corneal staining was assessed by
claims have been neglected [13]. The scarcity of clinical using Oxford staining scale [37].
trials is due to the difficulty of implementing a restricted Finally, other studies were conducted, such as question-
dietary intervention [33]. The evaluation of diet efficacy is naire, Tear Break-Up Time (TBUT), and Schirmer's test
difficult because of different factors, such as certain expecta- were conducted [37]. Witham et al. concluded that an extract
tion to a food, religious beliefs or cultural traditions and oth- containing ratio of omega-3 fatty acids or esters to maqui
ers [33]. berry (from 12:1 to 150:1) had high therapeutic activity [37].
It was claimed that this formulation showed a significant polyphenols, isoflavonoids, anthocyanidins, phytoestrogens,
improvement in osmolarity scores and anti-inflammatory terpenoids, carotenoids, limonoids, phytosterols, glucosi-
effect. Additionally, it attributed in up regulation of the lac- nolates and polysaccharides [36, 42]. Phytochemicals affect
rimal gland, but there was no improvement in corneal stain- the body by different mechanisms [34]:
ing [37]. • They act as a substrate for different biochemical reac-
MacRedmond et al. [38] used Conjugated Linoleic Acid tions.
(CLA) to assess its efficacy and safety for mild asthma. CLA
• They act as a catalyst or cofactor in enzymatic reactions.
has been known for its biological regulatory effects [38]. A
double blind, prospective, randomized clinical study was • They inhibit enzymatic reactions.
conducted on 28 overweight participants against a placebo • They improve the absorption and stability of nutrients.
group [38]. Different parameters were assessed via obtaining
sputum samples, measuring inflammatory mediators, evalu- • They act as specific growth factors to improve the
ating spirometry and Airway Hyper-Responsiveness (AHR) growth of beneficial bacteria.
[38]. This study showed that CLA had a significant therapeu- • They inhibit harmful, intestinal bacteria.
tic effects on overweight mild asthmatic participants by im-
proving Body Mass Index (BMI) and AHR [38]. • They eliminate toxins.
2.1.1.2. Herbals • They act as ligands that exhibit antagonistic or agonistic
effect on cell receptors.
They are the oldest recognized form of nutraceuticals.
So-called “Ayruveda” is the oldest written prescription of Eugenol (4-allyl-2-methoxyphenol) is a phytochemical
natural remedies, which was written by Indians [24]. Herbals compound, which is extracted from cloves [43]. Eugenol has
are the products that consist of a whole, fresh plant or its been known for its anesthetic and local antiseptic effects
part, such as dried leaf, fruit, roots, or concentrated extract [43]. In higher concentrations, it has an antioxidant, an-
[2, 24]. Nowadays there is an extensive demand on using timutagenic and anticancer effect [43]. Ghosh et al. [44] used
herbals as nutraceuticals to promote health [2]. eugenol in treatment of melanoma. Melanoma is one of the
fastest growing tumors in developing countries that is resis-
Bassino et al. [39] studied the effect of white Willow tant against chemotherapy, immunotherapy and vaccines
Bark (WWB) and 1,2-decanediol (DD) on acne vulgaris. [44]. Moreover, E2F is a protein, which is responsible for
Acne vulgaris is a skin disease, which is most common in continuous proliferation of melanoma cells [44].
adolescence. One of the main problem with acne is that it
may lead to permanent scars [39]. The main causes of acne Ghosh et al. [44] designed in-vitro and in-vivo models to
are the accumulation of Propionibacterium acnes and hy- assess the efficacy of eugenol against melanoma [44]. Mela-
perkeratinization [39]. Bassino et al. [39] conducted in-vitro noma cell line was tested by using different concentrations of
assessment by using human adult keratinocyte cell line eugenol and isoeugenol [44]. In-vivo experiment was con-
(HaCaT). Enzyme Linked Immunosorbent Assay (ELISA) ducted on female mice that established B16 melanoma. Fi-
was performed to measure pro-inflammatory cytokines [39]. nally, Ghosh et al. concluded that eugenol down regulated
This study concluded that using WWB alone or in combina- E2F1, E2F2 and E2F3 proteins which have contributed in
tion with DD had a positive effect on acne treatment [39]. melanoma growth [43, 44]. Anchorage-dependence and an-
chorage-independence were inhibited to melanoma cell cul-
Chang illustrated the use of Traditional Chinese Medicine tures [44]. Lastly, the tumor size was reduced by 40% after
(TCM) as an anticancer agent [40]. In this literature review, treatment with eugenol [44].
Chang stressed on the efficacy of polysaccharides class on
cancer treatment and prevention [40]. Polysaccharides can be 2.1.1.4. Polyunsaturated Fatty Acids (PUFAs)
extracted from different plants such as Silybum marianum L. Fatty acids have essential beneficial properties for any
(milk thistle) [41]. Polysaccharides exert a significant anti- living organisms [45]. Fats can be classified according to
oxidant activity [41]. Chang showed the use of polysaccha- their degree of saturation to saturated fatty acids, monoun-
rides as immunomodulatory because of their β1,3 1,4 or 1,6 saturated fatty acids and polyunsaturated fatty acids. Polyun-
branch chains and their affinity to β-glucagon receptors [40]. saturated Fatty Acids (PUFAs) have been categorized based
Hence, polysaccharides have antitumor activity [40]. Moreo- on the position of the first double bond, located close to the
ver, more than 200 species showed antitumor activity terminal methyl group of the backbone chain. The most
whether fungi or plants [40]. Basidiomycetes family is one common and significant PUFAs are omega-3 and omega-6
example that exhibits antitumor activity due to its polysac- PUFAs. Omega-3 PUFAs have been used as supplemental
charides [40]. It has been found that polysaccharides have therapy for cardiovascular diseases, bipolar depression,
better clinical outcome as an adjunctive therapy with chemo- asthma and diabetes. Additionally, omega-3 PUFAs reduce
therapy and radiation in different types of cancer [40]. the level of lipid in serum so they have been defined as “es-
2.1.1.3. Phytochemicals sential fatty acids” [46].
Phytochemicals are chemical constituents (secondary PUFAs have been heavily used as nutraceuticals due to
metabolites) that are extracted from plants. Phytochemicals their beneficial effects; however, unfortunately, they have
exert specific biological effects [2, 42]. They may affect the low chemical stability because of the presence of oxygen
metabolic activity or exert biochemical reactions [2]. They leading to oxidation [47]. Hence, their efficacy would be
are classified according to their chemical structures into reduced along with toxic byproducts generation [47]. Subse-
quently, different novel delivery systems, such as, nanoe-
mulsion [47], emulsion [18] liposomes and nanoparticles [54]. However, the probiotics have a significant role in
[48] have been used to improve their stability. catabolizing these polyphenols and improving their absorp-
tion [54]. Hence, phenol-based prebiotics showed positive
Serini et al. [49] designed Solid Lipid Nanoparticles (SLN)
results in cancer treatment. Finally, synbiotics have signifi-
to encapsulate omega-3 PUFAs into to treat or prevent colo-
rectal cancer. The lipid matrix of SLNs had resveratrol that cant effect on treating cancer because they enhance the sur-
vival rate of probiotics [54].
was esterified with stearic acid. The designed system en-
hanced the physicochemical properties and the delivery of Damaskos et al. [55] illustrated the use of prebiotics,
omega-3 PUFAs. Moreover, SLNs prevented the degradation probiotics and synbiotics in the treatment of Inflammatory
and oxidation of omega-3 PUFAs and improved their anti- Bowel Disease (IBD), which is known to be idiopathic [56].
neoplastic efficacy [49]. Throughout the systemic review of Several hypotheses were introduced to explain the causes of
various novel nutraceuticals’ carrier systems in this manu- IBD, such as genetic impairment, immune dysregulation,
script, multiple studies and patents discussing PUFAs appli- barrier dysfunction and microbial flora [55, 56]. Probiotics
cations as nutraceuticals would be reviewed. have different mechanisms of action to aid in preventing and
treating IBD [55]. For example, Lactobacillus decreases
2.2. Probiotics and Prebiotics
translocation of normal flora bacteria. Probiotic also inhibits
Lately, both prebiotics and probiotics are classified as the production of Interleukin-6 (IL-6). Furthermore, Bifi-
nutraceuticals [2, 50]. Probiotics are a new term that was dobaterium inhibits distorted T-cell activation and increases
originated from the phrase “for life”. They are live, benefi- interleukin-10 (IL-10) [55].
cial microorganisms, which enhance health and prevent dis-
On the other hand, prebiotics have different mechanisms
eases [50, 51]. In the 90’s, Metchnikoff proposed the idea of
of action. Prebiotics regulate colonic mucosa physiology via
a beneficial bacteria for the human and suggested using it as
the production of Short Chain Fatty Acid (SCFA) [55]. The
treatment. Metchnikoff used bifidobacteria to treat infantile most common prebiotics that are used in treatment of IBD
diarrhea. Afterwards, Havenaar and Huisint Veld introduced
include lactulose, inulin and lactosucrose [55]. Finally, syn-
the modern definition of probiotics: “as a viable mono or
biotics were being developed to achieve better effect, better
mixed culture of bacteria which, when applied to animal or
compliance and cost effectiveness [55]. Different synbiotics
man, affects the host beneficially by improving the properties
were tested and showed better effect against IBS. For exam-
of the indigenous flora” [51]. Bifidobacterium and Lactoba-
ple, a study reported that a combination of Bi. breve, Lacto-
cillus are examples of the most commonly used bacterial bacillus casei and galacto-oligosaccharides improved bowel
species as probiotics [51, 52].
function in a girl with short bowel syndrome [57].
The intensive researches in the probiotics field lead to a
discovery of a new field (prebiotics). Prebiotics were defined 2.3. Nutraceutical Enzymes
as nutrients that modify the microbial flora of GIT via stimu-
lating the beneficial bacteria growth or inhibiting the delete- Enzymes are main functional proteins in the body; the
rious bacterial growth [52, 53]. This definition was a subject body will stop functioning without them [36, 42]. Enzymes
of a debate because any carbohydrate or fermentable dietary are responsible for regulating body functions and alleviating
fiber that is ingested by the host is accessible to the normal health problems, such as hypoglycemia, hyperglycemia, di-
flora [52, 53]. This led to a new definition by the expert gestive problems and obesity [36, 42].
panel, which was defined as: “a substrate that is selectively Takabayashi et al. [58] aimed to treat chronic rhinosi-
utilized by host microorganisms conferring a health benefit” nusitis with nasal polyps (CRSwNP) with a nutraceutical
[53]. Moreover, the most commonly used prebiotics are ga- enzyme called nattokinase (NK). NK is a fibrinolytic enzyme
lactose containing oligosaccharides, xylose-containing oligo- [58]. NK is produced from Bacillus subtilis [58]. Immuno-
saccharides, oligofructose, fructo-oligosaccharides and bifi- histochemistry assay was conducted to assess the presence of
dogenic substrates [51]. nasal polyps. Moreover, clinical study was performed on
Products that contain a combination of prebiotic and pro- patients with CRSwNP and asthma for 12 weeks to evaluate
biotic are called synbiotics [51]. Pre- and probiotics can en- the mucus viscosity through different parameters, such as
hance the human health by different mechanisms, such as nasal discharge and sputum [58]. It was concluded that NK
competing with pathogenic organisms for nutrients, produc- improved nasal polyps mass and reduced the mucus viscosity
ing antitoxins or antibiotics against invasive pathogens, aid- significantly [58].
ing in neutrophil migration and producing some useful en-
zymes, such as ß-galactosidase, which helps in alleviating 2.4. Non-Traditional Nutraceuticals
the symptoms of lactose intolerance [42, 50].
2.4.1. Fortified Food
Thilakarathna et al. [54] illustrated the potential use of
probiotics and prebiotics in cancer prevention. Thilakarathna Fortified food was considered to be a part of nutraceuti-
et al. explained how gut microbes can prevent cancer pro- cals in some classifications. Fortified food, which is also
gression by demonstrating many mechanisms [54]. For in- known as “designer food”, is a food that is fortified by nutri-
stance, it was reported that probiotics have significant effi- ents, such as minerals, vitamins or/and other essential ele-
ciency on reduction of toxins and carcinogens. Moreover, ments to maximize its efficacy [2, 59]. At the beginning, it
polymerized polyphenols, such as ellagitannins and proan- was used in treating nutrient deficiencies [60]. The food for-
thocyanidins, aid in cancer prevention and progression, but tification was started in USA in 1940s through the food forti-
the complexity of their structure limited their absorption fication program, which aimed to enrich foods with neces-
sary nutritional elements. There have been successful trials improved the bioavailability of encapsulated phyto-active
of using these products to prevent diseases and improve compound.
health since decades. For instance, in 1924, salt was fortified
Vitamin D is another broadly used fortifying nutrient. It
with iodine to prevent goiter in USA [61]. Moreover, the
is a fat-soluble vitamin that is highly sensitive to oxygen,
milk was fortified by vitamin D via feeding cattle irradiated light and high temperature. Hasanvand et al. [69] developed
milk [62].
high amylose corn starch nanoparticles to encapsulate vita-
During the first and second world war, fortified food was min D3. In this study, milk was used as a food model to be
utilized to alleviate nutrient deficiency among population fortified. Vitamin D is insoluble in aqueous medium and
[60]. In 1941, flour that was enriched with thiamin, niacin, forms granular texture in milk [70]. However, in case of for-
riboflavin and iron was introduced and labeled “enriched” by tified milk with loaded vitamin D nanoparticles, the taste,
FDA [62]. Food fortification was introduced into the Middle homogeneity, and total acceptance of fortified milk were
East in the late 1970s. For example, the Kingdom of Saudi improved, and the bioavailability of vitamin D was enhanced
Arabia (KSA) introduced enriched flour [60]. [69]. Livney et al. [71] developed charged nanoparticles via
the interaction of oppositely charged β-lactoglobulin-
According to FDA, food fortification was classified into
polysaccharide and polysaccharide to form colloidal disper-
mandatory and discretionary. Mandatory fortified food
should adhere with the specific standards of identity that sion. The hydrophobic active compounds, such as Vitamin D
and oil-soluble vitamins, were loaded into the nanoparticles.
were outlined via FDA [62]. There were two mandatory for-
The novel vitamins’ nanoparticulate carrier provided stabil-
tified foods: First, the flour that was fortified by nutrients:
ity while maintaining transparency of beverage and food due
niacin, iron, riboflavin, thiamin and folic acid are considered
to is nanosized dimensions. Furthermore, the novel system
to be mandatory fortified food. Secondly, the fortification of
stabilized the loaded active compound against degradation
rice, breads, cereals, margarine, other grains and grain prod-
ucts have been also classified as a mandatory fortification by by oxidation and other chemical and enzymatic reactions. In
another study, Danino et al. [72] formulated beta-casein mi-
FDA. Hence, the mentioned nutrients should comply with
celles or nanoencapsulator to encapsulate hydrophobic forti-
the FDA standards [62]. The fortification of other forms of
fying nutrients such vitamin D. Physical characterization,
food were delineated as discretionary fortification by FDA
such as Transmission Electron Microscopy (TEM) analyses
[62].
and stability studies were conducted. Casein micelles
Fortified food is the most effective treatment for micro- showed high stability profile at a very low pH range as low
nutrient malnutrition for several reasons. First, fortified food as 2 and wide temperature ranges. Furthermore, the nano-
can be accessible to large number of population by choosing assembly provided small particles enough to keep transpar-
the most attractive food form [63]. Secondly, it is socially ency of clear beverages and food appearance. Per authors
acceptable because people prefer no change in food charac- claims, the micellar system is considered a suitable and sta-
teristics or food habits. Thirdly, fortified food can be intro- ble vehicle to deliver nutraceutical additives will maintaining
duced quickly, and its benefits are achieved quickly as well. beverages and other food products transparency.
Finally, most of people consider them safe and cost-effective
Vitamin D deficiency has shown high prevalence rates in
[63].
Europe and considered a pandemic problem [73]. Vitamin D
Folic acid represents a prominently used fortifying nutri- deficiency causes metabolic bone diseases, such as rickets in
ent. Folic acid is essential for DNA synthesis and repair. children and osteomalacia and osteoporosis in adults [74].
Folic acid deficiency has been correlated to various human Milk, dairy products and beverages that were fortified with
diseases, such as megaloblastic anemia, neonatal neural tube vitamin D had a positive influence on the daily intake of
defect and heart disease [64]. Hence, Canada obligated that vitamin D for adults in USA and Canada [75]. However,
cereals must be fortified with folic acid in 1998 [65]. Addi- vitamin D fortification is unsuitable for individuals who suf-
tionally, FDA approved fortified corn masa flour with folic fer from milk allergy or lactose intolerance [76]. Thus,
acid in 2016 [66]. A study was conducted on 2446 partici- Tangpricha et al. [76] replaced milk with orange juice that
pants in Canada to demonstrate the efficacy of folic acid was fortified with 1000 IU vitamin D. Moreover, 25-hydroxy
fortification on reduction in neural-tube defects rate. It was vitamin D test revealed that the serum level of 25-
reported that there was a 46% reduction in the rate of neural hydroxycholecalciferol was increased by 150% [76].
tube defect during a period of full-fortification [65].
Unfortunately, fortified food has drawbacks and adverse
Ruti, a flavonol glycoside, is a widely used fortifying effects associated with its excessive consumption. Excessive
nutrient. It has numerous pharmacological activities, such as intake of fat soluble vitamins can result in toxicity [62].
anti-inflammatory, anticancer, antiviral, hypolipidemic and There is a risk of metabolism interference. For example, zinc
others. Rutin, which is naturally found in fruits and plants, reduces both copper and iron absorption [62]. It was reported
has both free radical scavenging ability and antioxidant ac- that high intake of calcium causes prostate cancer and hip
tivity [67]. However, it suffers from low aqueous solubility fracture in men and women, respectively [77, 78]. Addition-
which limits its bioavailability. Babazadeh et al. [68] encap- ally, it was reported that calcium supplements could lead to
sulated rutin in food grade Nanostructured Lipid Carriers heart diseases, especially myocardial infarction [79].
(NLCs) to overcome its low solubility in aqueous phase and
2.4.2. Recombinant Nutraceuticals
polarity. Three different food models namely; milk, apple
juice and orange juice, were chosen to be fortified with the Recombinant nutraceuticals were categorized as non-
encapsulated rutin-NLC in this study. In this study, NLCs traditional nutraceuticals, which have been formulated by
using novel, biotechnological techniques, such as fermenta- pletely different electrical, mechanical, physical and chemi-
tion and genetic engineering [36]. Modifying the genetic cal properties [167]. Nanotechnology has gained extensive
material (DNA) of food alters its properties, which initiates popularity in the field of drug delivery system. Nowadays,
allergy [80]. Genetically modified food is useful in control- nanotechnology has been extensively applied in the field of
ling certain diseases [80]. However, the major drawbacks of nutraceuticals. Hence, the current market share of nanotech-
genetically modified foods are the possible harmful effects, nology in the nutraceutical industry is around 1 billion dol-
such as diseases, which have resistance against antibiotics. lars. It was also expected that the market share would reach
Furthermore, more studies should be done to evaluate the over 20 billion dollars in the next decade [168]. Facchi et al.
unknown, long term influence on human body [80]. [92] synthesized encapsulated curcumin nanoparticles, which
consisted of N, N-dimethyl chitosan, N,N,N-trimethyl chito-
Infants and adults mainly suffer from cow milk allergy
due to the presence of β-lactoglobulin (BLG) [81]. Hence, san and sodium tripolyphosphate in water-in-benzyl alcohol
emulsion medium. This system overcame the low solubility,
Orcajo et al. [81] produced β-lactoglobulin free milk by gen-
high crystallinity and poor oral bioavailability of curcumin.
erating DNA-free β-lactoglobulin gene in cow. Produced
Additionally, the conducted in-vivo and in-vitro studies
milk was more easily digested. It had lower binding affinity
showed the enhanced anticancer properties of this system, as
to Immunoglobulin E (IgE) than traditional milk [81]. For
shown in Table 1 [92].
the same reason, enhancement of milk composition was per-
formed through increasing casein milk concentration. Hence, Semyonov et al. [94] enhanced the bioavailability and
Brophy et al. [82] introduced additional genes encoding bo- solubility of genistein by loading it into enzymatically de-
vine β- and κ-casein into fibroblast of bovine female. Thus, veloped dextran nanoparticles. Genistein is isoflavone and it
the produced milk showed higher β-casein and κ-casein lev- has antioxidant and anti-inflammatory properties [94]. Wei
els [82]. et al. [138] designed nanoparticles, which were loaded with
Chinese yams, radix astragal, rhizoma anemarrhenae,
3. NEW INSIGHT INTO THE WORLD OF NUTRAC- chicken's gizzard-membranes, radix puerariae, raw gypsum,
EUTICALS rhizoma alismatis and/or others to treat or prevent many dis-
ease, such as diabetes, heart diseases and others [138].
Nutraceuticals formulations are hampered by many ob-
stacles that negatively affect their efficacy [83]. Many natu-
3.2. Nanospheres and Nanocapsules
ral active ingredients suffer from low solubility, poor perme-
ability, fast metabolism, short half-life and others [83]. For Both nanospheres and nanocapsules are polymeric
instance, curcumin has low solubility, poor oral bioavailabil- nanoparticles, which have a diameter with less than 1 μm
ity, limited tissue distribution, short half-life and rapid me- [169]. Nanocapsule has a vesicular structure which is sur-
tabolism [84]. Additionally, Epigallocatechin Gallate (EGCG) rounded by a polymeric membrane. The active ingredient is
is a bioactive compound in green tea that has a vasculo- encapsulated into nanocapsule. Nanospheres have a dis-
protective effect through its antioxidative and hypolipidemic persed polymeric matrix, which active ingredient is dis-
effects [85]. However, EGCG uses are limited because of its persed into [169]. Hu et al [103]. Made a polymeric nanopar-
fast degradation in the gut and low solubility [85]. These kinds ticle and conjugated it with chitosan. This system was loaded
of challenges that jeopardize the nutraceuticals existence push by curcumin to be used as antioxidant. Moreover, Hu et al.
scientists and formulators to use different novel systems to characterized this polymeric system via Fourier-Transform
maximize nutraceuticals safety and efficacy [83]. Infrared spectroscopy (FTIR) and proton Nuclear Magnetic
Resonance (1H NMR) analysis. The particle size and Poly
The process of entering an active, pharmaceutical ingre-
Disperse Index (PDI) were measured via Dynamic Light
dient into the body effectively and safely, is called drug de-
Scattering (DLS). Finally, zeta potential and the morphology
livery [86]. Introducing novel delivery systems to nutraceuti-
of nanoparticles were determined via laser doppler microe-
cal market was delayed due to its complex nature, high price
lectrophoresis and Transition Electron Microscopy (TEM),
and time consumption [86]. Hence, traditional forms have
been used for many years, but, as it was mentioned before, respectively (Table 1) [103].
they have many problems [15, 87]. Consequently, conven- In a patent by Ortiz et al. [148], it was claimed that acyle-
tional herbal dosage formulas have been developed since thanolamides could be loaded into nanocapsules polymeric
many years. For example, permeation enhancers, surface system, besides other novel delivery systems. Acylethanola-
modifiers, prodrug, colloidal lipid carriers and other novel mides were used in prevention or treatment of alcohol de-
carriers, have been developed [87]. There are many types of pendence syndrome, alcohol poisoning and pathological in-
novel delivery systems. Herein, the most common novel sys- toxication. In-vivo study was conducted on rats to measure
tems are mentioned. Recent published research papers [15- different parameters [148]. First, neuroinflammatory, which
20, 47, 85, 88-129] and patents [21, 37, 48, 130-166] adopt- was induced by alcohol intoxication protocol, was evaluated
ing novel formulation strategies in ultraceuticals are summa- by measuring blood ethanol level. Secondly, the signaling
rized in Table 1 and Table 2 respectively. route of neuroimmune (Toll-Like Receptor 4 (TLR4), mye-
loid differentiation primary response 88 (MyD88), Nuclear
3.1. Nanoparticles Factor Kappa-light-chain-enhancer (NF-kB)) was evaluated
after High Mobility Group Box 1 (HMGB1) activation alco-
Nanoparticle is a particle that has three nanoscale dimen- hol. Lastly, the withdrawal behavior was observed via con-
sions, which range approximately from 1 to 100 nanometer ducting elevated plus maze experiment [148], as shown in
(nm) [167]. The new synthesized nanoparticles have com- Table 2.
3.3. Metal Nanoparticles phobic nature and weak co-polymer interaction with zein.
Hence, a colloidal stabilizer, sodium caseinate (NaCas), was
Metals, such as silver (Ag), iron (Fe), zinc oxide (ZnO),
used to enhance the encapsulation insufficiency. It was
titanium oxide (TiO2), are prepared in the nano size range.
claimed that this system modulated the rate of fat digestion
Metal nanoparticles have many advantages, including rela-
and enhanced antioxidant activities. Antioxidant activity of
tively large surface area, good biocompatibility and good polyphenols was assessed via using ferric reducing antioxi-
catalytic activity [170]. Furthermore, superior selectivity,
dant power [111].
metal nanoparticles are usually isolable, dispersible and re-
usable catalysts [170]. Metal nanoparticles can be applied as Sun et al. [102] controlled the release of curcumin by
metal or metal-oxide, such as nano-Ag, nano-ZnO, nano-Cu encapsulating it into zein-shellac nanocomposite particles
and nano-TiO2. Each has its specific dimensions, homogene- (Table 1). Zein is the main storage protein in corn while
ousness and aggregative properties [171]. These different shellac is a resin that is produced from lac beetle [102]. The
characteristics influence the compound’s biological activity formulated zein-shellac nanocomposite showed better encap-
and toxicity [171]. sulation effectiveness, photochemical and thermal stability.
Moreover, this study showed that zein to shellac ratio (1:1) is
Otunola et al. [172] conducted a study to analyze silver
the most effective against curcumin degradation induced by
nanoparticles (AgNPs) biological activity (antimicrobial and
thermal or ultra violet (UV) light exposure [102]. Zein-
antioxidant activity) in three different herbal species namely; shellac nanocomposite had better stability in phosphate
garlic, ginger and cayenne pepper (Table 1) [172]. Each ac-
buffer saline (PBS) and simulated gastrointestinal conditions
tive ingredient was encapsulated into AgNPs. These metallic
[102].
nanoparticles had spherical shapes and average sizes of 3-
6nm, 3-22nm and 3-18 nm for garlic, ginger and cayenne
pepper, respectively [172]. It was concluded that AgNps 3.5. Self-Assembly Nanoparticles
exhibited more potent antibacterial activity against two Self-assembly technique is a powerful and cost efficient
gramnegative and two grampositive bacterial strains technique to control the self-organization of nanoparticles
[172]. Additionally, 1,1diphenyl2picrylhydrazyl (DPPH) [175]. This technique depends on controlling the repulsive
and 2,2Azinobis (3ethylbenzthiazoline6sulfonic acid) and attractive forces between particles to produce a variety
(ABTS) assays showed that AgNps had better antioxidant of self-assembled structures of nanoparticles. Self-assembly
activity [172]. alters the physical properties of the particles, such as optical,
In 2018, Bolisetty et al. [162] designed a novel, hybrid electronic and magnetic properties. It also enhances the bulk
system, which consisted of amyloid fibrils that were covered mechanical properties [175]. Various methods are used to
by iron nanoparticles on its surface (Table 2). The system enhance self-assembly, such as Langmuir-Blodgett tech-
was loaded with amyloid fibrils and minerals, such as iron nique, templating method and assisted self-assembly method
oxides, calcium phosphates and others [162]. It was claimed [175].
that the synthesized formulation was used in treating or pre- Some compounds have the ability to form self-assembled
venting iron deficiency anemia and diseases, which are asso- nanoparticles, such as chitosan (CS) and polyaspartic acid
ciated with zinc deficiency. Hemoglobin repletion bioassay (PAA) [85]. Self-assembled nanoparticles caught a great
was performed on rats to assess the relative bioavailability of attention in the field of nutraceuticals due to their potential
the hybrid system. As a result of that the bioavailability of cost effectiveness, simple preparation and biocomptability
the loaded ingredients was improved [162]. [176]. For example, EGCG has a vasculoprotective effect
through its antioxidative and hypolipidemic effect [85].
3.4. Composite Colloidal Nanoparticles However, EGCG uses are limited because of their rapid deg-
radation in the gut, (as it mentioned before). Thus, Hong
Composite nanoparticles are hybrid nanoparticles that
et al. [85] encapsulated EGCG into self-assembled nanopar-
consist of inorganic core (metal or metal oxide) and organic
ticles, which composed of chitosan and aspartic acid, as
shell (polymerized monomer, organic molecule, chromo- shown in Table 1. In-vivo study was performed on male New
phore, etc.) [173]. The first trial of composite nanoparticles
Zealand white rabbits. The results of the in-vivo study re-
synthesis was in late-90s via Vollath [174]. Composite
ported that loaded EGCG had better activity against athero-
nanoparticles have new electronic, magnetic, optical or bio-
sclerosis [85].
logical characteristics [173]. There have been many trials to
introduce nanocomposites into nutraceutical industry to en-
hance the efficacy of nutraceuticals. For instance, Jia et al. 3.6. pH Responsive Formulations
[21] coated pomegranate arils with both zinc oxide nanopar- A pH responsive system is a delivery method that con-
ticles and carboxymethyl cellulose (Table 2). This system trols the release of active ingredients by specific pH change
enhanced the anticancer, anti-inflammatory and antioxidant [177]. Different organs at the human body have different pH
activities of pomegranate. Jia and his team evaluated the ranges, such as stomach (pH 1.5-3.5), small intestine (pH
antioxidant activity via conducting the DPPH radical scav- 5.5-6.8) and colon (pH 6.4-7.0). Moreover, the tumor has a
enging technique [21]. specific pH value (around 7.4). Hence, pH responsive system
Donsì and his team synthesized zein-based composite represents an excellent candidate of site-specific targeting
colloidal nanoparticles to encapsulate epigallocatechin-3- [177]. Therefore, this system has been dragged into the nu-
gallate (EGCG) within it (Table 1) [111]. EGCG has hydro- traceutical industry.
Table 1. Recent published research papers adopting novel formulation strategies in ultraceuticals.
Main
Therapeutic Traditional/ Toxicity
Paper Title System Description Nutraceutical Efficacy Tests Characterization Year Refs.
and other Uses Novel System Tests
Ingredients
Oil Red O Staining

