Chapter 18

Nutraceutical and Pharmaceutical

Applications of Carotenoids

Masaki Honda

Abstract Carotenoids, the most common fat-soluble plant pigments in nature, play
important roles in scavenging peroxyl radicals and singlet oxygen in human. Dietary
carotenoids are considered to be beneficial for the prevention of various diseases,
including certain cancers, cardiovascular disease, and eye disease. Due to such
bioactivities of carotenoids, they are often used in nutritional supplements, skin
care cosmetics, and pharmaceutical products as well as in a natural color for foods and
feeds. In particular, the demands of β-carotene, lycopene, astaxanthin, lutein, zeax-
anthin, β-cryptoxanthin, and fucoxanthin are increasing for nutraceutical and phar-
maceutical applications in recent years. Although carotenoids exhibit high antiox-
idant activity in common, the bioactivity varies depending on the structure, e.g.,
lutein and zeaxanthin are effective for the prevention of eye disease, and fucoxanthin
exhibits a strong anti-obesity activity. The objective of this contribution is to review
the bioactivities and applications of commercially important carotenoids. Further-
more, the aspects of the recent progress in processing technology of carotenoids for
nutraceutical and pharmaceutical applications are also included in this review.

Keywords Carotenoid · Bioactivity · Application · Market size · E/Z-isomer

18.1 Bioactivity of Carotenoids

Most carotenoids have a 40-carbon basal structure including a system of conjugated

double bonds. Carotenoids can be roughly classified into the following two groups:
(1) carotenes, which are nonoxygenated molecules such as lycopene, α-carotene, and
β-carotene; (2) xanthophylls, which are oxygen-containing molecules such as lutein,
astaxanthin, and fucoxanthin (Fig. 18.1), and more than 750 naturally occurring
carotenoids have been identified until now (Maoka 2009).

M. Honda (B)
Faculty of Science & Technology, Meijo University, Shiogamaguchi, Tempaku-Ku, Nagoya
468-8502, Japan
e-mail: [email protected]

© Springer Nature Switzerland AG 2020 449

E. Jacob-Lopes et al. (eds.), Pigments from Microalgae Handbook,
https://doi.org/10.1007/978-3-030-50971-2_18
450 M. Honda

Fig. 18.1 Chemical structures of a (all-E)-lycopene, b (all-E)-α-carotene, c (all-E)-β-carotene,

d (all-E)-lutein, e (all-E)-astaxanthin, and f (all-E)-fucoxanthin

Carotenoids show strong antioxidant activity such as peroxyl radical and singlet
oxygen scavenging activities and the activity are related to the number of conjugated
double bonds in the molecule; carotenoids with more than 9 conjugated double
bonds display antioxidant activity (Di Mascio et al. 1989; Müller et al. 2011a).
Generally, the antioxidant activity is enhanced with increasing the number of conju-
gated double bonds. For example, astaxanthin, which contains 13 conjugated double
bonds, shows a higher singlet oxygen scavenging activity than that of β-carotene,
which contains 11 conjugated double bonds (Di Mascio et al. 1989; Ouchi et al.
2010). In addition, each carotenoid has unique bioactivity caused by the specific
structures in the molecule such as conjugated carbonyl and allene groups. Moreover,
several carotenoids such as β-carotene and β-cryptoxanthin are very important as
provitamin A. Since human and nonhuman animals cannot synthesize carotenoids,
the pigments must be supplemented in the diets, and thus the proper understanding of
their influence on the body is very important. The typical bioactivities of carotenoids
are summarized in Fig. 18.2 and the details are as follows .

18.1.1 Lycopene

Lycopene is an acyclic carotenoid principally responsible for the bright red color of
ripe tomatoes and tomato-based products as well as watermelons and gac (Momordica
cochinchinensis Spreng). Lycopene with 11 conjugated double bonds shows espe-
cially powerful antioxidant activity of the carotenoids. Di Mascio et al. (1989) have
reported that singlet oxygen scavenging activity of carotenoids, when β-carotene
is defined as a reference (=1.0), was higher in following order: lycopene (2.2) >
γ-carotene (1.8) > astaxanthin (1.7) > canthaxanthin (1.5) > α-carotene (1.4) > β-
carotene (1.0) > zeaxanthin (0.7) > lutein (0.6) > α-tocopherol (0.02). The singlet
18 Nutraceutical and Pharmaceutical Applications of Carotenoids 451