Colorimetric Assay:
Steatosis level was
assessed via qualitative
and quantitative
Three formulations (1, 2 assessment of oil red O
and 3) consisted of staining.
mixture of six
Oxidative Stress Assay:
nutraceutical ingredients, Silymarin
In vitro assessment of Antioxidant activity was
which were solubilized in Curcumin
nutraceutical evaluated via the
dimethyl sulfoxide (pure
compounds and novel Vitamin E expression of SOD22 gene
DMSO) solution. Steatosis Traditional MTT7
nutraceutical Docosahexaenoic and protein. - 2018 [15]
Formulation 1 consisted treatment (Mixture)
formulations in a acid 3
PPARα and PPARγ 4
of all six natural
liver-steatosis-based expressions were assessed
ingredients, while Choline
model by western blotting assay.
formulations 2 and 3 did Phosphatidylcholine
not have choline and lipid metabolism was
phosphatidylcholine, evaluated by assessing the
respectively. expression of LPL5
mRNA.
Lipid peroxidation assay
was conducted to evaluate
the effect of nutraceuticals
on H2O26 oxidative stress.
Particle size was
Entrapment efficiency
determined via DLS9.
was determined via UV-
The system consisted of Zeta potential was
Nanoscale delivery of VIS spectrophotometer8.
resveratrol that was determined via
resveratrol towards Protection efficacy of lipid
encapsulated in Solid Non- Electrophoretic Light
enhancement of Resveratrol Anticancer nanoparticles against MTT 2016 [88]
Lipid Nanoparticles traditional Scattering (ELS)
supplements and photodegradation was
(SLNs) or Nanostructured Caco-210 cell
nutraceuticals assessed via photostability
Lipid Carriers (NLCs). permeability
studies by using UV-VIS
spectrophotometer. evaluation was
conducted by HPLC11 .
The efficacy of
conjugation was
assessed by measuring
Effect of maillard the decrease in free
Resveratrol was
conjugates on the amino
encapsulated within
physical stability of
protein (zein) Non- groups via the OPA12
zein nanoparticles Resveratrol - - - 2015 [89]
nanoparticles, which were traditional assay
prepared by liquid
coated via conjugated The concentration of
antisolvent co-
polysaccharides. resveratrol was
precipitation
determined via UV-
VIS
spectrophotometer.
2 Superoxide dismutase 2
3 Peroxisome proliferator-activated receptor alpha
4 Peroxisome proliferator-activated receptor gamma
5 Lipoprotein lipase
6 Hydrogen peroxide
7 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
8 Ultraviolet–visible spectroscopy
9 Dynamic light scattering
10 Colorectal adenocarcinoma cells
11 High Performance Liquid Chromatography
12 o-Phthaldialdehyde
Table (1) contd….

Main
Ingredients
Concentration of
unreacted protein was
measured by Lowry
assay.
High performance
size exclusion
chromatography was
used to assess the
conjugation products
Mean particle size,
PDI13 and particle size
distribution were
measured by DLS14 .
The morphology of
nanoparticles was
evaluated via TEM15 .
Particle stability was
evaluated by
measuring particle
size of the system at
various environmental
stress (CaCl2,
temperature and pH).
The efficacy of
conjugation was
assessed by measuring
the decrease in free
amino
groups via the OPA
assay
The effect of
stabilization of
conjugated casein was
Improving Bioaccessibility efficiency evaluated via
resveratrol Biopolymer nanoparticles of the delivery system was determining the
bioaccessibility using consisted of a caseinate or assessed via using
decrease in turbidity
biopolymer caseinate dextran shell, gastrointestinal model.
Non- of conjugated system.
nanoparticles which was conjugated Resveratrol - The amount of the - 2015 [90]
traditional The encapsulated
and complexes: with resveratrol. entrapped bioactive
Additionally, its core resveratrol level was
Impact of protein- ingredient was measured
measured using a UV-
carbohydrate consisted of zein. via retention efficiency
visible
maillard conjugation assay.
spectrophotometer.
Mean particle size,
PDI and particle size
distribution were
measured by DLS.
The effect of UV16
light on the stability of
trans-resveratrol was
evaluated by UV-light
lamp and cabinet.
13 Polydispersity index
14 Dynamic Light Scattering
15 Transmission Electron Microscope
16 Ultra violet
Table (1) contd….

Main
Ingredients
The molecular weight

of nanocomplex was
measured via SDS-
PAGE17 technique.
Circular Dichroism
(CD) spectroscopy
was used to evaluate
the integrity of the
nanocomplex due to
the presence of
dextran.
OPA assay was used
to assess the extent of
Fabrication of glycation.
Whey protein isolate was
resveratrol-loaded The changes in the
conjugated with dextran
whey protein-dextran conformation and
to form a nanocomplex, Non-
colloidal complex for Resveratrol - - - various interactions 2018 [91]
which was loaded with traditional
the stabilization and were evaluated via
resveratrol in the form of
delivery of β-carotene fluorescence
emulsion.
emulsions spectroscopy.
The particle size, PDI,
and zeta-potential of
nanocomplex system
were measured by
DLS.
The morphology and
size of nanocomplex
were detected via
TEM.
The storage stability
of nanocomplex was
detected by UV-vis
Spectrophotometer.
The morphology and
the size of
nanoparticles were
assessed via SEM and
Curcumin was TEM.
encapsulated into
FTIR18 analysis
nanoparticles, which
Preparation and The studies of curcumin-
consisted of N, N- Thermogravimetric
cytotoxicity of N- controlled release were
dimethyl chitosan, Non- analysis
modified chitosan Curcumin Anticancer conducted in both MTT 2016 [92]
N,N,N-trimethyl chitosan traditional Zeta Potential was
nanoparticles applied simulated intestinal and
and sodium measured via DLS.
in curcumin delivery gastric fluid.
tripolyphosphate in
DSC19 analysis
water-in-benzyl alcohol
emulsion medium. The crystalline
structure of the system
was assessed via
wide-angle X-ray
scattering.
17 Sodium dodecyl sulphate-polyacrylamide gel electrophoresis

18 Fourier-transform infrared spectroscopy
19 Differential scanning calorimetry
Table (1) contd….

Main
Ingredients

nanocomplex system
were measured by
DLS.
Antioxidant The morphology and

Enhancement of size of nanoparticles
curcumin solubility Nanosuspension Anti
were assessed via
by phase change consisted of curcumin and inflammatory
Field Emission
Non-
from crystalline to d-α-Tocopherol Curcumin Antimicrobial - - Scanning Electron 2016 [93]
traditional
amorphous Polyethylene Glycol 1000 Anticancer Microscope (FE-
in Cur-TPGS Succinate (TPGS). SEM) and TEM.
AntiAlzheimer
nanosuspension FTIR analysis.
Woundhealing
Thermogravimetric
analysis
DSC analysis
X-Ray Diffraction
(XRD) analysis
nanocomplex system
were measured by
DLS.
The morphology of
nanocomplex was
The complexation ability assessed via cryo-
of freeze-dried dextran TEM.
Enzymatically powder was evaluated via The crystalline

Genistein was inclusion and
synthesized dextran structure of the system
encapsulated within Non-
nanoparticles and Genistein - complexation formation - was assessed via 2014 [94]
enzymatically developed traditional
their use as carriers through decreasing pH wide-angle X-Ray
dextran nanoparticles. and diluting DMSO20 in
for nutraceuticals. scattering.
water. The activity of the
system was assessed
via quantifying the
concentration of
released
fructose and glucose
by high-performance
anion-exchange
chromatography.
The quantification of
tangeretin content was
Tangeretin-loaded
Tangeretin was measured via
protein nanoparticles
fabricated from encapsulated within HPLC.
protein nanoparticles,
zein/ β-lactoglobulin: Anticancer The morphology of
which consisted of zein Non- protein nanoparticles
Preparation,
core and b-lactoglobulin Tangeretin Anti- - - 2014 [95]
traditional was assessed via
characterization, shell. inflammatory
TEM.
and functional
performance The particle size, PDI,
and zeta-potential
were measured by
DLS.
20 Dimethyl sulfoxide
Table (1) contd….

Main
Ingredients
The microstructure
and appearance of
were assessed via
optical microscope
and digital camera,
respectively.
The stability of
was evaluated by
measuring their
particle sizes at
various environmental
conditions, including
pH, temperature and
salt solutions.
and zeta-potential
were measured by
DLS.
The morphology of
NLC was assessed via
Entrapment efficiency
TEM.
was determined via UV-
Nanostructured Rheological analysis
VIS spectrophotometer.
Lipid Carrier (NLC) was conducted via a
as a strategy for In vitro antioxidant
Quercetin and linseed oil Antioxidant rotational rheometer.
encapsulation of activity was assessed by
were loaded within XRD analysis was
Anticancer UV-VIS
quercetin and linseed Nanostructured Lipid Quercetin Non- conducted via using a
oil: Preparation and Antibacterial spectrophotometer. - 2017 [96]
Carrier (NLC) via high Linseed oil traditional D8 Discover X-ray
In vitro pressure homogenization Anti- The in-vitro release of diffractometer
characterization method. Inflammatory quercetin was conducted
via measuring the DSC analysis
studies
concentration of released The storage stability
quercetin by using UV- analysis of NLC was
VIS spectrophotometer. conducted via
evaluating the
appearance, particle
size, quercetin loading
and entrapment
efficiency for three
months.
The morphology of
NLC was assessed via
TEM.
Quercetin loaded
and zeta-potential
biopolymeric
were measured by
colloidal particles The antioxidant efficacy
DLS and
prepared by Composite colloidal of nanoparticles was
Antioxidant electrophoretic
simultaneous nanoparticles consisted of Non- measured via Ferric
Quercetin Anti-cancer - mobility data. 2012 [97]
precipitation of quercetin and zein. traditional Reducing Antioxidant
Anti-viral The crystalline
quercetin with Power (FRAP) method.
structure of the system
hydrophobic protein
was assessed via
in aqueous medium
wide-angle X-ray
scattering.
FTIR analysis
UV–Vis spectroscopy
analysis
Table (1) contd….

Main
Ingredients
The volatile oils were

quantified via Gas
Chromatography
coupled to Mass
Spectrometry
Chemical In-vitro antimicrobial (GC/MS).
composition and activity was assessed by The particle size, zeta
antibacterial activity It is used as food using agar diffusion potential and PDI
of Eugenia brejoensis Nanoemulsions consisted preservative due technique through plate were measured by
of Eugenia brejoensis Eugenia brejoensis Non-
essential oil to its cavity. - DLS. 2018 [98]
nanoemulsions essential oil and tween essential oil traditional
antimicrobial Inhibitory effect of the Attenuated Total
against Pseudomonas 80.
activity. nanoemulsion was Reflectance Fourier-
fluorescens evaluated by using ham Transform Infrared
slices. spectroscopy (ATR-
FTIR) was used to
assess the different
functional groups of
Eugenia brejoensis
essential oil.
Microbiological
evaluation was
conducted via
counting both total
aerobic mesophilic
bacteria, total yeasts
and molds counts.
Fruits quality
evaluation:
a) Soluble Solids
Content (SSC) was
measure by Atago
Digital
Refractometer.
b) Titratable acidity
was measured via
Nano- titration technique.
ZnO/carboxymethyl c) The pH of the
cellulose-based active Pomegranate arils were Anti- pomegranate was
Antioxidant activity of the
coating impact on carcinogenic measured via a pH
coated with both Nano- Non- system was evaluated via
ready-touse Pomegranate Anti- - meter. 2017 [99]
ZnO21 and carboxymethyl traditional the DPPH radical
inflammatory
pomegranate during cellulose. scavenging technique. d) Weight Loss (WL)
Antioxidant
cold storage of the fruits was
calculated in the term
of the percentage of
starting fresh
pomegranate weight.
e) The content of fruit
juice was measured in
the term of Juice
Percent (JP).
The pH differential
method was conducted
to measure the Total
Anthocyanin
Concentrations (TAC).
Total Phenolic (TP)
concentrations were
assessed according to
Folin–Ciocalteu
procedure.
21 Zinc oxide
Table (1) contd….

Main
Ingredients
The efficacy of curcumin

to induce the growth
inhibition was assessed
via [3H] thymidine (3H-
TdR) incorporation assay.
Enzyme-Linked
Immunosorbent Assay
(ELISA) was conducted to
assess the expression of
Interleukin (IL-6), Tumor
Necrosis Factor-a (TNF-α)
Curcumin modulates
and interleukin-12 subunit
macrophage
beta (IL-12B (p40)).
polarization through
the inhibition of the Atherosclerosis The polarization and
Curcumin solution Curcumin Traditional mechanism of None - 2015 [100]
Toll-like receptor 4 treatment
expression and its macrophage were
signaling pathways assessed via western blot
and flow cytometry.
The confirmation of
curcumin molecular
mechanism on the
polarization of
macrophage was
conducted by inhibitors,
including small interfering
RNA, Toll-Like Receptor
4 (TLR4) and Mitogen-
Activated Protein Kinase
(MAPK).
Reactive Oxygen Species
(ROS) scavenge ability of
Phospholipid
systems was assessed via
concentration was
calculating the scavenging
measured via a
superoxide anion (O2•−)
phospholipid assay
via CmVe in the term of
kit.
curcumin concentration.
The superoxide, which The diameter of
was generated in xanthine systems was measured
Curcumin was loaded via a coulter
Loading of curcumin oxidase and hypoxanthine
within phospholipid Antioxidant submicron particle
in macrophages using Non- anion system, was
vesicles or lipid- Curcumin Anti- assessed via a - analyzer. 2008 [252]
lipid-based traditional
nanospheres (CmVe and inflammatory
nanoparticles chemiluminescence probe The zeta potential was
CmLn).
L-120. assessed via DLS.
In-vivo study was Confocal scanning
conducted on male Wister microscope analysis
rats. Moreover, confocal
The morphologies of
scanning analysis was
CmVe and CmLn
used to examine its bone
were assessed via
marrow, spleen, and liver
TEM.
after the formulation
injections.
Particle size, PDI and
Encapsulation efficiency zeta potential were
Preparation, was determined via UV- measured via DLS.
Zein-shellac Anti-
characterization and DSC analysis
carcinogenic VIS spectrophotometer.
stability of curcumin- nanocomplex was loaded Non-
within curcumin. Curcumin Anti- In vitro kinetic release test - FTIR analysis 2017 [102]
loaded zein-shellac traditional
inflammatory of Cur was conducted
composite colloidal The morphology of
Antioxidant under simulated
particles system was assessed
gastrointestinal fluids. via Atomic Force
Microscopy (AFM).
Table (1) contd…..

Main
Ingredients
The physical stability

of the colloidal
dispersions was
assessed via a
Turbiscan Lab.
Photochemical
stability assessment
Thermal stability
assessment
FTIR analysis
1
H NMR23 analysis
Biocompatible
polymeric The cellular uptake of Particle size and PDI
nanoparticles with FITC22 labeled was were measured via
Curcumin was loaded
exceptional evaluated via fluorescence DLS.
into polymeric
gastrointestinal nanoparticles, which was Non- microscope. Zeta potential was
stability as Curcumin Antioxidant - determined via laser 2018 [103]
synthesized by sodium traditional Entrapment efficiency and
oral delivery vehicles caseinate and stearic acid- doppler
loading efficiency were
for lipophilic conjugated chitosan. determined via UV-Vis microelectrophoresis.
bioactives spectrophotometer. The morphology of
nanoparticles was
assessed via TEM and
CCD camera.
The optical densities
were assessed via UV-
Vis
spectrophotometer.
The content of
curcumin was
Entrapment efficiency and measured via HPLC.
loading efficiency were
determined via HPLC. FTIR analysis
Antioxidant activity of the Emulsifying

Fabrication of properties were
ovalbumin/κ- Anti- system was evaluated via
Curcumin was loaded evaluated by
carcinogenic the DPPH radical
carrageenan complex into nanoparticles, which Non- measuring the
nanoparticles as a Curcumin Anti- scavenging technique. - 2019 [104]
consisted of ovalbumin traditional absorbance after the
inflammatory The in-vitro release of
novel carrier for and κ-carrageenan. formation of emulsion
Antioxidant curcumin was conducted
curcumin delivery directly.
via using UV-VIS
spectrophotometer under Particle size, PDI and
simulated gastric and zeta potential were
intestinal environments. measured via DLS.
The morphology of
nanoparticles was
assessed via SEM
under simulated
gastric and intestinal
environments.
The particle size and
PDI were measured
A novel approach by DLS and Photon
based on lipid Alpha lipoic acid was Correlation
nanoparticles encapsulated within Non- Spectroscopy (PCS).
(SLN®) Alpha lipoic acid Anti-aging - - 2005 [105]
solid lipid nanoparticles traditional The crystalline
for topical delivery of (SLN). structure of the system
-lipoic acid was assessed via
Wide-angle X-ray
scattering..
22
Fluorescein isothiocyanate
23
Proton nuclear magnetic resonance
Table (1) contd….
Main
Ingredients
DSC analysis
UV–Vis spectroscopy
analysis
Rheological analysis
was conducted via a
rotational rheometer
Entrapment efficiency and
loading capacity were The particle size, zeta
determined via HPLC. potential and PDI
Quercetin was In vitro release study was were measured by
encapsulated in conducted via using DLS and TEM.
Quercetin- biodegradable HPLC. DSC analysis
nanostructured lipid nanostructured lipid
carriers: Non- Cell apoptosis was The encapsulated
carriers (Q-NLC) via a Quercetin Anticancer MTT 2014 [106]
Characteristics and traditional assessed via using both system was evaluated
phase inversion-based
annexin V binding and via Raman
anti-breast cancer technique.
propidium iodide spectroscopy.
activities In vitro
permeability techniques. The crystalline
The cellular uptake and structure of the system
localization of labeled Q- was assessed via X-
NLC were assessed via ray diffraction.
fluorescence microscopy.
The particle size, zeta
potential and PDI
were measured by
DLS and particle
electrophoresis
instrument.
Fluorescence
spectroscopy was
used to assess the
conformational
structure of the
system.
The change in the
secondary structure of
zein was observed via
circular dichroism
spectroscopy.
Zein and propylene glycol The crystalline
The binary complex alginate (PGA) formed a Entrapment efficiency and structure of the system
based on zein and binary complex in a loading capacity were was analyzed by a
propylene colloidal dispersion determined by UV-VIS wide-angle X-ray
Non-
system. The quercetin Quercetin Antioxidant spectrophotometer. - diffractometer (XRD) 2016 [107]
glycol alginate for traditional
was loaded in the binary
delivery of complex by using anti- The interactions
quercetagetin solvent co-precipitation between quercetin,
method. zein and PGA were
assessed by using
Small Angle X-Ray
Scattering (SAXS).
FTIR analysis
A field emission
scanning electron
microscope (FE-
SEM) was used to
evaluate the micro-
morphology of the
system after
lyophilization and
heating.
The physical stability
of the system was
evaluated via the
LUMiSizer.
Table (1) contd….

Main
Ingredients
Nanochemopreventio
Epigallocatechin-3-gallate The particle size, zeta
n by encapsulation of
(EGCG) was The In vitro absorption
(-)-epigallocatechin- potential and PDI
encapsulated inside cross was mainly predicted
3-gallate with Chemo- were measured by
linked nanoparticles, Epigallocatechin-3- Non- from the apparent DLS and Atomic
bioactive preventive MTT 2012 [108]
which consisted of gallate traditional permeation rate (Papp)
peptides/chitosan potential Force Microscopy
chitosan (CS) and across the Caco-2 cell
nanoparticles for (AFM).
caseinophosphopeptides monolayers.
enhancement of its HPLC-MS analysis
(CPPs).
bioavailability
potential and PDI
were measured by
Cellular uptake and Epigallocatechin gallate The cellular uptake of DLS.
cytotoxicity of labeled nanoparticles was
(EGCG) was loaded Electrophoretic
chitosan– assessed via fluorescence
within nanocomplex mobility was assessed
caseinophosphopepti particles, which consisted Epigallocatechin Chemopreventiv Non- microscopy.
MTT via a Zetasizer Nano- 2012 [19]
des nanocomplexes of gallate e potential traditional Intestinal permeability of ZS90.
loaded with the system was evaluated
caseinophosphopeptides FTIR analysis
epigallocatechin by using cell monolayer
(CPPs) and chitosan (CS). The morphology of
gallate model (Caco-2).
system was assessed
via Atomic Force
Microscopy (AFM).
potential and PDI
were measured by
DLS.
Improving
effectiveness of (-)- Entrapment efficiency and The morphology of
epigallocatechin Epigallocatechin gallate loading capacity were the nanoparticles was
gallate (EGCG) (EGCG) was loaded in determined via HPLC. assessed by TEM.
against rabbit self-assembled The release study was The stability of
Epigallocatechin Atherosclerosis Non-
atherosclerosis by nanoparticles, which conducted via using - nanoparticles was 2014 [85]
gallate treatment traditional
EGCG-loaded consisted of chitosan HPLC. evaluated at different
nanoparticles and polyaspartic acid In-vivo study was pH via measuring
prepared from (PAA). performed on male New their particle size and
chitosan and Zealand white rabbits. zeta potential.
polyaspartic acid
In-vitro stability study
was conducted at
simulated gastric and
intestinal conditions.
Encapsulation efficiency The particle size, zeta
Bioactive and in-vitro release were
Epigallocatechin gallate potential and PDI
peptides/chitosan assessed via using HPLC.
(EGCG) was loaded were measured by
nanoparticles DLS.
within nanocomplex Cellular antioxidant
enhance cellular Epigallocatechin-3- Antioxidant Non-
particles, which consisted activity assay - The morphology of 2013 [109]
antioxidant activity gallate Anticancer traditional
of Cellular uptake of the nanoparticles was
of (-)-
caseinophosphopeptides nanoparticles was assessed by Atomic
epigallocatechin-3-
(CPPs) and chitosan (CS). evaluated by inverted Force Microscopy
gallate.
fluorescence microscope. (AFM).
EGCG was encapsulated

Antioxidant The particle size, zeta
into polymeric The antioxidant activity of
nanocomplexes for potential and PDI
nanocomplex, which Epigallocatechin-3- Antioxidant Non- the nanoparticles was
delivery of - were measured by 2016 [110]
consisted of phenolic acid gallate (EGCG) Anticancer traditional evaluated by DPPH24
epigallocatechin-3- DLS.
grafting chitosan and radical assay.
gallate 1
H NMR25 analysis
caseinophosphopeptide.
24 2,2-Diphenyl-1-picrylhydrazyl
25 Proton nuclear magnetic resonance
Table (1) contd….