Fig. 18.2 Typical health effects of carotenoids

oxygen scavenging activity of lycopene was one hundred or more times as high
as that of α-tocopherol. Ample studies have demonstrated that the daily intake
of lycopene-rich foods can significantly reduce risk of cancer and cardiovascular
disease (Mordente et al. 2011; Wang et al. 2010). Lycopene is accumulated in
various tissues and organs of human, e.g., liver, intestine, and prostate, by eating
lycopene-rich foods such as tomatoes. Especially, a large amount of lycopene is
accumulated in prostate and ample studies have addressed that higher dietary and
circulating lycopene concentrations are inversely associated with prostate cancer
risk. For example, Etminan et al. (2004) reported that high intakes of tomato or
tomato-based products were associated with approximately 10 to 20% reduction in
prostate cancer risk, which was investigated in a meta-analysis of studies published
from 1966 to 2003. Experimental and epidemiological studies also demonstrated that
lycopene would act as a chemopreventive agent against lung cancer, gastric cancer,
and breast cancer (Mein et al. 2008; Wang et al. 2010). Moreover, several studies
suggested that oxidized low-density lipoprotein (LDL) is implicated in the pathogen-
esis of atherosclerosis, and the atherosclerosis could be attenuated by lycopene, which
inhibit LDL oxidation (Cheng et al. 2017; Palozza et al. 2010). In fact, some dietary
studies have demonstrated that tomato products rich in lycopene increase resistance
of LDL to oxidation against human (Silaste et al. 2007; Upritchard et al. 2000).
Besides the above, several reports suggested that lycopene may have antidiabetic
and anti-obesity activities as well as improvement in skin type (Darvin et al. 2008;
Kuhad et al. 2008; Marcotorchino et al. 2012). There are especially many reports
on health benefits of lycopene compared to other carotenoids and active empirical
research on lycopene bioactivity has been carried out in recent years. Furthermore,
452 M. Honda

since lycopene is abundant in the tomato, which is one of the most popular and
widely consumed vegetables in the world, the carotenoid is easily ingestible. Thus,
it is considered that the marketplace is expected to further expand.

18.1.2 β-Carotene

β-Carotene, which has two unsubstituted β-ionone ring half-sites and 11 conjugated
double bonds, is a red-orange pigment found in many vegetables such as carrots and
spinach. β-Carotene is an important vitamin A source for human and the method for
industrial synthesis was established in half a century ago, so that the basic research
of the carotenoid has been done since quite a long time ago compared to other
carotenoids. Several studies reported that β-carotene would reduce risk of some
cancers such as stomach cancer and skin cancer (Blot et al. 1993; Köpcke and Krut-
mann 2008). On the other hand, some large-scale intervention studies of β-carotene
supplementation has not been shown any beneficial effect on cancer prevention or
shown an adverse effect on the incidence of lung cancer and gastric cancer with 20–
30 mg of β-carotene per day in smokers and workers exposed to asbestos (Albanes
et al. 1996; Omenn et al. 1996). Several researchers indicated that one of the largest
factors of that would excess intake of β-carotene: the normal intake of carotenoids
is approximately 1.5 mg per day for people in the United States (Druesne-Pecollo
et al. 2010). In fact, Siems et al. (2005) indicated that, obviously, on certain condi-
tions of high-dose carotenoid supplementation, both the antioxidant and prooxi-
dant reactions arise. Therefore, smokers and workers exposed to asbestos should
avoid high-dose β-carotene supplementation. β-Carotene would be effective against
erythropoietic protoporphyria. Ample studies have demonstrated that the oral dose
of β-carotene relieves the photosensitivity associated with the disease (Mathews-
Roth et al. 1974, 1977). In addition, the dietary β-carotene could have an age-related
macular degeneration-preventing effect (West et al. 1994). The simultaneous inges-
tion of β-carotene, zinc, and antioxidants such as vitamin C and vitamin E would
further enhance the preventive effect, i.e., trial participants who received a daily high-
dose supplement of β-carotene (15 mg), vitamin C (500 mg), vitamin E (400 IU),
and zinc (80 mg) had an approximately 25% reduced risk of progression from rela-
tively advanced early age-related macular degeneration stages to late age-related
macular degeneration (Age-Related Eye Disease Study Research Group 2001). On
the other hand, Tan et al. (2008) indicated that higher β-carotene intake may be
associated with a risk increase of age-related macular degeneration. From the above,
β-carotene shows various health benefits, especially high provitamin A activity, but
it is considered important to be aware of proper intake.
18 Nutraceutical and Pharmaceutical Applications of Carotenoids 453