Main
Ingredients
UV-vis spectroscopy
The In vitro release of analysis
EGCG was quantified by
HPLC under simulated FT-IR analysis
gastric condition. The morphology of

the nanoparticles was
The encapsulation assessed by TEM.
efficiency of EGCG was
assessed by dialysis Phenolic acid was
technique via using quantified by UV-vis
HPLC. spectrophotometer.
The stability of EGCG The solubility of the

was evaluated via HPLC system was evaluated
at neutral and alkaline pH. in alkaline and neutral
pH.
Antioxidant activity of
polyphenols was assessed
via using ferric reducing
antioxidant power. The particle size, zeta
potential and PDI
Zein-based colloidal Encapsulation efficiency
were measured by
particles for EGCG was loaded inside was evaluated by UV-Vis
Epigallocatechin-3- DLS and
encapsulation and zein-based composite Non- spectrophotometer.
gallate (EGCG) - - electrophoretic 2017 [111]
delivery of colloidal nanoparticles. traditional The Cumulative of mobility.
epigallocatechin released EGCG was
gallate The morphology of
evaluated under simulated
the nanoparticles was
digestion condition.
assessed by TEM.
The efficiency of EGCG
on lipolysis was evaluated
during intestinal digestion.
The in-vitro release of
EGCG was quantified The particle size and
spectrophotometrically. PDI were measured
Epigallocatechin Epigallocatechin-3-gallate by DLS.
gallate-loaded Encapsulation efficiency
was encapsulated into Epigallocatechin-3-
polysaccharide was evaluated by UV-VIS Zeta potential was
polysaccharide gallate Chemo- Non-
spectrophotometer. MTT measured by laser 2011 [112]
nanoparticles for nanoparticles, which preventive traditional
The cytotoxic activity of doppler velocimetry.
prostate cancer consisted of gum Arabic
chemoprevention and maltodextrin. nanoparticles was The morphology of
assessed via clonogenic the nanoparticles was
assay and caspase-3 assessed by TEM.
activation assay.
loading capacity were The size and
determined via HPLC. morphology were
The release study was assessed via SEM.
conducted via using The size and size
HPLC distribution were
Cellular uptake and measured by
fluorescent Brookhaven BI-MAS
Anticancer activities EGCG was loaded inside nanoliposome distribution analyzer.
of (_)- nanoliposomes, which were evaluated via Zeta potential was
epigallocatechin-3- were coated with fluorescence microscopy. measured via
gallate encapsulated chitosan. Epigallocatechin-3-
gallate Breast cancer Non- Intracellular uptake was DLS.
The chitosan-coated MTT 2013 [113]
nanoliposomes in treatment traditional evaluated by measuring EGCG was quantified
MCF7 breast cancer nanoliposomes consisted the total cellular protein
of amphipathic by HPLC.
cells concentrations via
phosphatidylcholine and bicinchoninic acid (BCA) The stability of
hydrophobic cholesterol. assay. nanoliposomes was
assessed via
The apoptosis efficacy of measuring the
nanoliposomes was changes in the
assessed via using a concentration, particle
DeadEndTM colorimetric size and zeta potential
terminal deoxynucleotidyl every 24 hrs.
transferase-mediated
dUTP-biotin nick and
labeling (TUNEL) kit.
Table (1) contd….
Main
Ingredients
The apoptosis efficacy of

encapsulated EGCG on
prostate carcinoma PC3
cells was evaluated via
Nanochemo- using apo-direct apoptosis

prevention: EGCG was loaded inside kit.
Epigallocatechin-3- Chemo-
Sustained release of polylactic acid (PLA) and gallate (EGCG) preventive Non- The angiogenesis efficacy
MTT - 2010 [114]
bioactive food polyethylene glycol traditional was evaluated by using
components for (PEG) nanoparticles. Anticancer
Ex ovo chick
cancer prevention chorioallantoic membrane
(CAM).
In-vivo study was
conducted on xenograft
mouse model.
In-vivo study was
conducted on xenograft
nude athymic mice to
assess the anticancer
efficacy.
loading capacity were
determined by Liquid
Chromatography/Mass
Oral administration Spectrometry (LC/MS).
of naturally The cumulative of EGCG
occurring chitosan- release was evaluated
based Epigallocatechin-3-gallate under simulated digestion The particle size, PDI
nanoformulated was encapsulated inside Epigallocatechin-3- Prostate cancer condition. and morphology were
- - 2014 [20]
green tea polyphenol bioresponsive chitosan gallate (EGCG) treatment measured by DLS and
EGCG effectively nanoparticles. The antitumor activity of TEM.
inhibits prostate the system against
cancer cell growth in prostatic tumor was
a xenograft model evaluated by measuring
the level of PSA26 via
ELISA assay.
Immunohistochemical
analysis,
immunoblotting analysis
and chemiluminescence
detection were conducted
to assess the anticancer
activity of nanoparticles.
Surface-weighted
mean diameter,
volume-weighted
mean diameters,
particle size
distribution and total
Tea polyphenols droplet surface area
It acts as anti-
association to Epigallocatechin-3- were measured via
oil-in-water emulsion proliferative and Traditional - - static light scattering. 2015 [115]
caseinate-stabilized gallate (EGCG)
oil-water interfaces pro-apoptotic.
Zeta potential was
measured via DLS.
The interfacial
dilatational elastic of
emulsion was
assessed via drop
shape tensiometery.
26 Prostate-specific antigen
Table (1) contd….

Main
Ingredients
DNA cell cycle analysis

Excellent anti- was conducted to evaluate
proliferative and pro- the apoptosis efficacy of
apoptotic effects of nanoparticles.
(-)-epigallocatechin-
In-vivo study was
3-gallate EGCG was loaded into Epigallocatechin-3-
Non- conducted on xenograft
encapsulated in chitosan Gallate (EGCG) - male nude mouse model. MTT - 2014 [116]
traditional
chitosan nanoparticles.
nanoparticles on Immunohistochemical and
human melanoma western blot analyses
cell growth both were conducted to assess
In vitro and In vivo the anticancer activity of
nanoparticles.
Chemical antioxidant potential and PDI
efficacy was evaluated via were measured by
Beta-Carotene (BC) was measuring ferric reducing DLS.
loaded inside antioxidant power, DPPH The crystalline
nanoparticles, which radical scavenging structure of the system
Beta-carotene activity, Cellular
consisted of Whey was assessed via X-
encapsulated in food Antioxidant Activity
Protein Isolate (WPI), ray diffraction.
protein nanoparticles Non- (CAA) and hydroxyl
Sodium Caseinate (SC), Beta-Carotene (BC) Antioxidant - Attenuated Total 2015 [117]
reduces peroxyl traditional radical scavenging
and Soybean Protein Reflectance Fourier-
radical oxidation in activity.
Isolate (SPI) via using Transform Infrared
Caco-2 cells
homogenization- In-vitro release of BC was Spectroscopy (ATR-
evaporation method. evaluated by using two FTIR) was used to
proteases to simulated assess the different
the gastric and intestinal functional groups of
conditions. nanoparticles.
DSC analysis.
BC Isomers was
evaluated via HPLC.
potential and PDI
were measured by
β-Carotene (BC) was DLS.
Thermal degradation
loaded into Extraction and
and isomerization of
β carotene in oil-in oil-in-water determination of BC
nanoemulsions in a Non- was quantified via
water Beta-Carotene (BC) Antioxidant - - 2016 [253]
combination with natural traditional HPLC.
nanoemulsions
antioxidants, including α- The stability of
supplemented with
tocopherol (AT) and nanoemulsions was
natural antioxidants
L-Ascorbic Acid (AA). assessed via
measuring the
changes in the
concentration, particle
size and zeta potential
for 30 days.
Fabrication of β- potential and PDI
β-Carotene was loaded
carotene were measured by
into oil-in-water
nanoemulsion-based static light scattering.
nanoemulsions by
delivery systems Non- The microstructure of
fabricating via using Beta-Carotene (BC) Antioxidant - - 2017 [119]
using dualchannel traditional nanoemulsion was
high-pressure dual-
microfluidization: assessed by optical
channel
Physical and and confocal
microfluidization.
chemical stability fluorescence
microscopy.
Table (1) contd….

Main
Ingredients
The chemical and

nanoemulsions were
assessed via
measuring the
changes in the
concentration, particle
size and zeta potential
for 14 days at
different thermal
conditions.
The morphology of
the nanoemulsion was
assessed by Atomic
Force Microscopy
(AFM).
The chemical and
nanoemulsions were
assessed via
measuring the
changes in the
β-carotene was
Eugenol improves concentration, particle
encapsulated into
physical and Antioxidant efficacy was size and zeta potential
nanoemulsions, which
chemical stabilities of Non- evaluated via DPPH and every 6 days at
consisted of whey Beta-Carotene (BC) Antioxidant ABTS27 assay. - ambient temperature. 2016 [120]
nanoemulsions traditional
protein, lecithin, eugenol
loaded The degradation
and soybean oil.
with β-carotene kinetics of BC was
assessed via UV-Vis
spectrophotometer.
potential and PDI
were measured by via
DLS.
The portioning of
eugenol between
soybean oil and water
was measured by
HPLC.
Interfacial tension was
measured via a drop
shape analysis
instrument.
Fabrication of Fish oil-in-water The zeta potential was

concentrated fish oil emulsions that contained It reduces the measured by particle
emulsions using high level of ω-3 risk of coronary electrophoresis.
heart The surface-weighted
dual-channel Polyunsaturated Fatty
disease, Non- mean particle
microfluidization: Acids (PUFA) was PUFA-rich fish oils - - 2016 [18]
hypertension, traditional diameter and PDI
impact of droplet prepared via
and enhances were determined via a
concentration on dual-channel
the brain static light scattering.
physical properties microfluidization
functions. The analysis of
and lipid oxidation technique.
rheological properties
of nanoemulsion was
conducted via
dynamic shear
rheometer.
27 2,2′Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt
Table (1) contd….

Main
Ingredients
The oxidative stability

of nanoemulsions
were assessed via
measuring the
concentration of lipid
hydroperoxides every
3 days by
spectrophotometer
potential and PDI
were assessed via a
particle
electrophoresis
Antioxidant efficacy of instrument.
Physical stability, It reduces the surfactants was assessed The stability of
autoxidation, and Omega-3 oil-in-water risk of coronary via the Oxygen Radical nanoemulsions was
photosensitized nanoemulsion was heart Absorbance Capacity assessed via observing
oxidation of ω-3 oils prepared via disease, Non- assay (ORAC). changes in the
Omega-3 oil - 2015 [47]
in nanoemulsions dual-channel inflammation, traditional Lipid oxidation was concentration, particle
prepared with microfluidization and enhances evaluated via measuring size and appearance
natural and synthetic technique. the brain hydroperoxides and (creaming or
surfactants functions. propanal by UV–VIS aggregation) at room
spectrophotometer. temperature for 24
hours.
The absorbance of
each surfactant was
assessed via UV-vis
spectrophotometer.
Dynamic mechanical
analyzer was used to
evaluate mechanical
properties and
Psychoactive softness of the system.
Controlled release of natural DSC scanning
caffeine from tablets Elastic controlled release substance Non-
Caffeine - - FTIR analysis 2019 [121]
of spray-dried casein of casein-caffeine tablet traditional
stimulant The released caffeine
gels
was quantified via
UV-Vis spectroscopy.
The morphology of
the system was
assessed by SEM.
potential and PDI
were assessed via
In vitro digestion of DLS under gastric and
lactoferrin- intestinal conditions.
Curcumin or caffeine was
glycomacropeptide loaded into chitosan Curcumin and
Caffeine
nanohydrogels coated nanohydrogel, Antioxidant efficacy was caffeine were
or Non- quantified via HPLC.
incorporating which consisted of Antioxidant evaluated via DPPH - 2018 [16]
Curcumin traditional
bioactive compounds: Lactoferrin (Lf) and assay. Both Lf and GMP
Effect of a chitosan Glycomacropeptide were quantified via
coating (GMP). reversed phase HPLC.
The digestion process
of nanohydrogels was
assessed
via TEM.
Table (1) contd….
Main
Ingredients
Grafting ratio was

assessed via Folin–
Ciocalteu assay.
UV-Vis spectroscopy
analysis
FT-IR analysis
DSC analysis
The crystalline
structure of the GA-g-
CS films was assessed
via X-ray diffraction.
The color of the
synthesized GA-g-CS
films was evaluated
via SC-80C
Colorimeter.
The thickness of GA-
Effect of grafting g-CS films was
method on the assessed by Mitutoyo
physical property Antioxidant efficacy was digital micrometer.
Gallic acid grafted Non-
and antioxidant Gallic acid Antioxidant evaluated via DPPH - 2019 [17]
chitosan (GA-g-CS) film traditional The light
potential of chitosan assay.
transmittance and
film functionalized
opacity of GA-g-CS
with gallic acid
films was assessed by
UV-Vis spectroscopy.
The water vapor
permeability of the
synthesized GA-g-CS
films was evaluated
via using test tube.
Mechanical properties
of GA-g-CS films,
including elongation
at break and tensile
strength were assessed
by TMS-Pro
texture analyzer.
The microstructure of
the GA-g-CS films
was assessed via
SEM.
Zeta potential was
measured via
Anticancer
Encapsulation of Antimicrobial DLS.
garlic extract using Rheological analysis
Antioxidant
complex coacervation Garlic acid was was conducted via a
Hypolipidemic Antioxidant efficacy was
with whey protein encapsulated into rotational parallel
Non- evaluated via DPPH and
isolate and chitosan coacervates, which Gallic acid Anti - plate rheometer. 2019 [122]
traditional ABTS assay.
as wall materials consisted of whey protein inflammatory Spectrophotometric
followed by spray isolate and microparticles. Hypoglycemic analysis
drying
Anticoagulant
The Folin–Ciocalteu
Antihy-
was used to measure
pertensive
the Total Phenolic
Content (TPC).
Table (1) contd….

Main
Ingredients
Different properties of
microparticles were
assessed, including
solubility,
hygroscopicity, water
activity and moisture
content.
Microparticles
morphology was
evaluated via SEM.
DSC analysis
FTIR analysis
Structural properties
of GAg-CS were
Antioxidant efficacy was evaluated by NMR
Grafting of gallic acid
evaluated via DPPH, and UV−Vis
onto chitosan
ABTS, superoxide spectrophotometer.
enhances antioxidant
Gallic acid was grafted radicals, metal chelating Total Phenolic (TP)
activities Non-
onto chitosan (GAg-CS). Gallic acid Antioxidant ability, β-carotene-linoleic - concentrations was 2014 [123]
and alters rheological traditional
acid, lipid peroxidation assessed according to
properties of the
inhibition and total Folin–Ciocalteu
copolymer
antioxidant capacity procedure.
assay. Rheological analysis
was conducted via a
rotational rheometer.
Anthocyanins were
quantified via HPLC-
MS.
The color of the
synthesized BSSCE
films was evaluated
via SC-80C
Colorimeter.
The thickness of
BSSCE films was
assessed by Mitutoyo
digital micrometer.
The water vapor
Antioxidant activity of the permeability of the
Preparation and synthesized BSSCE
system was evaluated via
characterization of the DPPH assay. films was evaluated
Black soybean seed coat Antioxidant
antioxidant and pH- Black Soybean Seed
extract was loaded into pH-sensing food Non- The change of the film via using test tube,
sensitive films based Coat Extract - which was covered 2019 [124]
pH-responsive chitosan packaging traditional color according to pH was
on chitosan and black (BSSCE)
film. materials evaluated by using digital with silica gel.
soybean seed coat
camera and SC-80C Moisture content and
extract water solubility were
colorimeter.
evaluated.
The light
transmittance and
opacity of BSSCE
films was assessed by
UV-Vis spectroscopy
Mechanical properties
of BSSCE films,
including elongation
at break and tensile
strength were assessed
by TMS-Pro texture
analyzer.
Table (1) contd….

Main
Ingredients
DSC analysis
Microparticles
morphology was
evaluated via SEM.
FTIR analysis
XRD analysis
Rheological analysis
was conducted via a
rotational rheometer.
Fibers morphology
was evaluated via
Interpenetrating SEM.
network gels Cross-linked, soluble Enhancing food The texture profile
composed of gelatin dietary fibers consisted of stability Non- analysis was
Tomato peels - - 2019 [125]
and soluble dietary gelatin chains and tomato Improving food traditional performed via using
fibers peels. texture TA-XT plus texture
from tomato peels analyzer.
Water holding
capacity, freeze-thaw
stability and swelling
capacity were
evaluated.
Grafting ratio was
Ciocalteu assay.
UV–vis spectroscopy
analysis
FT-IR analysis
1
Protocatechuic acid Protocatechuic acid H NMR spectroscopy
grafted onto chitosan copolymer was analysis
Non- system was evaluated via
chitosan: grafted via carbodiimide Protocatechuic acid Antioxidant - CP-MAS28 NMR 2016 [126]
Characterization and traditional the DPPH and reducing
mediated cross-linking spectroscopy analysis
power assay.
antioxidant activity reaction.
DSC analysis
The morphology and
size of nanoparticles
were assessed via
SEM.
X-ray diffraction
analysis
system was evaluated via:
1- DPPH assay Grafting ratio was
2- Superoxide hydroxyl
Preparation, Ciocalteu assay.
radical scavenging
characterization and UV–Vis spectroscopy
Gallic acid, ferulic acid Gallic acid activities assay
antioxidant activity analysis
and caffeic acid were Non- 3- Reducing power
of phenolic acids Ferulic acid Antioxidant - 2013 [127]
grafted onto N,O- traditional assay FT-IR analysis
grafted Caffeic acid
carboxymethyl chitosan. 1
H NMR spectroscopy
carboxymethyl 4- Thiobarbituric acid
chitosan reactive substances analysis
assay was used to X-ray diffraction
evaluate the inhibi- analysis
tion effect of lipid
peroxidation.
28
Cross polarization magic angle spinning
Table (1) contd….
Main
Ingredients
FT-IR analysis
The effect of the 1
H NMR spectroscopy
molecular Chitosan gallates
Antioxidant activity of the analysis
architecture on the copolymer was prepared Non-
Gallic acid Antioxidant copolymer was evaluated MTT The crystallographic 2016 [128]
antioxidant via free radical grafting traditional
via DPPH assay. of copolymer was
properties of chitosan reaction.
gallate assessed via X-ray
diffraction analysis.
potential and PDI
were assessed via
DLS.
Pickering emulsions The morphology of

co-stabilized by Gastro-stabilized, prepared system was
composite protein/ sustained release assessed via TEM.
In-vitro release study was
polysaccharide Pickering oil-in-water The microstructure of
conducted to assess the
emulsion was synthesized Non- the emulsions was
particle-particle - - effect of gastric digestion - 2018 [129]
by using Lactoferrin traditional evaluated by optical
interfaces: Impact on on the microstructure of
nanogel particles (LFN) light microscope.
In vitro gastric Pickering emulsion.
and leuconostoc citreum
stability The gastric stability of
(INP).
Pickering emulsion
was evaluated by
observing the
proteolysis patterns
via SDS-PAGE29
analyses.
29 Sodium dodecyl sulphate-polyacrylamide gel electrophoresis
Khan et al. [20] designed bioresponsive chitosan used as a controlled delivery system due to its gel swelling
nanoparticles. These nanoparticles were loaded with EGCG, property as a response to pH [178]. Additionally, caffeine is
which released slowly at acidic, gastric condition and rapidly a natural ingredient that is mainly used in modulating cogni-
at alkaline, intestinal condition. Hence, the system protected tive brain functions [179].
EGCG against acidic degradation so that bioresponsive
nano-EGCG was successfully administered orally. Addition- 3.7. Nanohydrogel
ally, in-vivo study was performed on xenograft nude athymic
mice to evaluate the anticancer efficacy. As a result of that Nanohydrogel is a water-swellable, cross-liked polymeric
this system showed greater efficacy in treating prostate can- system that does not dissolve in water [180]. It improves
cer, as shown in Table 1 [20]. nutraceuticals bioavailability and selectivity [181]. Nanohy-
drogel is mostly prepared by two main steps. First, the po-
Wang et al. [124] used pH responsive system in a differ-
lymeric system is synthesized. Secondly, the formed bio-
ent application (biodegradable food packaging). Chitosan has
polymers are cross-linked. Hydrophilic nutraceutical ingre-
good mechanical strength and gas permeability. It is also
dients are mixed with the formed biopolymer before synthe-
edible and biodegradable [124]. Hence, Wang and his team sis of hydrogel system. In contrast, lipophilic nutraceutical
loaded Black Soybean Seed Coat Extract (BSSCE) into pH-
ingredients are encapsulated into lipid droplets, such as
responsive chitosan film. BSSCE is a plant-derived phenolic
emulsion or nano-emulsion. Nanohydrogel has three-
compound that has antioxidant activity. The synthesized chi-
dimensional structure, large surface area and hydrophilic
tosan-BSSCE film that consisted of 15 wt% of BSSCE was
nano-sized networks. Hence, this structure controls the re-
the best food packaging and antioxidant. Finally, the system
lease of active ingredient and enhances bioavailability and
improved UV-vis light barrier characteristics, antioxidant stability [180].
activity, mechanical strength, thermal stability and other
properties [124]. Bourbon et al. [16] synthesized chitosan coated nanohy-
drogel, which consisted of lactoferrin (Lf) and glyco-
Tan et al. [121] designed a novel, controlled release ma-
macropeptide (GMP) (Table 1). In this study, the effect of
trix that consisted of casein gel to sustain the release of caf-
chitosan on active ingredient delivery was assessed. Hence,
feine (Table 1). Casein is a milk protein that is considered a curcumin and caffeine were used to represent a lipophilic
good candidate for delivering and targeting [178]. Casein
model and hydrophilic model, respectively [16]. Antioxidant
possesses excellent criteria as a delivery system, including
efficacy was evaluated via conducting DPPH assay. The
high ion binding affinity, small size, water binding capacity,
system increased the bioaccessibility of the lipophilic model
high stability and good emulsifying properties. It can also be
to 72%. Moreover, coated curcumin preserved 70% of its 3.8.2. Solid Lipid Nanoparticles (SLNs) and Nanostructure
antioxidant activity under simulated gastric and intestinal Lipid Carriers (NLCs)
condition. However, the free curcumin showed a loss of 68%
SLNs and NLCs have been introduced into the delivery
of its antioxidant activity under the same conditions [16].
systems since 1990 as substitutes of traditional liposomes,
The bioaccessibility of coated caffeine and its free form were
63% and 59%, respectively [16]. polymeric nanoparticles and emulsions [182].
3.8.2.1. Solid Lipid Nanoparticles (SLNs)
3.8. Lipid Based Carriers Solid Lipid Nanoparticles (SLNs) have spherical struc-
3.8.1. Liposomes ture and nano-ranged size (around 40 to 1000 nm). SLNs
consist of surfactant (0.1 to 30 % w/w) and solid fat (0.5 to
Liposome is traditional lipid-based carrier. It was pre- 5%). They are solid at body and ambient temperature [182].
pared for the first time by Alec D Bangham in 1965 [182]. Furthermore, particle size, stability and drug loading depend
Liposomes are spherical vesicles that consist of a lipid bi- on type of lipid and surfactant [185]. SLNs are considerably
layer membrane and an aqueous cavity. The coinage of suitable for both hydrophilic and lipophilic drugs [186].
liposome was originated from two Greek terms namely; lipid However, the drug loading capacity depends on drug lipo-
(fat) and soma (body). Liposomes have been classified based philicity [187]. Moreover, system instability during storage
on their size, preparation and lamellarity. First, according to and high water content have been reported as disadvantages
their size, they have been classified into small, intermediate [187].
and large. Secondly, according to preparation, they have
α-Lipoic acid is a natural antioxidant that is utilized in
been categorized into reverse-phase evaporation liposomes
antiaging topical preparation. It has low irritation effect
or vesicle extruded technique. Lastly, liposomes have been
compared to other antiaging agents. Additionally, α-lipoic is
categorized into monolamellar, oligolamellar or multilamel-
lar vesicles [183] based on their lamellarity. useful for treating delicate areas (area around the eye) [105].
α-lipoic acid suffers from chemical degradation, which leads
Moreover, liposomes are able to protect active ingredi- to bad odor in topical preparations. Souto et al. [105] solved
ents against enzymatic degradation. Moreover, they are such problem by incorporating α-lipoic acid into SLNs.
flexible, biocompatible and non-toxic carriers. They have the Moreover, loaded α-lipoic acid showed higher occlusive ef-
merits of dual drug delivery by loading drugs with different fect. Hence, the system increased skin hydration and protec-
physicochemical properties in their core and lipid bilayer tion against UV irradiation [105].
[184]. For hydrophobic drugs, liposomes improve their solu-
Furthermore, Reyes et al. [165] claimed that both phar-
bility, stability and bioavailability [184]. However,
maceutical or natural ingredients, such as ellagic acid dehy-
liposomes suffer from some drawbacks, such as short half-
drate, vitamins and/or minerals can be loaded into solid
life, poor stability, low loading capacity and high cost.
nanoparticles, lipid-based carrier, lipid-containing nanoparti-
Liposomes are removed rapidly via reticuloendothelial sys-
tem. cles, tablets, sealed conduit or others (Table 2). It was also
claimed that these systems were used in treating and prevent-
Gao et al. [142] loaded natural ingredients into liposomal ing hyperglycemia, obesity, diabetes type I & II, gestational
system. Moreover, it was claimed that the system could also diabetes, latent auto-immune diabetes, metabolic syndrome,
be formulated in the form of sustained released tablets, gel Alzheimer, liver disease, kidney disease, and others [165].
powder, lotion and other dosage form (Table 2). The natural
ingredients were crocin, crocetin, green tea extract, curcu- 3.8.2.2. Nanostructure Lipid Carriers (NLCs)
min, resveratrol, panax ginseng extract, α-lipoic and/or L- Nanostructure Lipid Carriers (NLCs) are considered a
carnitine. The synthesized formulation was used in treating modification of SLNs [182]. The main modification is that
cancer and improving health [142]. In another patent, Un- the lipids of NLCs are a mixture of both solid and liquid oils.
derwood et al. [149] prepared nanoparticles of whole fruits Therefore, NLCs enhance stability and drug loading [181].
(black chokeberries, cherries, plums, blueberries, pomegran- NLCs were introduced in 1999 to overcome SLNs draw-
ates, raspberries, cranberries and/or black elderberries) and backs, such as low drug loading capacity and instability
encapsulated them into emulsion and/or liposome. It was (drug expulsion) [187].
claimed that the prepared formulation was used in decreasing
Resveratrol is a naturally occurring anticancer agent
symptoms of arthritic pain, diabetes, gout and others [149]
[188]. However, resveratrol suffers from photosensitivity,
(Table 2).
low solubility and oral bioavailability [189]. Neves et al.
Moreover, Richard et al. [144] formulated pegylated or [88] utilized SLNs and NLCs to encapsulate resveratrol.
cationic liposomes or niosome to encapsulate the active in- Both systems enhanced trans-resveratrol protection against
gredients into. It was claimed that the natural components photodegradation. Furthermore, NLCs succeeded to improve
were parts of natural plants, such as coffee bean, aloe vera, resveratrol encapsulation. Additionally, NLCs prevented its
hazelnut oil, almond oil and others. Furthermore, Richard rapid crystallization and release in GIT. Clearly, both sys-
and his team claimed that their system had many uses such tems enhanced resveratrol oral bioavailability for cancer
as rejuvenation of stratum corneum and epi-dermis, treat- treatment, as shown in Table 1 [88].
ment of acne and anti-wrinkles. The morphology and size of
3.8.3. Nanoliposome
vesicles were evaluated by TEM. Lastly, particle size, PDI
and zeta potential were measured via DLS [144]. Nanoliposomes are lipid vesicles in nano-sized scale
[168]. The reduction of liposomal system size leads to in-
creased surface area. Hence, the bioavailability of 3.9. Dendrimers

nanoliposomes is enhanced [168]. Therefore, nanoliposomes
Dendrimers are highly branched and nanoscaled polym-
are used widely in nutraceuticals industry to maximize the
eric macromolecules, which have a three-dimension struc-
safety and efficacy of these products. For example, EGCG
ture. The term of dendrimer came from the Greek term ‘den-
has low stability in water and physiological fluid [190].
Therefore, de Pace et al. [113] loaded EGCG into dron’ [195]. Dendrimers were first introduced in 1978 by
Vogtle [195]. Dendrimers have three basic components:
nanoliposome, which composed of phosphatidylcholine and
core, repeated units (branches) and terminal functional
cholesterol to overcome this problem. Moreover,
group. The core of dendrimers consists of polymer, such as
nanoliposomes were coated with chitosan to enhance the
polyamidoamine (PAMAM), ethylene diamine (EDA), dia-
absorption, as shown in Table 1.
minobutyl (DAB), polypropylimine (PPI) and others. The
3.8.4. Nanoemulsion branches of dendrimers are residues, such as carboxyl group,
amino group and other groups, which are attached directly to
Nanoemulsion was invented for the first time in 1950. It
the core. The size of dendrimers can be controlled by num-
is a single-phase and stable system. Nanoemulsion is a nano-
bers of these added groups, which are coined as (generation).
sized emulsion with nano-sized droplets (20-600 nm) [191].
It generally consists of oil, water, surfactant and cosurfac- Dendrimers are considered attractive drug delivery sys-
tant. Nanoemulsions were classified into three categories: tems because they can be fully controlled [196]. The size,
water in oil, oil in water and bi-continuous nanoemulsions. surface charge and architectural structure can be easily modi-
Nanoemulsions are usually translucent dispersions due to fied. The active ingredient can be encapsulated into their
their small droplet size which prevents flocculation. They are core or conjugated with their surface [196]. In contrast to
suitable for hydrophobic drugs delivery due to high solubili- traditional polymers, dendrimers are highly soluble, biocom-
zation capacity [191]. Nanoemulsion is utilized beneficially patible and polyvalent with definite molecular weight [197].
in drug delivery since it increases the loading capacity, sta- Dendrimers have high entrapment efficiency, very small size
bility and bioavailability of drugs [192]. Nanoemulsion can up to 5 nm and low dispersity index [198]. Additionally,
allow sustained or controlled release [193]. active component can be either attached to the surface or
chemically reacted with the functional group [196].
Gamay et al. [158] prepared nutraceutical formulation
containing theobromine, caffeine, amino acids and other However, the major drawback of dendrimers is their cy-
ingredients to modulate the cognitive brain functions, im- totoxicity, which is highly related to their cationic character-
prove memory and enhance energy. Nanoemulsion was pre- istics. These nanoparticles react strongly with the cell mem-
pared via sodium alginate as encapsulant and cocoa protein brane causing cell lysis [199]. There were different trials
as emulsifier. Nanoemulsion with stabilized fat droplet re- using dendrimers to deliver natural ingredients. For example,
sulted in controlled release of the active ingredients (Table 2) Krueger et al. [136] claimed that they loaded ammonia oxi-
[158]. In another patent, acylethanolamides were encapsu- dizing microorganisms into novel delivery systems, such as
lated in nanoemulsion to treat or prevent alcohol dependence emulsion, nanocapsules, liposomes, dendrimers and others. It
syndrome and alcohol intoxication, as shown in Table 2 was also claimed that this system was able to treat neuro-
[148]. logical, nasal or sinus disorders, diabetes, bacterial vaginosis
and dermal diseases [136].
β-Carotene has an important role in improving vision and
treating vitamin A deficiency since it is the precursor of vi-
tamin A [118]. β-carotene is a hydrophobic nutraceutical, 3.10. Biopolymer Nanoparticles
which requires novel system for its delivery due to its limited
Biopolymers are polymers of natural origin, including
solubility. Luo et al. [119] encapsulated β-carotene into oil-
proteins, polysaccharides and nucleic acids [200]. Further-
in-water nanoemulsions via high-pressure, dual-channel mi-
more, they have been mostly classified based on their struc-
crofluidization. Moreover, its dispersibility in water and sta-
ture into inclusion, hydrogels and polyelectrolyte complexes
bility were enhanced by using quillaja saponins and whey
[201]. Their particle size is considered to be a critical factor
protein isolate as emulsifiers. Luo and the rest of the team that affects the physicochemical characteristics, encapsula-
measured the particle size, zeta potential and PDI by static
tion, GIT stability and absorption of active ingredient [201].
light scattering technique. Additionally, the microstructure of
Biopolymer nanoparticles are suitable for clinical application
nanoemulsion was assessed by optical and confocal fluores-
because they are biodegradable, non-toxic and biocompatible
cence microscopy, as shown in Table 1 [119].
[200]. Moreover, proteins are highly stable and have good
Mendes et al. [98] formulated a nanoemulsion to encap- binding capacity. Thus, protein based nanoparticles are
sulate Eugenia brejoensis essential oil to use it as a food pre- highly promising model as a drug carrier [200]. A wide
servative. The synthesized nanoemulsion showed greater range of proteins have been utilized to produce nanoparticles
antimicrobial activity (Table 1). Moreover, omega-3 polyun- including casein, collagen, zein, elastin, silk fibroin and oth-
saturated fatty acids have great efficiency to reduce risks of ers [202].
coronary heart diseases [194]. Thus, Uluata et al. [47] for-
Patel et al. [97] prepared zein-quercetin colloidal com-
mulated oil-in-water nanoemulsion via dual-channel micro- posite nanoparticles to overcome many quercetin problems,
fluidization technique to encapsulate omega-3 into it. It was
such as poor aqueous solubility, low bioavailability and ex-
reported that this formulation reduced the risk of coronary
tensive intestinal degradation (Table 1). Quercetin is a natu-
heart disease and inflammation. It also enhanced the brain
ral flavone that exhibits anticancer, antiviral and antioxidant
functions (Table 1) [47].
Table 2. Recent patents adopting novel formulation strategies in ultraceuticals.
Main Traditional
Patent System Therapeutic Toxicity
Patent Title Nutraceutical /Novel Efficacy Tests Characterization Year Refs.
Number Description and other Uses Tests
Ingredients System
Efficacy of nanoparticles
on healing skin irritation
was assessed via FLIM1.
In-vivo study:
a) Dermal irritation
Gel consisted of
Composition Skin regeneration reduction was observed
cross linked The size of
and method for Non- visually in injected rabbits.
EP2229175A4 chitosan and Glucomannan Wound healing - nanoparticles was 2015 [130]
dermal traditional b) Proliferation and
glucomannan measured via SEM1.
regeneration intradermal distension of
nanoparticles.
collagen within dermis
was assessed.
c) The histology of lesions
was observed via light
microscopy.
The size of
nanoparticles was
assessed via light
microscopy and
Colorview Soft
Imaging Systems
camera.
The morphological
Probiotic bacteria In-vivo study: (mice) structure of
were encapsulated Immunophenotypic nanoparticles was
Microparticles into microparticles, evaluation of peripheral measured via SEM.
It was used in
for the which was consisted lymphocytes was The survival rate of
preventing and
encapsulation of EP2868206A2 of chitosan and Probiotic Non-
treating immune conducted. - probiotic bacteria 2016 [131]
probiotics, casein, which was bacteria traditional was evaluated.
system The resistance of probiotic
preparation and cross-linked with
impairment. bacteria was evaluated The bacterial count
uses thereof calcium salts,
vanillin or under gastric condition. and death cycle
tripolyphosphate. were assessed.
The storage stability
was conducted at
25°C.
The encapsulated
bacteria were
evaluated via
fluorescence light
microscopy.
DSC analysis
The crystalline
structure of the
system was assessed
via wide-angle X-
ray diffraction.
Co-crystals
consisted of FTIR1 analysis
nutraceutical Raman
Nutraceutical
US201002042 (epigallocatechin-3- spectroscopy
co-crystal gallate, quercetin, or Quercetin Non- analysis
compositions
04A1 - - - 2010 [132]
hesperitin) and co- traditional Thermogravimetric
crystal former analysis
(caffeine,
theobromine, or Digital microscopic
theophylline). image of the system
was taken.
The solubility of
quercetin was
assessed via UV-
VIS
spectrophotometer1.
Table (2) contd….

Main Traditional
Ingredients System
Solubility was
assessed via HPLC.
Particle size, PDI
and zeta potential
Composition
were determined via
comprising
DLS1.
curcumin-
captured The morphological
ginsenoside and Curcumin was Antibacterial activity was structure of
It was used in
phospholipid- encapsulated within assessed by MIC1 via nanoparticles was
preventing and
based lipid WO20181359 controlled Non- using agar dilution measured via light
Curcumin treating - 2018 [133]
nanoparticle as 12A2 ginsenoside or traditional method. microscopy.
Helicobacter
effective phospholipid-based
pylori infection. The entrapment of
ingredient for nanoparticles.
curcumin was
preventing or
assessed via HPLC.
treating
Helicobacter Storage stability of
pylori infection nanoparticles was
assessed by
measuring their zeta
potential for a year
in refrigerator.
In-vivo study (rats):
a) The body weight of
each rat was measured.
b) The levels of uric acid
and iron were assessed for
homogenized liver Temperature
specimens. stability of
crystalline xylose-
It was used in c) Cytokines and leptin
Crystallized Enteric coated isomerase was
preventing and were quantified.
xylose isomerase pellets consisted of assessed by
treating non-
in prevention of crystalline xylose- Crystalline d) The quality control of measuring its
US201700564 alcoholic fatty
the development isomerase, which xylose- - clinical chemistry - activity. 2017 [134]
85A1 liver and
of non-alcoholic co-crystallized with isomerase fructose-related parameters was evaluated The pH-dependency
fatty liver a magnesium salt or disorders. by the control serum of the system
disease a bivalent metal salt. Lyonorm Human N. activity was
e) Histopathological and assessed via
pathogenic assessment measuring the level
were conducted. of fructose.
f) Different parameters,
including TAG1, ALT1,
AST1, GMT, glucose,
cholesterol, albumin, and
insulin were measured.
The morphological
structure and size of
nanoparticles were
Red propolis The active measured via SEM.
caseinates, Red propolis ingredients DSC analysis
process for caseinates were were red Antioxidant activity was
Antibacterial FTIR-ATR analysis
producing red loaded into propolis assessed via DPPH1 test.
propolis immediate released caseinates and Anti- The dissolution of
caseinates, WO20181263 microcapsules, other natural Non- Antibacterial activity was red propolis
inflammatory - 2018 [135]
composition, use 04A1 which were coated ingredients, traditional evaluated by disk diffusion caseinates was
of the red with a binary such as green Antioxidant method through using assessed via UV-Vis
propolis system (sodium coffee, Staphylococcus aureus and spectrophotometer.
caseinates and casein and silicon vitamins, Pseudomonas aeruginosa.
Polyacrylamide gel
use of the dioxide). espresso and
electrophoresis was
composition others. conducted to assess
the integrity of
protein
encapsulating agent.
Table (2) contd….