18.1.3 Astaxanthin

A xanthophyll, astaxanthin, is principally responsible for the dark-red color and is

present in various marine animals such as salmon, trout, red seabream, and microor-
ganisms such as Haematococcus pluvialis and Paracoccus carotinifaciens (Ambati
et al. 2014). It has a structure composed of 2-β ionone rings and a conjugated polyene
chain at the center, with hydroxyl and keto moieties on each ionone ring. Astaxan-
thin has 13 conjugated double bonds in the molecule, and thus the carotenoid shows
very high antioxidant activity (Di Mascio et al. 1989; Ouchi et al. 2010). As with
other carotenoids, ample studies indicated that astaxanthin would reduce risk of
certain cancers, e.g., lung cancer and colon cancer (Kowshik et al. 2014; Palozza
et al. 2009). Several researches have indicated that astaxanthin exerts anti-apoptosis,
anti-proliferative, and anti-invasion influences via different molecules and pathways:
nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), signal trans-
ducer and activator of transcription 3 (STAT-3), and peroxisome proliferator-activated
receptor gamma (PPARγ) (Zhang and Wang 2015). Astaxanthin is closely involved
in eye health. Astaxanthin is capable of passing the blood-brain barrier and will
deposit in the retina of mammals (Dhankha et al. 2012). Several studies indicated
that the daily astaxanthin intake could improve eye fatigue such as against visual
display terminal workers, and it might increase retinal capillary blood flow in eye
(Kidd 2011; Nagaki et al. 2005, 2006). In addition, several studies reported that
dietary astaxanthin can accumulate in animal brain and indicated that the carotenoid
may be useful as a preventive and/or therapeutic agent for Alzheimer type dementia
(Che et al. 2018; Manabe et al. 2018; Rahman et al. 2019). For example, Rahman
et al. (2019) investigated the role of astaxanthin on hippocampal insulin resistance
in rat model of Alzheimer’s disease, and revealed that astaxanthin showed neuropro-
tective and anti-amyloidogenic effects in neurohistology. Moreover, ample studies
indicated that astaxanthin would have a skin protecting function. Namely, astaxan-
thin can prevent skin thickening and reduce collagen reduction against UV-induced
skin damage, and topical administration of astaxanthin liposomes containing cationic
lipid inhibited melanin production in skin exposed to UV (Ambati et al. 2014; Hama
et al. 2012; Yamashita 2013).

18.1.4 Lutein and Zeaxanthin

Lutein and zeaxanthin are xanthophylls, which are principally responsible for yellow-
orange color found in vegetables such as artichoke and corn as well as in egg yolk
(Perry et al. 2009). Both carotenoids have high singlet oxygen quenching activitiy
(Di Mascio et al. 1989) and dietary lutein and zeaxanthin would have a potential
role in the prevention and treatment of several cancers such as colorectal cancer and
lung cancer (Gallicchio et al. 2008; Männistö et al. 2006). Lutein and zeaxanthin are
concentrated in the primate retina, where they form the macular pigment, and thus
454 M. Honda

multiple studies have focused on their beneficial roles in eye health. Most clinical
epidemiological researches supported that lutein and zeaxanthin have reduce the risk
of some eye diseases, e.g., age-related macular degeneration, cataract, and retinitis
pigmentosa (Ma and Lin 2010; Stringham et al. 2010). The powerful blue-light
filtering activity and antioxidant activity of these carotenoids may be responsible for
the protective effects (Junghans et al. 2001; Kijlstra et al. 2012). Moreover, lutein and
zeaxanthin are present in human skin, and animal studies have provided evidence of
significant efficacy against UV-induced skin damage (Roberts et al. 2009).

18.1.5 β-Cryptoxanthin

β-Cryptoxanthin, a major source of vitamin A, is a yellow xanthophyll found abun-