Main Traditional
Ingredients System
Clinical Study
a) Tear osmolarity value
The active was measured via
ingredients were TearLab® Osmolarity
Formulations System.
loaded into soft gel It was used in
containing
capsules. treating ocular b) Matrix
omega-3 fatty
Additionally, it was Omega-3 fatty diseases and metalloproteinase-9
acids or esters acids or esters Traditional/
US201802432 claimed that the other disease, (MMP-9) level was
thereof and non- - - 2018 [37]
53A1 active ingredients Maqui berry such as cancer, evaluated by conducting
maqui berry traditional
could be loaded into extract inflammation the InflammaDry test.
extract and
nanoparticles and and heart c) Corneal staining was
therapeutic uses
other sustained disorders. assessed by using Oxford
thereof
released, novel staining scale.
formulations.
d) Questionnaire, TBUT1,
and Schirmer's Test were
were conducted.
Treatment of
neurological,
It was claimed that nasal or sinus
the active disorders
Ammonia ingredients were
oxidizing encapsulated into Anti-
Ammonia inflammatory
microorganisms novel delivery Traditional/
WO20180577 oxidizing
for use and systems, such as Treatment of non- - - - 2018 [136]
10A1 micro-
delivery to the emulsion, bacterial traditional
organisms
intranasal nanocapsules, vaginosis
system liposomes, Treatment of
dendrimers and dermal diseases
others.
Treatment of
diabetes
The formulation
Bioproduct was used for The antifungal activity of
based on treating different the system against Candida
selenium diseases such as, was assessed via
nanoparticles in skin injuries,
The system measuring MIC1 of
a honey matrix fungal infection,
consisted of candida albicans.
for the WO20181761 Selenium dermatophyte Non- Particle size
treatment of selenium Clinical study was - 2018 [137]
68A1 Honey infection and traditional measurement
complex injuries nanoparticles and conducted by applying the
other skin
and honey matrix. formulation on an 80-year
diseases, which
dermatological have been caused patient and evaluating
infections by chronic wound tissue
diseases, such as reconstitution.
diabetes.
Acute
toxicity was
assessed on
The active mice.
ingredients The formulation Long term
were Chinese was used to treat animals’
yams, Radix or prevent many toxicity test
Diabetes
astragal, disease, such as Clinical study was was
preventing and
Rhizoma diabetes, heart conducted on volunteers to conducted
treating
The natural anemarrhenae, diseases and evaluate the efficacy of the on animals.
nutritional
CN106174011 ingredients were chicken's others. Non- system by checking certain
formula a) - 2016 [138]
A loaded into gizzard- traditional symptoms, such as fatigue,
nanoparticles It was used for pathological
nanoparticles. membranes, palpitation weight
and preparing Improving the
Radix reduction, palpitation and examination
and processing immunity and was
puerariae, raw others.
method thereof salivation. conducted
gypsum,
Rhizoma It was used as on animals
alismatis antiaging. ‘organs.
and/or others b) Liver
serum level
was
measured.
Table (2) contd….
Main Traditional
Ingredients System
Th active
ingredients The formulation
were gingerol was used for
It was claimed that
(e.g., 6- treating or
the active
gingerol) preventing
ingredients could be
different
loaded into different Or shogaol
Methods and diseases, such as
delivery systems, (e.g., 6-
compositions for WO20181293 Charcot Marie Non- Particle size
such as shogaol) - - 2018 [139]
the treatment of 15A1 tooth disease, traditional measurement
nanoparticles,
disease Or myoclonic
microemulsion (oil-
capsaicinoid seizures, tardive
in-water), film
(e.g., dyskinesia,
coated micro-
capsaicin) or Friedrich's ataxia
crystals and others.
other natural/ and side effects
pharmaceutica of cancer.
l ingredients.
In-vivo study: (mice)
The active
ingredients were Liver enzyme level was
Compositions, loaded into measured for
acetaminophen-induced The content of the
methods, and microsphere, Myristica
and CCl4 induced system was
medical liposome or other extract The system was
hepatotoxic model. analyzed via HPLC.
compositions for US201700358 delivery systems. used to prevent
Astragalus - - 2017 [21]
treatment of and 29A1 Additionally, it was or treat hepatic GSH1, SODs1 and TG1 Particle size
extract
maintaining the also claimed that the disorders. were measured. measurement
health of the active ingredients Poria extract
liver could be conjugated In vitro histopathological
with monoclonal or scoring was conducted on
polyclonal antibody. ethanol-induced
hepatotoxic models.
The efficacy of anti-
anxiety, learning ability
and memory activity were
evaluated via using
Novel elevated plus maze.
composition of
Nigella sativa The effect of the Thymoquinone was
seeds to treat formulation on AchE1 Toxicologic measured via
anxiety, stress inhibitory assay was al study was HPLC.
and sleep Treatment of evaluated via using conducted
Black cumin sleep disorders Ellman's method. on Albino Black cumin oil
disorders with
US201801259 Free flowing extract Wistar rats, (fatty acid) was
significant Enhancing the - The efficacy of the system 2018 [140]
memory 14A1 powder Thymoq- and different evaluated via gas
memory on sleep quality was chromatography.
enhancement uinone vital
assessed via using sleep
properties and a Anti-anxiety parameters The storage stability
quality index (PSQI).
process for were was assessed.
producing the The efficacy of the system assessed.
same on anxiety depression
anxiety stress scales-21
(DASS-21).
The effect of the system on
U373-MG and IMR32 cell
line were studied.
Foods contained
plant-derived
miRNA. Apoptosis The alignment rate
The transfection efficiency was
Nutraceutical between every
Additionally, it was of labeled plant-miRNA assessed via
plant derived Plant- couple (human and
claimed that other was assessed via flow measuring
microRNA functional Non- plants) of miRNAs
EP3216869A1 formulations could Anticancer cytometry analysis and the was assessed via 2017 [141]
elements for be a mixture of microRNA or traditional trypan blue assay. percentage using MirCompare
treatment of natural ingredients an extract
The expression of SIRT11 of algorithm.
cancer and pharmaceutical
and Bcl-21 was assessed. hypodiploid
ingredients nuclei.
(ibuprofen and
paracetamol).
Table (2) contd….

Main Traditional
Ingredients System
Crocin
It was claimed that
the natural Crocetin
Compositions
ingredients could be Green tea
containing
loaded into extract
enriched natural Anticancer
liposomal system. Non- Crocin was
crocin and/or Curcumin
US9211298B Moreover, the Enhancing traditional quantified via
crocetin, and - - 2015 [142]
2 system could also Resveratrol human health HPLC and qNMR1
their
be formulated in the analysis.
therapeutic or Panax ginseng
form of sustained
nutraceutical extract
released tablets, gel
uses
powder, lotion and α-lipoic
other dosage form.
L-carnitine
It was claimed that Treatment of

Therapeutical Rhizoma
the active sexual
methods, corydalis
ingredients could be dysfunction
formulations extract Clinical evaluation was
and US201800712 loaded into lipid Antidepressant Non-
conducted by using self- - - 2018 [143]
nutraceutical 69A1 nanoparticles, Pure curcumin traditional
Anticancer assessment of volunteers.
formulations emulsion, micelles
Curcuminoid
or other dosage Treatment of
extracted
formula. Alzheimer
Hydrophilic or The morphology

hydrophobic active and size of vesicles
ingredients were were assessed via
Apparatus and The active TEM.
encapsulated into It was used in
method for ingredients
liposome or rejuvenation of The particle size of
preparing were parts of stratum corneum
niosome. The The distribution and niosome and
cosmeceutical US natural plants,
phospholipid was Non- penetration of hyaluronic liposome was
ingredients 2017/0181940 PEG-ylated or such as coffee and epidermis. - 2017 [144]
containing epi- traditional acid were assessed via tape determined via
A1 cationic. bean, aloe Treatment of
dermal delivery stripping method. decompression rate.
vera, hazelnut acne
mechanisms Moreover, the oil, almond oil Particle size, PDI
active ingredient and others. Anti-wrinkles and zeta potential
could be were determined via
unimolecular or Brookhaven
multimolecular. ZetaPlus.
It was claimed that
the active
ingredients could be
encapsulated into
liposomes, The efficacy of the system
Combination of polymeric vesicles, was evaluated by
The formulation
active agents for nanospheres, conducting a clinical study
Collagen was used in Non-
WO20141910 nanoemulsion and on 105 volunteers.
treating skin treating and traditional/ - - 2014 [145]
aging 56A1 other dosage Vitamin B3 preventing skin traditional Macrophotographs
formula. Moreover,
aging. analysis was conducted.
the formulation
could be prepared in
the form of
ointment, cream,
milk, powder and
others.
Nocturnin level was
assessed via ELISA1 test.
Exopolysaccharide
Exopolysacchari Type I collagen was
was loaded into The formulation
de for the quantified by ELISA test.
lipid nanoparticles, Exopolysacch was used in
treatment microemulsion or aride was The total concentration of
treating or HPLC analysis.
and/or care of liposomes. produced by Non- protein was assessed via
preventing skin
the skin, culture WO20150632 Moreover, the Halomonas traditional/ BCA1 Protein assay. - FTIR analysis 2016 [146]
40A1 aging and
media and formulation could anticariensis traditional
improving skin The reduction in the level
compositions be prepared in the bacterial condition. of lipid accumulation was
thereof form of cream, gel species.
assessed via measuring
cream, powder and
lipid content by fluorescent
others.
assay.
Table (2) contd….

Main Traditional
Ingredients System
In-vitro release of free

glycerol was assessed via
fluorometric assay.
Clinical study was
conducted on 21 female
volunteers to assess the
following parameters;
a) Thigh contours
reduction
b) Smoothening effect
c) Thermography of fat
evenness
d) Skin firmness
e) Scoring of intensity of
cellulite.
The active
ingredients were
loaded into The efficacy of the system
Oenothera
Compositions liposomes. was evaluated by
biennis oil Non-
and methods for US8728549B Moreover, the Eczema conducting a clinical study
traditional/ - - 2014 [147]
treating skin 2 formulation could Vitamin B12 treatment on volunteers. The
traditional
conditions be prepared in the reduction in eczema
Vitamin E
form of ointment, symptoms were assessed.
cream, skin patches
and others.
In vivo study (rats):
a) Neuroinflammatory,
which was induced by
alcohol intoxication
protocol, was assessed by
measuring blood ethanol
level.
It was used in b) The signaling route of
The active
prevention or neuroimmune (TLR41,
Compositions ingredients were
treatment of MyD881, NF-kB1) was
for the loaded into
alcohol assessed after HMGB11
prevention nanoemulsions, Traditional/
WO20171786 Acylethanola dependence activation via alcohol.
and/or nanocapsules non- - - 2017 [148]
82A1 mides syndrome,
treatment of polymeric traditional c) The withdrawal
alcohol
alcohol use nanoparticles or behavior was evaluated via
poisoning and
disorders other delivery conducting elevated plus
pathological
systems. maze experiment.
intoxication.
The efficacy of the system
was assessed by evaluating
different parameters, such
as proinflammatory
mediator sand blood
corticosterone, levels of
TNF-α1, I L-1 β1 and
others.
Whole fruits Antioxidant

(black Anti-
chokeberries, inflammatory
Compositions cherries,
Nanoparticles were Antiaging
comprising plums,
WO20180484 encapsulated into Non- Particle size
nanoparticles blueberries, It was used in - - 2018 [149]
89A1 emulsion and/or traditional measurement
derived from pomegranates, decreasing
liposome.
whole fruit raspberries, symptoms of
cranberries arthritic pain,
and/or black diabetes, gout
elderberries) and others.
Table (2) contd….

Main Traditional
Ingredients System
The size of
nanoparticle was
evaluated by photon
correlation
spectroscopy.
Zeta potential was
determined by
electrophoretic laser
doppler
It was claimed Ex-vivo bioadhesion study anemometry.
The active that the active Antioxidant was conducted to assess Nanoparticles
Nanoparticles ingredients were the adherent concentration
ingredients Anti-aging morphology was
comprising a loaded into of nanoparticles in porcine
could be assessed via TEM
vegetable biodegradable Fungicide buccal mucosa via
US9974753B natural and light
hydrophobic nanoparticles, It was claimed fluorescently labeled
products such Non- microscopy.
protein and a 2 which consisted of as curcumin, that it was used nanoparticles. - 2013 [150]
traditional The solubility of
water miscible hydrophobic protein in treating and
oil such as In-vitro release was zein was studied by
non – volatile (zein). preventing other
peppermint quantified by using spectrophotometric
organic solvent
essential oil or health problems. rhodamine dye under monitoring the
and uses thereof
drug such as simulated saliva fluid and turbidity changes in
chlorhexidine. gastrointestinal condition. zein solution.
Encapsulation
efficiency of zein
nanoparticles was
assessed by
quantifying the
concentration of
encapsulated active
ingredients spectro-
fluorimetrically.
The formulation
was used in
appetite
The active suppressant and
ingredients were weight loss. It
loaded into was also claimed
liposomes. that it reduced
Moreover, the the pain, which
formulation could Mitragyna was associated
In-vitro release study was
Compound and be prepared in the speciosa plant with chronic The active
conducted under simulated
method for form of non-gelatin extract diseases, such as ingredients were
US201801691 Non- gastric and intestinal
reducing capsule, an HPMC1 cancer, trauma
condition. - analyzed via UV 2018 [151]
72A1 or and neurological traditional
appetite, fatigue capsule, energy bar, spectrophotometer
and pain carbonated drink, Synthesized diseases. The pharmacokinetic of and HPLC analysis.
suppositories and mitragynine It was also use in the system was studied.
others. The formula different
could have diseases, such as
sustained, extended Parkinson’s
or immediate disease, Wilson’s
release. disease,
rheumatoid
arthritis and
others.
The active
ingredients were
loaded into multi
layered
microcapsules,
Pharmaceutical
which consisted of
or nutraceutical
water insoluble Natural or
composition In-vitro release of active
US201801405 layer, anionic pharma- Non-
with resistance - ingredient was studied - - 2017 [152]
56A1 (meth)acrylate ceutical active traditional
against the according to USP.
copolymer layer and ingredient
influence of
alginic acid coat.
ethanol
The polymeric
system was pH
stimulated,
sustained release
system.
Table (2) contd….
Main Traditional
Ingredients System
The active
ingredients
were epigallo
Anti-aging
catechin
formulation The active
gallate Anti-acne
with stabilized US9901533B ingredients were Non-
(EGCG), - - - 2018 [153]
Epigallo 2 loaded into Antiaging traditional
glucosamine,
Catechin polymeric structure.
resveratrol,
Gallate (ECGC)
proteins
vitamin A
and/or others
In-vivo study:
a) The efficacy of the
system on reducing the
weight of prostate was Oral toxicity
assessed. test on
The active The active rodents
Pharmaceutical ingredients were ingredients Treatment of b) Serum glucose and
and encapsulated into were abscisic prostate triglyceride were Reproduc-
US8536224B enlargement Non- measured. tion toxicity
nutraceutical liposomes, micelles, acid, and/or - 2013 [154]
2 traditional test was
compositions of microemulsions or salts, Diabetes c) The weight gain of the
abscisic acid other delivery derivatives assessed via
treatment tested offspring was
systems. and analogs two-
measured.
generation
d) The mortality rate of study.
offspring was evaluated.
e) Neurotoxicity test was
conducted.
The active Particle size
ingredients were The system was measurement
carried or loaded used in treating
into waxes, Vitamin C, and preventing Vitamin E was
Nutraceutical carbohydrates, eye diseases, measured via
Vitamin E
chocolate or fluorescence
WO20111072 gums, oils, proteins, especially Non-
compound fats and liposomes. Zinc macular - - analysis and RP- 2013 [155]
59A1 traditional
chocolate degeneration and HPLC1.
The system was Copper
product cataract
formulated in the Vitamin C was
Xanthophyll formation
form of chocolates quantified by UV-
or compound spectroscopy and
chocolate products. HPLC.
It was claimed
that the active
The active
ingredients
ingredients were
could be
Nanoparticle encapsulated into
antioxidant
compositions nanoparticles,
such as L-
and methods as which consisted of Clinical study:
glutathione or Size and particle
carriers of phospholipid.
US201602630 lipoic acid, tGSH1 and GSSG1 were size distribution
nutraceutical Additionally, it was - - - 2018 [156]
47A1 carotenoids assessed via Tietze's were assessed via
factors across claimed that the
such as enzymatic method. DLS.
cell membranes dosage formula
cryptoxanthin,
and biological could be
vitamins such
barriers transdermal,
as vitamin E
periocular, intraoral
or other
or others.
natural
ingredients.
In-vivo study:
a) The weight reduction
Size distribution
Compositions and prevention of induced
was determined by
and methods for colitis were assessed.
It was used in DLS and electron
treatment of
WO20180982 Broccoli-derived treating intestinal Non- b) Histological scoring microscopy.
intestinal Broccoli - 2018 [157]
47A1 nanoparticles inflammation traditional examination was
inflammation Zeta potential was
and colon cancer. conducted on colon.
and colon measured via DLS.
cancer c) Immunohistochemistry
analysis was conducted.
d) ELISA analysis
Table (2) contd….
Main Traditional
Ingredients System
e) Immunoblotting was
conducted to assess cell
lysates.
f) RT-PCR analysis was
conducted to assess the
expression of genes in
CD4+ T cells.
g) Activation of T cell was
evaluated via flow
cytometry.
h) IL-121 and TNF1 levels
were measured.
k) Colon was imaged by
confocal laser microscope.
There were other different
tests were conducted.
Theobromine
Caffeine
Amino acids
Nanoemulsion
consisted of sodium Amino acid The system was
Neuro- used in
alginate, derivative (n
transmitter and modulating the
polysaccharide acetyl l-
brain cognitive brain
(encapsulant) and tyrosine)
modulating oral functions.
cocoa protein Traditional/
delivery system US201802360 Cocoa Viscosity
(emulsifier). It was used in non- - - 2018 [158]
for 16A1 measurement
Carbohydrate changing mood, traditional
enhancement of The system was
cognitive also prepared in the Taurine enhancing
functions and form of emulsion energy and
Alpha-
energy system. improving
glyceryl
memory.
phosphoryl
choline
Glucuronolact
one
In vitro bioavailability of
the system was assessed in The active
mice via HPLC. ingredients were
measured via UV-
The bioavailability of the
spectrophotometry.
system across the skin was
assessed via HPLC. FTIR analysis
Curcumin-polymer The stability was assessed Particle size, size

Site specific complex was via UV spectroscopy. distribution and
Curcuminoid
curcumin- encapsulated into morphology were
components It was used in The inhibitory efficacy of
polymer nanoparticle or measured via SEM.
(curcumin, treating cancer, the system on activity of
molecular microparticles. TLR-41 was evaluated. DSC analysis
US201800648 bisdemethoxy neurodegeneratio Non-
complexes and Moreover, the - 2018 [159]
21A1 curcumin, n, inflammation traditional TNF-α1 level was assessed Curcumin loading
methods of system was
demethoxycur and immunod- via ELISA assay. capacity was
treating colon prepared in the
cumin and eficiency. analyzed UV-Vis
diseases and form of tablet, In-vitro curcumin pH
others) spectrophotometer.
inflammation suspension, cream dependent intracellular
and others. 1
delivery was evaluated via HNMR analysis
flow cytometer.
The crystalline
The plasma centration of structure was
curcumin was assessed via assessed via X-ray
HPLC in mice. diffraction.
The anticancer effect was
assessed via MTT1 assay
Table (2) contd….