dantly in red chili, papaya, and Satsuma mandarin (Citrus unshiu Marc.) (Breithaupt
and Bamedi 2001; Takayanagi et al. 2011). β-Cryptoxanthin may be effective for
reduction in the risks of lung and oral cancers and stimulate the repair of DNA
oxidation damage due to strong antioxidant activity (Leoncini et al. 2015; Lorenzo
et al. 2008; Männistö et al. 2004). A number of studies have addressed that the
carotenoid would have the preventive role in osteoporosis. β-Cryptoxanthin has stim-
ulatory effects on osteoblastic bone formation and inhibitory effects on osteoclastic
bone resorption, and they induce increase of bone mass (Yamaguchi and Uchiyama
2003, 2004). In addition, the carotenoid has an effect on the gene expression of
several proteins which are associated with osteoblastic bone formation and osteo-
clastic bone resorption (Uchiyama and Yamaguchi 2005; Yamaguchi 2012). Some
epidemiological studies also support that the intake of foods rich in β-cryptoxanthin
may reduce risks of osteoporosis and osteoarthritis (Sugiura et al. 2008; Wang et al.
2007). Moreover, β-cryptoxanthin has anti-obesity activity (Shirakura et al. 2011;
Takayanagi et al. 2011). For example, Takayanagi et al. (2011) reported that oral
administration of Satsuma mandarin (Citrus unshiu Marc.) rich in β-cryptoxanthin
repressed body weight, abdominal adipose tissue weight, and serum lipid concentra-
tions in obese model mouse. They also confirmed by gene expression analysis that
the carotenoid can alter cytokine secretion and cell proliferation. In addition, high
plasma levels of β-cryptoxanthin were associated with a lower risk of atherosclerosis
(Nakamura et al. 2006).

18.1.6 Fucoxanthin

Fucoxanthin, an allenic xanthophyll, is an orange-colored pigment found abun-

dantly in edible brown seaweeds such as kombu (Laminaria japonica) and wakame
(Undaria pinnatifida) (D’Orazio et al. 2012). As with other carotenoids, fucoxan-
thin had strong anti-cancer and anti-angiogenic activities as well as high antioxi-
dant activity (Hosokawa et al. 2004; Sachindra et al. 2007; Sugawara et al. 2006;
18 Nutraceutical and Pharmaceutical Applications of Carotenoids 455

Terasaki et al. 2019). For example, Hosokawa et al. (2004) reported that fucox-
anthin significantly reduced the viability of human colon cancer cell lines such as
HT-29, Caco-2, and DLD-1 cells. In addition, fucoxanthin has gained much atten-
tion for its anti-obesity and anti-diabetic effects due to a unique mechanism. Maeda
et al. (2005) reported that fucoxanthin induces uncoupling protein 1 (UCP1) expres-
sion in white adipose tissue (WAT), and UCP1 can dissipate energy via fatty acid
oxidation and heat production. Moreover, the carotenoid enhanced insulin resistance
and improved blood glucose levels via the up-regulation of glucose transporter 4
(GLUT4) in skeletal muscle and downregulation of adipocytokines related to insulin
resistance in WAT (Maeda 2015; Maeda et al. 2009; Miyashita et al. 2010). Thus,
foods rich in fucoxanthin, such as brown seaweeds, are expected to have a preventive
effect on metabolic syndrome.

18.1.7 Other Carotenoids

In addition to the above carotenoids, functional studies of α-carotene, canthaxan-

thin, and capsanthin are well documented. These carotenoids have powerful antiox-
idant activity (Di Mascio et al. 1989; Ouchi et al. 2010) and may have anti-cancer
activity (Kim et al. 2009; Tanaka et al. 2012) like other carotenoids. For example,
epidemiological and animal studies indicated that capsanthin appears to possibly
exert a potent inhibitory effect on colon carcinogenesis (Kim et al. 2009; Narisawa
et al. 2000). Moreover, multiple studies have reported some other health benefits of
α-carotene, canthaxanthin, and capsanthin: high plasma levels of α-carotene were
associated with a lower risk of atherosclerosis (D’Odorico et al. 2000); canthaxanthin
would have immunomodulatory activity, i.e., the carotenoid enhanced the prolifer-
ation and function of immune competent cells (Esatbeyoglu and Rimbach 2017);
dietary capsanthin increased in plasma HDL-cholesterol level (Aizawa and Inakuma
2009). In recent years, bioactivities of several rare carotenoids such as adonixan-
thin and siphonaxanthin are spotlighted. In detail, adonixanthin found abundantly
in astaxanthin synthesize bacteria such as Paracoccus sp. and Agrobacterium sp.
have very high antioxidant activity of carotenoids (Maoka et al. 2013). Furthermore,
Iwata et al. (2018) reported that dietary adonixanthin may protect against brain
damage induced by cerebral hemorrhage, including structural and functional symp-
toms. Siphonaxanthin, a marine carotenoid from green algae such as Codium fragile
and Caulerpa lentillifera (Sugawara et al. 2014), effectively induced apoptosis in
human leukemia (HL-60) cells (Ganesan et al. 2011) and inhibited angiogenesis
by downregulating fibroblast growth factor 2 (FGF-2)-mediated intracellular signals
in vascular endothelial cells (Ganesan et al. 2013). More than 750 naturally occur-
ring carotenoids had been reported until now, but their functional studies have been
carried out only in part. Hence, further progress in this research area is expected in
the future.
456 M. Honda

18.1.8 Z-Isomer of Carotenoids

Since carotenoids contain multiple conjugated double bonds, a large number of

geometric isomers are theoretically possible. In fact, Z-isomers of carotenoids are
widely present in plants, processed foods, and animal bodies. For example, more than
20% of total lycopene is present as the Z-isomers in some processed tomato products
such as tomato sauce and tomato soup (Honda et al. 2017a), and more than 30% of
total astaxanthin is present as the Z-isomers in human plasma (Coral-Hinostroza et al.
2004). Recently, ample studies have addressed that Z-isomers of carotenoids such as
lycopene and astaxanthin showed higher bioavailability and antioxidant activity than
the all-E-isomers (Cooperstone et al. 2015; Müller et al. 2011; Yang et al. 2017a).
For example, a human oral administration test reported by Cooperstone et al. (2015)
showed that Z-isomer-rich tangerine tomato juice (containing 94% total Z-isomer
content of lycopene) was over 8 times more bioavailable than an all-E-isomer-rich red
tomato juice (containing 10% total Z-isomer content of lycopene). On the other hand,
several studies have reported that Z-isomers of β-carotene showed less bioavailability
than the all-E-isomer (During et al. 2002; Gaziano et al. 1995). In fact, although a
great amount of the Z-isomers of lycopene (>50% of the total lycopene) and astax-
anthin (>30% of the total lycopene) was present in human serum, the total amount of
β-carotene Z-isomers was less than 10% (Coral-Hinostroza et al. 2004; Stahl et al.
1992). In addition, although there are limited evidences, several carotenoid Z-isomers
exhibit higher bioactivities such as anti-cancer activity and anti-atherosclerosis effect
than the all-E-isomers. For example, (9Z)-β-carotene from the green halophilic alga
Dunaliella sp. would have higher anti-atherogenesis and anti-atherosclerosis effects
than the all-E-isomer (Harai et al. 2008; Relevy et al. 2015). Nakazawa et al. (2009)
reported that fucoxanthin Z-isomers showed higher anti-cancer activity than the all-
E-isomer, that is evaluated by measuring the potent inhibitory effects on human
promyelocytic leukemia cells (HL-50) and colon cancer cells (Caco-2). These func-
tional changes between all-E-isomer and Z-isomers of carotenoids may be caused
by the change in the physicochemical properties such as solubility and crystallinity
(Honda et al. 2018a; Murakami et al. 2017), e.g., Honda et al. (2018a) reported that the
solubility in ethanol of astaxanthin containing 63.2% Z-isomer was approximately
700 times higher than that of the all-E-isomer, and (all-E)-astaxanthin was present
in the crystal state, while the Z-isomers were present in an amorphous state, that
was confirmed by differential scanning calorimetry (DSC), powder X-ray diffrac-
tion (XRD), and scanning electron microscopy (SEM) analyses. The effects of Z-
isomerization of carotenoids on the bioavailability, antioxidant activity, and bioac-
tivity are summarized in Table 18.1. To my best knowledge, among the over 750
naturally occurring carotenoids, only approximately 10 carotenoids have been char-
acterized in terms of the effects of Z-isomerization. Thus, there is still considerable
room for development of this research area.
18 Nutraceutical and Pharmaceutical Applications of Carotenoids 457

Table 18.1 Summary of the effects of Z-isomerization of carotenoids on the bioavailability,

antioxidant activity, and bioactivity
Carotenoids Bioavailability Antioxidant activity Bioactivity
Lycopene • Ea< Zb (Sun et al. • E  Z (Müller et al. –
2016) 2011b)
• E < Z (Cooperstone • E  Z (Böhm et al.
et al. 2015) 2002)
• E < Z (Unlu et al. 2007)
α-Carotene – • E ≈ Z (Böhm et al. –
2002)
β-Carotene • E > Z (Deming et al. • E ≈ Z (Böhm et al. Anti-atherogenesis
2002) 2002) activity:
• E > Z (During et al. • E > Z (Lavy et al. • E < Z (Harai et al.
2002) 1993) 2008)
• E > Z (Gaziano et al. • E < Z (Levin et al. Anti-atherosclerosis
1995) 1997) activity:
• E > Z (Stahl et al. 1995) • E < Z (Relevy et al.
2015)
Astaxanthin • E < Z (Yang et al. • E < Z (Yang et al. –
2017a) 2017a)
• E < Z (Coral-Hinostroza • E  Z (Yang et al.
et al. 2004) 2017b)
• E  Z (Østerlie et al. • E < Z (Liu and Osawa
2000) 2007)
Canthaxanthin – • E < Z (Venugopalan Pro-apoptotic activity:
et al. 2013) • E < Z (Venugopalan
et al. 2009)
Fucoxanthin – • E ≈ Z (Zhang et al. Anti-cancer activity
2014) • E < Z (Nakazawa
• E > Z (Kawee-ai et al. et al. 2009)
2013)
Lutein • E > Z (Yang et al. • E  Z (Yang et al. –
2018)c 2018)
• E < Z (Yang et al.
2018)d
Zeaxanthin – • E  Z (Böhm et al. –
2002)
a all-E-Isomer of carotenoid.
b Z-Isomer of carotenoid.
c Evaluated by a digestion model.
d Evaluated in Caco-2 cells
458 M. Honda