Main Traditional
Ingredients System
The bioavailability of the
system was assessed.
Gene expression was
assessed via real-time PCR
system.
Clinical study:
a) Clinical study was
conducted to measure the
It improved
serum glucose level
insulin
resistance, cell (post-prandial sugar,
longevity and fasting sugar, insulin
dehydroepiandro fasting and insulin post
sterone (DHEA) prandial).
level by gene b) Renal function was
regulation. The morphology
assessed via measuring
and size of vesicles
It was used in serum creatinine, serum
were assessed via
treating and uric acid and Blood Urea
TEM.
preventing Nitrogen (BUN).
Modified Particle size, PDI
Resveratrol cardiovascular c) Lipid profile was
resveratrol WO20180423 Non-
nanoparticles was Resveratrol problems, assessed via measuring - and zeta potential 2018 [160]
composition and 24A1 traditional were determined via
coated with tree fat. metabolic different parameters, such
use thereof DLS.
syndrome, as HDL1, VLDL1, LDL1
apoptosis, and others. Morphology was
muscular assessed via SEM.
e) Anti-Müllerian
dystrophy, stress Hormone (AMH) level
resistance and was measured.
others.
f) The bioavailability of
Anticancer the system was assessed by
Anti- measuring resveratrol level
inflammatory in blood sample via LC-
Antiaging MS1.
g) SIRT1 gene expression
and TXNIP1 gene
downregulation were
measured.
e) Testosterone and
dehydroepiandrosterone
(DHEA) levels were
measured.
Inflammatory In vivo study (mice)
bowel disease a) Anti-inflammatory
treatment efficacy was assessed
It was used in via measuring inflam-
Green alga poly- matory markers such as
treating and
saccharification Nano-green algae IL-6 and TNF-α. Particle size and
preventing
nano-selenium was encapsulated Chlorella morphology of
CN106539092 different Non- b) Different symptoms,
and preparation into polysaccharide poly- - nanoparticles were 2017 [161]
A diseases, such as traditional including diarrhea, fecal
method and nano-selenium saccharide measured using
application particles. hyperlipidemia, occult blood and others, TEM.
thereof atherosclerosis, were detected.
diabetes and c) Histopathological
other examination of the inte-
inflammation- stinal inflammation was
related diseases. conducted.
Hemoglobin repletion
bioassay was conducted in
rats to assess the relative
bioavailability of the
Amyloid It was used in system.
Composite The morphology of
fibrils treating or
materials The hybrid system The sensory performance nanoparticles was
preventing iron
comprising consisted of Minerals (iron of the system was evaluated by TEM.
deficiency
amyloid fibrils WO20181669 amyloid fibrils, oxides, Non- evaluated and further
anemia and - Storage stability 2018 [162]
and 47A1 which had iron calcium traditional confirmed via changing in
diseases, which was assessed via
nanoparticulate nanoparticles on its phosphates color of food matrices.
were associated changing in
nutritional surface. and others) The digestion kinetics was
with zinc turbidity.
minerals assessed via conducting
deficiency.
acidic dissolution and
enzymatic hydrolysis tests
to evaluate the ability of
active ingredient delivery.
Table (2) contd….
Main Traditional
Ingredients System
Cell bioavailability and
proliferation were
assessed.
The count of lymphocytes
was evaluated via light
microscope.
The effect of the system on
dsDNA was assessed by
measuring the intact DNA
Combination of via densitometric analysis.
bioenergy and In-vivo study (rats):
nutra-epigenetic
a) The serum level of
metabolic MTT
aspartate aminotransferase
regulators, Toxicity
(AST), transpeptidase
nutraceutical was
transaminase glutamyl
compounds in evaluated by
The system was (GGT) and alanine
conventional
used in treating aminotransferase (SGPT) determining
and mortality
metabolic were measured.
nanotechnology- Amino acids rate of brine
based syndrome, such b) Macroscopic
(glycine, shrimp
combinations, WO20172134 as obesity, Non- examination of different
Nanoparticles arginine and
hyperglycemia, organs was conducted.
(Artemia - 2017 [163]
for reversing 86A2 cysteine) traditional salina cyst).
and preventing gout, diabetes c) The serum levels of
cellular Resveratrol type 1 and 2 and The acute
glucose, creatinine, uric
senescence others. and sub-
acid and cholesterol were
accelerated by chronic
measured.
chronic damage toxicity
In-vivo study (rats and studies were
caused by
rabbits) conducted.
diabetes and
other complex a) CBC test was
chronic performed.
degenerative b) glucose, uric acid and
diseases cholesterol levels were
measured.
c) Weight gain of animals
was observed.
A clinical study was
conducted on a 48-year old
man and different
parameters including body
weight, LDL, HDL and
others, were measured
In vivo study (mice):
a) The liver was examined
via confocal microscopy
after labeled formula
administration.
b) The cellular uptake of Nanoparticles were
DiR1 labeled ginger visualized via
nanoparticles was assessed atomic force
via using Kodak image microscopy.
station 4000MM Pro Particle size, PDI
system. and zeta potential
The active
ingredients were c) Western blot analysis were determined via
Compositions was conducted to assess DLS.
loaded into Ginger
and methods for US201801406 Treatment of the nuclear translocation of
nanoparticles, Non- HPLC analysis
treatment of 54A1 or alcohol induced Nrf21. - 2018 [164]
exosome-like traditional TLC1 analysis
alcohol induced Grapefruit liver injury
nanoparticles or d) The concentration of
liver injury In-vitro stability was
liposome-like ROS1 was measured.
nanoparticles. assessed by
e) The amount of labeled measuring the
ginger derived- particle size and
nanoparticles in the surface charge of
peripheral blood was the system under
measured via confocal gastric and intestinal
microscopy. conditions.
f) ALT and AST levels
were measured.
g) Histopathological
examination of liver was
conducted.
Table (2) contd….
Main Traditional
Ingredients System
Clinical study:
a) Adverse effects such as
persistent cold, nausea,
vomiting and others, were
observed.
b) Mini-mental state exam
(MMSE) was conducted to
measure cognition.
c) Attention and
psychomotor speed were
assessed via
Composition
and method for the digit symbol
It was used in
improving The active substitution test.
It was claimed that treating neuro-
cognitive ingredients d) Stroop test was
the active degenerative
function and were ginseng, conducted to evaluate the
ingredients were disease and
brain ginsenoside, processing speed and
loaded into neurological
bioavailability of WO20181488 green tea, Non- parallel processing.
phospholipid catechin
disorders. - - 2018 [48]
ginseng and 21A1 traditional
nanoparticles, and/or It was also used e) Logical memory I and II
ginsenosides and
nanoemulsion, essential fatty in improving the were performed to
treating neuro-
micelle, or acid. cognition measure immediate and
degenerative
liposome. rejuvenation of delayed recall.
disease and
neurological the brain. f) MRI1 scanning was
disorders conducted.
g) Brain bioavailability
was studied via
determination of
gensinsoide concentration
in brain extract by LC-
MS1.
f) The brain activity was
evaluated via blood
oxygenation level
dependent (BOLD)
imaging.
Cell membrane integrity
was evaluated.
The glucose uptake was
determined in treated
culture cells, including
mouse myoblast C2C121
cells and MEF1 cells via
using fluorescently labeled
glucose.
It was used in
Comparison between
treating and In-vitro
insulin treated culture cells
The active preventing cytotoxicity
and ellagic acid dehydrate
The active ingredients hyperglycemia, test was
treated culture cells, was
ingredients were were obesity, diabetes assessed on
conducted to evaluate the
loaded into solid pharmaceutica type I & II mouse
efficacy of both on glucose
Use of ellagic nanoparticles, lipid- l ingredients diabetes,
uptake.
embryonic
acid dihydrate based carrier, lipid- or natural gestational Traditional/ fibroblasts.
US201703673
in food products containing ingredients, diabetes, latent non- In-virto localization of The - 2017 [165]
90A1 glucose transporter
and nanoparticles, such as ellagic auto-immune traditional determinatio
nutraceuticals acid diabetes, (GLUT4) was assessed by n of cell
tablets, sealed
dehydrate, metabolic confocal laser microscopy. proliferation
conduit or others.
vitamins syndrome, In-vitro activation of AKT1 rates was
and/or Alzheimer, liver and MAPK1 pathways was evaluated by
minerals. disease, kidney imaged by using flow
disease, and immunocytochemistry cytometry.
others. labeling.
In-vivo study (mice):
a) body weight and blood
glucose level were
measured.
b) Gross locomotor
activity was assessed in
home cage via infrared
motion detector.
Table (2) contd….
Main Traditional
Ingredients System
Clinical study:
a) Physical examination
b) X-ray
It was claimed c) Radiological
that the active investigations
ingredients
were d) Matrix
glucosamine, metalloproteinase 3
type II (MMP3) level was
collagen, measured.
doco- e) Total health assessment
Composition
sahexaenoic was conducted on
and method to
acid, eico- The system was osteoarthritis patients.
alleviate joint Microdispersion
sapentaenoic used in treating
pain using low US9675635B Non- f) Osteoarthritis of the
or acid, olive oil, and alleviating - - 2017 [166]
molecular 2 traditional knee and lower extremity
astaxanthin, joint pain
weight Nanodispersion pain were assessed via
Pro- symptoms.
hyaluronic acid Western Ontario
inflammatory
and astaxanthin McMaster (WOMAC).
low molecular
weight g) Pain parameters was
microbial measured via visual analog
fermented scale.
sodium
h) Physical functions were
hyaluronate
evaluated by laquesne's
fragments
index.
and/or others.
k) The psychometric
properties of medical
outcomes study sleep scale
were assessed.
effects. This study showed that this system improved the The chemical conjugation has stronger and more permanent
molecular stability of quercetin against pH degradation and interaction [204]. Protein nanoparticles can be stabilized
UV irradiation and high antioxidant activity [97]. further via coating with conjugated polysaccharides [204].
In American patent, Salman et al. [150] formulated bio- Davidov-Pardo et al. [89] encapsulated resveratrol into
degradable nanoparticles, which consisted of hydrophobic protein (zein) nanoparticles, which were coated via conju-
protein (zein). Further, natural products, such as curcumin, gated polysaccharides by Maillard reaction. The efficacy of
oil (peppermint essential oil) or pharmaceutical drug, such as conjugation was assessed by measuring the decrease in free
chlorhexidine was loaded into biodegradable nanoparticles. amino groups via the o-Phthaldialdehyde (OPA) assay [89].
It was claimed that the system can be used as antioxidant, As a result of that the limited water solubility, oral bioavail-
anti-aging and fungicidal agent. Salman et al. [150] con- ability and chemical instability of resveratrol were reduced.
ducted ex-vivo bioadhesion study to assess the adherent con- Furthermore, casein was adsorbed to hydrophobic particles.
centration of nanoparticles in porcine buccal mucosa via Additionally, dextran prevented aggregation via steric repul-
fluorescently labeled nanoparticles. Moreover, the size of sion. Hence, coating with caseinate-dextran resulted in
nanoparticle was assessed by photon correlation spectros- avoiding particle aggregation, as shown in Table 1 [89].
copy. Zeta potential was also determined by electrophoretic
3.11.1. Cross-linked Biopolymer Nanoparticles
laser doppler anemometry. Nanoparticles morphology was
evaluated by TEM and light microscopy, as shown in Table Cross-linking is the process of linking chains of a poly-
2 [150]. mer by covalent or noncovalent bonding to form three di-
Biopolymers nanoparticles can be conjugated or cross mensional structures [205]. Cross-linking is performed to
enhance mechanical properties and aqueous stability of bio-
linked to enhance their physical and chemical properties and
polymers [206].
improve their safety and efficacy.
Hu et al. [108] encapsulated EGCG, chemopreventive
3.11. Conjugated Biopolymer Nanoparticles agent, into cross-linked nanoparticles of chitosan (CS) and
caseinophosphopeptides (CPPs). Cross-linking CS with
Biopolymers can be utilized in their natural form. How- CPPs enhanced EGCG oral bioavailability and reduced CS
ever, physical, chemical or enzymatic modifications are per- cytotoxicity. In addition, crosslinking increased nanoparti-
formed to improve their properties [203]. For example, pro- cles biocompatibility (Table 1) [108].
tein covalently bonded to polysaccharide showed better
Glucomannan polysaccharide stimulates fibroblast pro-
solubility and emulsifying properties [204]. Conjugation
may be reversible (physical) or irreversible (chemical) [203]. liferation which aids in wound healing [207]. Hence, Heber
et al. [130] formulated cross-linked nanoparticles that were Moreover, protocatechuic acid is a natural phenolic com-
composed of chitosan and glucomannan to enhance wound pound with antioxidant activity. Protocatechuic acid was
healing and skin regeneration (Table 2). Heber et al. [130] used in traditional Chinese medicines [126]. Therefore, Liu
evaluated the efficacy of nanoparticles on healing skin irrita- et al. [126] grafted protocatechuic acid onto chitosan by
tion via Fluorescence Lifetime Image Microscopy (FLIM). cross-linking reaction to enhance its antioxidant activity (Ta-
Moreover, in-vivo study was conducted on rabbits to assess ble 1). Antioxidant activity of the grafted system was as-
certain parameters. First, dermal irritation reduction was sessed via the DPPH and reducing power assay. Grafting
observed visually in injected rabbits. Secondly, proliferation ratio was evaluated by Folin–Ciocalteu assay. The morphol-
and intradermal distension of collagen within dermis was ogy and size of nanoparticles were assessed via SEM [126].
assessed [130].
3.11.1.3. Nutraceuticals Toxicity
3.11.1.1. Nanosuspension
The global consumption of nutraceuticals is dramatically
Nanosuspension is one of the novel approaches that increasing, which is driven by the mistaken assumption that
solves low solubility of drugs [208]. Nanosuspension con- they are safe because they are either a food or food deriva-
sists of a nanosized particle that is stabilized by surfactants tive [214]. However, side effects and toxicity have been con-
[209]. In this dispersion, nanosized core is surrounded by tinuously reported not only due to ingestion of the nutraceu-
surfactant molecules. Furthermore, nanosuspension enhances tical itself but also owing to the possibility of contamination.
drug stability and ensures high drug loading [210]. Oral Nutraceuticals could be contaminated with pesticides, other
bioavailability is also improved as a function of solubility toxic plants, metals, fertilizers or even deliberate adulteration
[208]. Another major advantage of nanosuspension is that it with chemical drugs [214]. Additionally, due to the complex
can encapsulate insoluble compounds [93]. Hence, many nature of herbal products and the presence of many phyto-
formulators have tried to use nanosuspension as a delivery chemicals, many studies reported the incidence of drug-
system in nutraceutical industry [93]. herbal interaction after co-administration [215]. Such inter-
action could result in over exposure to the drugs that elevate
Curcumin has beneficial effect on cancer and Alzheimer
the incidence of toxicity and severe side effects. It could also
treatment [84]. However, the pharmacological application of
lead to inhibition of the drug efficacy and lower therapeutic
curcumin has been limited due to its low solubility and poor
outcomes [215].
oral bioavailability [84]. Thus, Shin et al. [93] fabricated
nanosuspension of curcumin and α-Tocopherol Polyethylene A remarkable number of commonly used nutraceuticals
Glycol 1000 Succinate (TPGS) by using ultrasonic homog- are associated with severe adverse effects and toxicity [34].
enization technique. The prepared nanosuspension improved Ginkgo biloba extracts, are rich in flavonoids and are com-
curcumin water solubility and dissolution rate. The particle monly recommended for the elderly patients to improve the
size, PDI, and zeta-potential of nanocomplex system were peripheral circulation. Ginkgo biloba also is indicated for age
measured by DLS [93]. Moreover, the morphology and size associated dementia, alzheimer, schizophrenia and cerebral
of nanoparticles were assessed via field emission scanning insufficiency [216]. However, it is reported that the exposure
electron microscope (FE-SEM) and TEM. Different analyses to high doses of Ginkgo biloba extracts over long periods of
were performed, such as Fourier-Transform Infrared Spec- time is associated with spontaneous bleeding. Additionally,
troscopy (FTIR) analysis, thermogravimetric analysis, differ- many animal studies showed the carcinogenicity of Ginkgo
ential scanning calorimetry (DSC) analysis and X-ray dif- biloba [217].
fraction analysis, as shown in Table 1 [93].
Furthermore, green tea extracts contain catechins, which
3.11.1.2. Graft Copolymers have anticancer properties. Green tea extracts are also used
to prevent obesity and metabolic disorders [218], but over
Graft copolymers are polymers of two or more different
exposure could result in nephrotoxicity, hepatotoxicity and
monomers. One monomer is the main chain (backbone),
reproductive toxicity [219]. Moreover, it was reported that
which is chemically bonded to side chains (branches). Ac-
the ingestion of caffeine causes anxiety, tachycardia, osteo-
cording to the synthetic techniques, the branches may be
porosis and reproductive disorders, especially in early adult-
randomly or equally distributed along the backbone [211]. hood exposure [220]. Many other commonly consumed
Grafting is usually performed to modify specific properties
herbal products, such as cinnamon, aloe vera and St. John`s
in polymers such as wettability, biocompatibility and me-
wort are associated with toxic side effects, including carci-
chanical properties [212]. Grafting can be done through dif-
noma, hepatotoxicity, genotoxicity and mutagenicity [219].
ferent techniques, such as chemical grafting, living polym-
erization, photochemical grafting, enzymatic grafting, 3.11.1.4. Nutraceutical Contaminants
plasma radiation and radiation grafting [212]. The presence of nutraceutical contaminants represents
Gallic acid is a natural triphenolic compound, which has one of the most threatening issues of using nutraceuticals.
strong antioxidant and apoptosis activities [213]. Hence, Wu Pesticides are considered the most dangerous nutraceutical
et al. [128] developed chitosan gallates copolymer by free contaminants owing to the severe toxicity resulting from
radical graft reaction (Table 1). Gallic acid was encapsulated their ingestion. Toxicity may vary from mild skin rash to
into the synthesized system to be used as antioxidant. Anti- serious respiratory, neurological and reproductive disorders.
oxidant activity of the copolymer was evaluated via DPPH However, the use of pesticides is necessary to maintain the
assay. As a result of that the grafted copolymer showed en- quality of the medicinal herbs [214]. Thus, strict limits of
hanced antioxidant activity because of the increase in substi- residual contents of pesticides must be followed. Among the
tution degree and the reduction in molecular weight [128]. different classes of pesticides, organochlorines can persist in
the herbal product for longer duration and result in the most nated from the body rapidly and it loses its activity [228]. It
harmful toxic effect after chronic exposure [219]. was also reported that Saint John’s Wort included treatment
failure of anti-depressant drugs and loss of oral contraceptive
Other important contaminants of nutraceuticals are heavy
efficacy [228].
metals, including lead, cadmium, mercury and arsenic. The
World Health Organization (WHO) has specified guidelines The bioavailability of fexofenadine, which is P-
and limits for the presence of environmental contaminants, glycoprotein receptor substrate, is significantly improved
such as heavy metals in the final herbal product [221]. Heavy when co-administrated with P-glycoprotein inhibitor phyto-
metals toxicity could result from acute exposure to high con- chemicals [215]. Several phytochemical flavonoids, includ-
centration of heavy metals or chronic exposure to low con- ing naringenin, genistein and quercetin, are P-glycoprotein
centrations of heavy metals. The adverse effects of metal phytochemical inhibitors. Subsequently, the ingestion of
toxicity include cancer, cardiovascular toxicity, neurological nutraceuticals containing P-glycoprotein inhibitors with po-
disorders, hepatic and renal dysfunction [222]. tent substrate drugs, such as irinotecan, digoxin or cy-
closporine, could result in life-threatening toxicity [231].
Pyrrolizidine alkaloids are naturally occurring plant sec-
ondary metabolites, which induce developmental toxicity, Organic Anion Transporting Polypeptide receptor
genotoxicity, carcinogenicity and hepatotoxicity in animal (OATP) is another key transporter in drug absorption and
studies [13]. Meanwhile, it was reported that their acute tox- disposition [232]. Iijima et al. [233] conducted a study on 98
icity is manifested by liver damage [223]. These types of medical herbs commonly used in Japan to detect the interac-
alkaloids exert the toxic action because of their strong alky- tion between some nutraceuticals and pharmaceutical drugs.
lating nature. They react with cellular proteins and DNA It was found that 12 herbal species suppressed the function
causing cellular dysfunction and tissue necrosis [224]. Pyr- of the intestinal organic anion transporting polypeptide 2B1
rolizidine alkaloids are widespread in nearly 6000 species of (OATP2B1) receptor by less than 20% [233]. Additionally,
plant. In Europe, Mulder et al. [225] analysed 1105 samples seven herbal species enhanced the activity of the receptor by
of food and food derivative products, which were collected more than 150% [233].
from online websites and supermarkets. The study showed
Consequently, co-administration of these herbal products
that 60% of the food supplement products were contami-
dramatically affects the absorption and bioavailability of
nated with pyrrolizidine alkaloids [225].
substrate drugs, including bosentan, benzyl penicillin, al-
Finally, mycotoxins are fungal secondary metabolites iskiren, fexofenadine, glibenclamide, unaprostone, statins,
that could be formed during plant cultivation or storage and other pharmaceutical medications [234].
[226]. The ingestion of mycotoxins contaminated product
3.11.1.6. Nutraceuticals Advanced Delivery Systems Toxic-
causes severe adverse effects, such as carcinogenicity, hepa-
ity
totoxicity, mutagenic and teratogenic disorders. Aflatoxins,
ochratoxins and citrinin are among the most commonly de- Recently, the incorporation of nutraceuticals into nano
tected mycotoxins in food supplements [226]. delivery systems is rapidly emerging. These advanced deliv-
ery systems are used to improve the absorption and bioavail-
3.11.1.5. Nutraceuticals – Drug Interaction
ability of nutraceuticals, provide targeted and controlled re-
Recently, many studies have reported numerous nu- lease profile and enhance the stability of phytochemicals,
traceutical-drug interactions. The interaction nature may be which are susceptible to degradation [235]. Nano-sized nu-
through interfering with the metabolic pathway of the drug traceuticals improve the efficacy of nutraceuticals due to
or affecting the drug transporters [227]. Owing to the com- their unique, different chemical and physical properties after
plex nature and absence of pharmacokinetic, pharmacody- nanonization. However, the same advantageous, physico-
namics and safety studies for nutraceuticals, it is challenging chemical properties of nano particles are the principle cause
to predict the incidence of nutraceutical-drug interactions of human toxicity [235].
[6].
The safety of nano delivery system is questionable.
Some of the reported interactions could be serious and Moreover, limited information and studies are available con-
life-threatening. For example, aspirin and some non-steroidal cerning the absorption, metabolism, distribution, excretion
anti-inflammatory drugs interact with herbal products con- and toxicity of nano systems. Understanding the nano parti-
taining ginkgo, turmeric, ginger, ginseng, chamomile and cles interaction with the biological systems at the molecular
garlic. Consequently, this reported interactions increased the level is essential to predict their mechanism of action and
risk of bleeding due to the inhibition of platelet aggregation safety [236]. Among the commonly reported adverse effects
ability [228]. of nano particles are respiratory disorders, cardiovascular
diseases, carcinogenicity and shorter life expectancy. It was
The cytochrome P450 (CYP) enzymes are one of the
also reported that most of these adverse effects are triggered
mostly expressed metabolic enzymes in the liver and small
by the oxidative stress and inflammation induced by the nano
intestine [229]. Additionally, they are involved in the meta-
particles at the molecular level [235].
bolic pathways of many pharmaceutical drugs [230]. Saint
John’s Wort herbal extract is among the mostly reported In a recent study, Zhang et al. [237] synthesized gold,
nutraceuticals that induces wide range of CYP, including silver, platinum and palladium nanoparticles to load three
CYP1A2, CYP2C9, CYP2C19, CYP3A4 and CYP2E1. In- different dietary supplements, including vitamin C, (−)-
duction of these enzymes results in accelerating the metabo- epigallocatechin gallate and gallic acid. The hydroxyl radical
lism of the consumed drugs. Subsequently, the drug is elimi- scavenging activity of the synthesized systems were as-
sessed. Surprisingly, they found that the prepared nanoparti- The absence of common global regulations and legaliza-
cles decreased the hydroxyl radical scavenging ability of the tions will be a major obstacle for nutraceutical market
antioxidant phytochemicals and generated a Reactive Oxy- growth soon. WHO and the United Nations Food and Agri-
gen Species (ROS). Hence, this system resulted in cellular cultural Organization (FAO) have released several guidelines
damage and toxic effects in biological systems [237]. regarding the safety and quality of food and food supple-
ments with emphasis on herbal products [13]. Till now,
The European Food Safety Authority (EFSA) suggested
many countries are following the “Codex Alimentarius”
an approach to assess the toxicity arising from the incorpora-
guidelines reported by FAO and WHO in 1992, as interna-
tion of nanotechnology in the food products and food deriva-
tionally recognized regulations for manufacturing and mar-
tives. The guidelines titled: “Guidance on the risk assess-
keting of food and its derivatives [13]. The International
ment of the application of nanoscience and nanotechnologies
in the food and feed chain” recommended a set of physico- Regulatory Cooperation for Herbal Medicines (IRCH) was
formed in 2006 by 33 national and regional members with
chemical parameters to be evaluated for nanoparticles [238].
WHO support. The purpose of IRCH is to create interna-
The EFSA list of parameters have included [238]:
tional regulations for herbal medicinal products [243]. The
• The identity and chemical of nanoparticles. creation of nutraceutical global regulation, with confined
• The particle size of nanoparticles. definition, quality parameters and safety aspects, is essential
for the consumer health and nutraceutical industry growth
• The physical properties of nanoparticles. [243].
• The morphology of nanoparticles. According to the global market reports, United States
• Particle and mass concentration. nutraceutical market is the largest followed by Asia-Pacific
[244]. According to the (DSHEA) and the Food and Drug
• The specific surface area of nanoparticles. Administration Modernization Act of 1997, manufacturers of
• The surface chemistry of nanoparticles. nutraceuticals are responsible for the safety and labelling of
the products. Moreover, the nutraceutical product must com-
• The surface charge of nanoparticles. ply with current good manufacturing practice guidelines
• The redox potential of nanoparticles. [25]. The Dietary Supplement and Non-prescription Drug
Consumer Protection Act of 2006 obligated the manufactur-
• Partition and solubility properties.
ers to report any adverse events associated with nutraceutical
• Dustiness, viscosity, density and pour density. intake to the FDA [245]. Unlike pharmaceutical products, no
FDA approval is required for manufacturing and selling of
• The chemical reactivity of nanoparticles.
dietary supplements or nutraceuticals in the United States
• The photocatalytic activity of nanoparticles. [25]. However, The Food Safety Modernization Act of 2011
Recently, the focus is increasing on development of pre- mandates the FDA to detect and act against any safety
dictive models and high throughput approaches to aid in the threatening marketed products. In 2016, the FDA released a
early assessment of nano systems toxicity. This concept, draft guidance titled “Dietary Supplements: New Dietary
which is known as "safety by design", will facilitate the Ingredients Notifications and Related Issues: Guidance for
process of nano delivery systems design and allow the manu- Industry”, which provides information on the procedures that
facturing of safer systems. The implementation of safety by are required for submitting new dietary ingredients and data
design concept in drug discovery helped to reduce the risk of that are needed for safety evaluation [245].
drug withdrawal from the market for safety issues from 50% Japan is the largest nutraceutical market in Asia with a
to only 20% [239]. share of 70% and the second largest globally after the United
States [2]. In Japan, the use of herbs for medication is tradi-
4. NUTRACEUTICALS GLOBAL MARKET AND tional and known as “Kampo Medicine” [233]. The Japanese
REGULATIONS Ministry of Health, Labor and Welfare (MHLW) has estab-
lished the Consumer Affairs Agency (CAA) to regulate the
In 2016, the global market of nutraceutical was $198.7 nutraceuticals labelling and to ensure credibility of its health
billion and estimated to be $285 billion by 2021 with a com- claims and safety [242]. According to the CAA, nutraceuti-
pound annual growth rate (CAGR) of 7.5% [240]. By 2025, cal products are classified either as Foods with Nutrient
the market is expected to reach $578.23 billion with a CAGR Functional Claims (FNFC) or as Foods for Specified Health
of 8.8% [42]. Around 50% of the population in USA con- Uses (FOSHU). The first type of nutraceuticals (FNFC) in-
sumes dietary supplements [241]. The globally increased cludes vitamins and minerals, for which the agency is only
demand on nutraceuticals is driven by the emergence of responsible for setting the standard minimum and maximum
healthy lifestyles, increased adverse effects associated with daily intakes. Meanwhile, the (FOSHU) includes nutraceuti-
pharmaceutical drugs and the claims of nutraceutical safety cals with labelled physiological effect for health enhance-
and efficacy [242]. In contrast to the rapid growth of the ment. Further, a premarketing approval is needed for this
market, the regulations of nutraceuticals are slowly evolving category. It is also worthy to mention that any claim for dis-
with unclear and variable definitions for the term “nutraceu- ease risk reduction is not permitted [242].
tical” all over the world. Hence, nutraceuticals are not regu-
lated as pharmaceutical products in certain countries but as The Chinese nutraceutical market share is the second in
food supplements [13]. Asia-Pacific after Japan. However, it is estimated that China
will be the largest nutraceuticals market by 2020 [244]. The
Chinese Health Care Association (CHCA) was created by require animals or human clinical trials before registration of
the Ministry of Health to supervise and regulate the nu- nutraceuticals [250, 251].
traceutical industry in China [242]. Similar to the United
States FDA, the China`s State Food and Drug Administra- CONCLUSION
tion (SFDA) is responsible for dietary supplements monitor-
ing and registration. It is now known as China Food and The global consumption of nutraceuticals is rapidly grow-
Drug Administration (CFDA) [242]. The Indian nutraceuti- ing, which is driven by its alleged safety and efficacy. Re-
cal market is one of the most evolving markets with 18% cently, the incorporation of advanced nanosized drug delivery
CAGR in the last three years [244]. Food supplements repre- system as a platform for nutraceutical formulation is gaining
sent nearly 60% of the Indian market while vitamins and attention. This is influenced by the promising results obtained
minerals account for 40% share of the market [242]. regarding the bioavailability, safety, targeting and stability of
the nutraceuticals tested. Hence, various drug delivery systems
The Food Safety and Standards Authority of India were adopted, including nanoparticles, liposomes, dendrimers,
(FSSAI) was founded by the Indian government in 2006 to phytosomes, nanoemulsion and others.
act as a regulating authority for the food and food supple-
ment products in India [246]. According to the FSSA, nu- However, many challenges arise from nutraceutical for-
traceuticals are defined as “food processed or formulated to mulation concerning their efficacy, safety and regulations. A
satisfy particular dietary requirement for a physiological global definition was not identified by concerned institu-
condition or specific disorder” [246]. FSSAI monitors dif- tions. Regulatory bodies have not been implemented to con-
ferent processes, including manufacturing, packaging and trol and regulate nutraceuticals worldwide. This review arti-
labeling of nutraceuticals [247]. Additionally, FSSAI also cle provides a literature review of the most recent state-of-
puts restrictions on advertisements of nutraceuticals [247]. the-art technologies in nutraceuticals formulation and it dis-
The Indian Pharmacopoeia Commission also plays a rule in cusses the prospective challenges and the different attempts
standardization of the medicine’s quality including the me- to overcome it.
dicinal herbal products by publishing monographs in the
Indian Pharmacopoeia [242]. CURRENT & FUTURE DEVELOPEMENTS
The European Union nutraceutical market is the third The current status of nutraceuticals, cosmeceuticals and
largest after United states and Asia – Pacific with Germany food supplements in the global market is alarming. The cha-
and France contributing to nearly 50% of the market share otic scene starts with the terminology and categorization,
[244]. In Germany, a federal commission known as Com- where these products are not considered medications. No
mission E, was responsible for creating monographs to de- uniform, consistent or standardized regulations govern the
scribe the safety and efficacy of herbal products since 1978 manufacturing, sales or marketing of such products. All of
[243]. In the United Kingdom, herbal products are not con- these products are sold with major therapeutic claims as
sidered dietary supplement. They must also comply with the natural safer substitutes to medications. Most of these prod-
Traditional Herbal Registration (THR) regulations. There- ucts can be easily bought from online retail stores such as
fore, evidence of safety, quality and efficacy of the herbal Amazon or eBay without any real regulations or controls
product must be proven [243]. [22]. Furthermore, many sellers use the novel carrier tech-
nologies as an attraction strategy to increase sales.
The European Food and Safety Authority (EFSA), which
has been created according to the General Food Law Regula- Finally, it is concluded that the term “nutraceutical” is
tion of the European Parliament, is responsible for regulation poorly defined across the globe and from a regulatory per-
of food and food supplements in Europe [248]. The EFSA spective not clearly classified either as a category of food or
responsibilities include assessment of the beneficial health pharmaceuticals. Subsequently, it is a challenging task for
claims and the associated adverse effects with food and sup- the regulatory authorities in the different parts of the world.
plements intake [13]. According to EFSA, a health claim is However, clear and common regulations for nutraceuticals
defined as “ any message or representation that states, sug- will be urgently needed in the near future to cope with rap-
gest or implies that a relationship exists between a food idly emerging trends and demands in the global market.
category, a food or one of its constituents and health” [1].
Consequently, a supplement is classified according to its CONSENT FOR PUBLICATION
health claims in one of the following categories; “general
Not applicable.
function claims”, “new function claims” and “claims regard-
ing disease risk reduction and child development or health”
[1]. Moreover, Rapid Alert System for Food and Feed FUNDING
(RASFF) is reporting systems for monitoring and acting to None.
detect any hazard regarding the food and food derivatives
risk. RASFF was founded in the EU since 1979 [248]. CONFLICT OF INTEREST
Finally, some countries, such as Australia and China still The authors declare no conflict of interest, financial or
classify and regulate nutraceuticals as food [13]. Further- otherwise.
more, some countries, such as Argentina, Colombia and Bra-
zil, follow a simplified registrationbased way for nutraceuti-
ACKNOWLEDGEMENTS
cal regulations [249]. In contrast, other countries, such as
China, Brazil and Taiwan, outlined strict regulations and Declared none.
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Recent Patents on Drug Delivery & Formulation 2019, 13, 105-156