18.2 Nutraceutical and Pharmaceutical Applications

of Carotenoids

18.2.1 Market Size

The market size of carotenoids was valued at $1.5 billion in 2014 and is expanding
year by year, i.e., compound average growth rate (CAGR) from 2014 to 2019 is
estimated at 3.9% (Business Communications Company 2015). The aging of citizens
in developed countries is a serious social problem. Since carotenoids have preventive
effects against age-related diseases such as age-related macular degeneration and
Alzheimer type dementia, this aspect is considered to be boosting the demand for
carotenoids. In addition, the demands for natural food colorants and color-restoring
feed with carotenoids for farm animals and cultured fish drive the global carotenoids
market growth. Lycopene, β-carotene, astaxanthin, lutein, zeaxanthin, canthaxanthin,
and capsanthin are the major carotenoids, which are available commercially. The
carotenoid market would have several changes in recent years. Namely, the market
share for major carotenoids in 2010 was higher in the order of β-carotene (22%) >
lutein (20%) > astaxanthin (19%) > canthaxanthin (7%) > lycopene (6%) (Business
Communications Company 2011), whereas prospective that in 2021 would be higher
in the order of β-carotene (26%) > astaxanthin (25%) > lutein (18%) > canthaxanthin
(10%) > lycopene (6%) (Rammuni et al. 2019). The market size of astaxanthin has
growth potential and is expected to rise sharply owing to its increasing usage in a
antioxidant for health food and an animal and fish feed ingredient. Moreover, the
commercially available carotenoids are mainly synthesized chemically, whereas a
portion is obtained through natural sources such as fermentation and extraction from
plants or algae. Natural carotenoid category is anticipated to have the high growth in
the future due to the increase in consumer demand for natural products.

18.2.2 Distribution Form and Applications

Commercially available carotenoids are mainly distributed as the (1) dried ground
powder of carotenoid-rich plants, microalgae, and bacteria, (2) oil suspension (oleo-
resin or the diluted product by vegetable oil), (3) liquid or dried emulsion formulation,
and (4) beadlet formulation (high carotenoid concentrated powder). The carotenoid
concentration of the dried ground powders and emulsion formulations is around a few
weight percent (1–3 wt%). On the other hand, as for the oil suspensions and beadlet
formulation, products with various carotenoid concentrations are distributed, which
are normally from a few weight percent to 50 wt%. Generally, the prices of carotenoid
products are depending on the carotenoid content. The typical applications of each
formulation are shown below.
18 Nutraceutical and Pharmaceutical Applications of Carotenoids 459

(1) Dried ground powder: farm animal and fish feeds, foods, and extract materials
for carotenoids
(2) Oil suspension (oreolesin): supplements (soft capsule) and cosmetics
(3) Liquid or dried emulsion formulation: food and beverage colorings and
cosmetics.
(4) Beadlet formulation: foods and supplements (tablet).

18.2.3 Processing

Carotenoids can be obtained from plants, algae, and bacteria, or can be produced
by chemical synthesis. Generally, carotenoids are present in the all-E-configuration
that has high hydrophobicity and high crystallinity. These properties limit their use
for food and cosmetic industries, and thus many commercially available carotenoid
products are subjected to the emulsification and micronization treatments. However,
the efficiencies of carotenoid processings such as extraction, emulsification, and
micronization are very low due to their properties of high hydrophobicity and
high crystallinity, and that results in price increase and quality deterioration of the
carotenoid products. Therefore, many studies have been carried out to improve the
carotenoids processing efficiency. For example, as for carotenoids extraction, extrac-
tion conditions (type of solvent, temperature, and time) and extraction apparatus are
well studied, and as for the emulsification, type of emulsifier as well as emulsification
conditions and apparatus are well documented. In recent years, carotenoid processing
utilizing a green solvent, supercritical CO2 (SC-CO2 ), which is non-toxic and easily
separated from the products, has been extensively examined. However, there are few
practical examples for carotenoid processing because most carotenoids are very low
solubility in SC-CO2 . Very recently, it was revealed that Z-isomers of carotenoids
were higher solubility in solvents including SC-CO2 and lower crystallinity than the
all-E-isomers (Honda et al. 2018a; Murakami et al. 2017). By utilizing the change
in the physicochemical properties via the Z-isomerization, several studies success-
fully improved the efficiency of carotenoid processing using SC-CO2 . For example,
Honda et al. (2017b, 2018b) demonstrated that the thermal Z-isomerization pre-
treatment to tomato pulp and gac (Momordica cochinchinensis Spreng.) markedly
improved the SC-CO2 extraction efficiency of lycopene. Moreover, when Z-isomer-
rich carotenoids were used as the raw material for emulsification and micronization
processings using SC-CO2 as a mediator, those efficiencies were notably improved
compared with using the all-E-isomers (Kodama et al. 2018; Ono et al. 2018), e.g.,
in emulsification of β-carotene using SC-CO2 as the organic phase, the encapsulated
efficiency of β-carotene Z-isomers was 21.2 times higher than that of the all-E-
isomer (Ono et al. 2018). For the sustainable development of carotenoid products in
the future, further development of carotenoids processing with SC-CO2 is expected
and utilizing the change in the physicochemical properties of carotenoids by the
Z-isomerization may be breakthrough of that realization.
460 M. Honda

Fig. 18.3 Applications of commercially used carotenoids

18.2.4 Nutraceutical and Pharmaceutical Applications

The major applications of carotenoids are for “bioactive agent” such as nutritional
supplements and cosmetics, and “color” for foods and beverages, and animal and
fish feeds (Fig. 18.3). Focusing on the nutraceutical and pharmaceutical segments,
the primary applications of each carotenoid are summarized below.

18.2.4.1 Lycopene

The main application of lycopene is nutritional supplement appealing high antioxi-

dant activity and reduce risks of prostate cancer and cardiovascular disease: approx-
imately 80% of global lycopene consumption was supplement in recent years. From
the early 2000s, the demand for the cosmetic segment is also increasing year by
year because in addition to the development of the emulsification technology, its
high antioxidant singlet oxygen scavenging activity and skincare effect were demon-
strated. Furthermore, the recent demands for natural food colorants drive lycopene
market as a colorant agent for a number of food products. Mainly, synthetic lycopene
and extracted lycopene from tomatoes are available commercially. The tomato
extracts rich in lycopene are also expected to be health benefits from components
other than lycopene such as phytoene, phytofluene, and β-carotene. Most lycopene
in the market is the all-E-form, e.g., the content of lycopene Z-isomers, which have
higher bioavailability and antioxidant activity than the all-E-isomer, in tomato oleo-
resin sold by LycoRed Ltd. (Lyc-O-Mato® ; Beer-Sheva, Israel), which is the biggest
18 Nutraceutical and Pharmaceutical Applications of Carotenoids 461

producer of natural lycopene, is around only 10% (Honda et al. 2017a). However,
recently, Licofarma S.r.l. (Galatina, Italia) has sold lycopene supplements appealing
high Z-isomer content. Since the functional study and manufacturing technique
development on lycopene Z-isomer have been carried out in recent years, further
demand for (Z)-lycopene is expected to increase.

18.2.4.2 β-Carotene

β-Carotene currently has two major applications, i.e., colorant for food products
and supplements. There is almost no food segments that does not use β-carotene as
a colorant. For example, the yellowish pigment, β-carotene, is used for beverages
such as fruit-based juices and carbonated drinks, margarine, ice cream, and so on.
The major concept of β-carotene supplement is based on the understanding that the
carotenoid has antioxidant activity and can reduce risk of some cancers. However,
several reports indicated that an excessive intake of β-carotene under certain circum-
stances such as smokers and workers exposed to asbestos may stimulate the develop-
ment of cancer and the carotenoid act as a prooxidant (Albanes et al. 1996; Omenn
et al. 1996). Therefore, it is important to pay attention to its intake. As minor applica-
tions, β-carotene is used for a fertility increasing agent in animal feed (Folman et al.
1987) and an anti-wrinkle and natural bronzing agent in cosmetics (Kim et al. 2009).
The major source of β-carotene is chemical synthesis, but the shares of algae extrac-
tion, fermentation, and palm oil are increasing in recent years. β-Carotene from the
green halophilic alga Dunaliella sp. contains the 9Z-isomer in large quantity (some-
times, around 50% of total β-carotene isomers). Since the isomer would have higher
anti-atherogenesis and anti-atherosclerosis effects than the all-E-isomer (Harai et al.
2008; Relevy et al. 2015), the demand of supplements using Dunaliella sp. as the
β-carotene source has been expanding.