1. INTRODUCTION The oldest written document that included different 12 reci-

2212-4039/19 $58.00+.00 © 2019 Bentham Science Publishers

Oil Red O Staining

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Table (1) contd….

The molecular weight

17 Sodium dodecyl sulphate-polyacrylamide gel electrophoresis

Table (1) contd….

The particle size, PDI,

Antioxidant The morphology and

Enzymatically powder was evaluated via The crystalline

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The volatile oils were

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The efficacy of curcumin

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The physical stability

Antioxidant activity of the Emulsifying

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EGCG was encapsulated

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gastric condition. The morphology of

The stability of EGCG The solubility of the

The apoptosis efficacy of

Nanochemo- using apo-direct apoptosis

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DNA cell cycle analysis

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The chemical and

Fabrication of Fish oil-in-water The zeta potential was

27 2,2′Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt

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The oxidative stability

Grafting ratio was

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Table (1) contd….

Pickering emulsions The morphology of

29 Sodium dodecyl sulphate-polyacrylamide gel electrophoresis

creased surface area. Hence, the bioavailability of 3.9. Dendrimers

Table 2. Recent patents adopting novel formulation strategies in ultraceuticals.

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Hydrophilic or The morphology

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In-vitro release of free

Whole fruits Antioxidant

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Curcumin-polymer The stability was assessed Particle size, size

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