18.2.4.3 Astaxanthin

The greater part of the astaxanthin consumption has been the colorant for fish and
shrimp. Astaxanthin is widely found in aquatic animals and it has a major role in their
body color. However, since the aquatic animals cannot biosynthesize astaxanthin,
they need to take the pigment from diets. The consumers check the fish and shrimp
quality by pigmentation on them. Hence, the feeding of astaxanthin is very important.
As many governments support for promoting aquaculture, the demand of astaxanthin
has further growth potential as a pigment coloring agent. Moreover, multiple studies
demonstrated that dietary astaxanthin offers numerous health benefits for humans
such as brain health improvement and healthy vision, and thus the carotenoid is
often used for nutritional supplement. In addition, since astaxanthin may exert its
benefits on skin homeostasis, it is gaining popularity and acceptability in cosmetics
manufacturers and numerous wellness spa service providers.
462 M. Honda

18.2.4.4 Lutein and Zeaxanthin

A global market for lutein was established in the segment of eye health as a stan-
dalone, occasionally together with zeaxanthin. Thus, the major application of lutein
and zeaxanthin is nutritional supplement appealing eye health. The supplements
would protect from detrimental effects of computer display light exposure and reduce
the risk of age-related macular degeneration. Lutein is also deal as a medicine for eye
disease, which is listed on the Australian Register of Therapeutic Goods (ARTG).
In addition, helenien (lutein dipalmitate) is widely used as a medicine for the visual
disorders (Khan et al. 2014). Helenien is often isolated from the blossom leaves of
Helenium autumnale. Recently, chronic eye disorder age-related macular degener-
ation accounted for over 50% of blindness cases in North America, and it should
favor the supplements and medicine demands. Lutein and zeaxanthin are also used
for feed as a colorant for egg yolks and broiler skin, and marigold is widely used as
their source. Feeds containing lutein and zeaxanthin derived from marigold result in
a strong yellowish or even orange color hue of the yolks.

18.2.4.5 Canthaxanthin

The major application of canthaxanthin is feeds, e.g., coloring hen’s egg yolks
and fish pigmentation. Since its lower price compared to other carotenoid sources
for feeds such as astaxanthin, the consumption for the industry is expanding year
by year. Although the market size is small (around 10% of total canthaxanthin
market size), canthaxanthin is used for the nutraceutical and pharmaceutical applica-
tions. Namely, the carotenoid is used for supplement appealing antioxidant activity,
anti-atherosclerosis activity, and enhancement of fertility and sexual performances.
Since canthaxanthin is also promoted as a self-bronzing agent, it is used for some
creams and lotions. In addition, as canthaxanthin has a bright red color, it is
popular in coloring pharmaceutical tablets. This application is widespread, but the
volumes consumed are not many. The market for nutraceutical and pharmaceutical
applications of canthaxanthin is expanding year by year especially in North America.

18.2.4.6 Other Carotenoids

Since the bioactivities such as reduction risk of osteoporosis and anti-obesity activity
of β-cryptoxanthin and fucoxanthin, respectively, were reported in the middle of the
2000s (Uchiyama and Yamaguchi 2005; Maeda et al. 2005), the development of
supplements containing their carotenoids has been actively carried out and their
market sizes are growing larger every year especially in Japan. Generally, the natural
sources are used for the supplements, i.e., the major source of β-cryptoxanthin is
Satsuma mandarin (Citrus unshiu Marc.) and that of fucoxanthin is edible brown
seaweeds such as kombu (Laminaria japonica) and wakame (Undaria pinnatifida).
In addition, α-carotene and capsanthin also have markets in supplement appealing
18 Nutraceutical and Pharmaceutical Applications of Carotenoids 463

antioxidant, anti-cancer, and anti-atherosclerosis activities. However, in many cases,

their carotenoids are used together with the other carotenoids such as β-carotene and
lutein, and are sold as a multi carotenoid supplement. Capsanthin has relatively big
market share of carotenoids (around 10% of carotenoid market in 2010), but the main
applications are not for supplements but for food colors and feeds.

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