Vitamin E and Derivatives in Skin Health Promotion

Abstract

Vitamin E is fundamental for a proper function of human cells. Mostly obtained from vegetable oils, it has antioxidant and non-antioxidant actions. At times, its oral intake or skin application are employed. Oral intake is recommended in some cases. Differently, the topical application is a part of daily skin routine. Both in oral or in topical formulations, it is employed in its isoforms or derivatives. Tocopherols and tocotrienols are isoforms while derivatives are synthetic forms. In pharmaceutical and cosmetic formulations, vitamin E and its derivatives are widely used due to its antioxidant and photoprotective properties. However, the clinical success treatment is often impaired by its low skin penetration, high lipophilicity, and chemical instability. A rational formulation design in the development of novel vitamin E dosage forms is required. In this chapter, the most successful and innovative approaches towards Vitamin E and its derivatives loaded in formulations for skin health promotion are reviewed. Conventional and nanoparticle-based formulations enable vitamin E chemical stabilization, and they are suitable vehicles for its release on the skin. Further, nano-sized carriers can increase vitamin E content in formulations as well as favor its skin penetration.

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
Chapter
Vitamin E and Derivatives in Skin
Health Promotion
Júlia SchererSantos, Guilherme DinizTavares
and Thaís NogueiraBarradas
Abstract
Vitamin E is fundamental for a proper function of human cells. Mostly obtained
from vegetable oils, it has antioxidant and non-antioxidant actions. At times, its
oral intake or skin application are employed. Oral intake is recommended in some
cases. Differently, the topical application is a part of daily skin routine. Both in oral
or in topical formulations, it is employed in its isoforms or derivatives. Tocopherols
and tocotrienols are isoforms while derivatives are synthetic forms. In pharmaceuti-
cal and cosmetic formulations, vitamin E and its derivatives are widely used due to
its antioxidant and photoprotective properties. However, the clinical success treat-
ment is often impaired by its low skin penetration, high lipophilicity, and chemical
instability. A rational formulation design in the development of novel vitamin
E dosage forms is required. In this chapter, the most successful and innovative
approaches towards Vitamin E and its derivatives loaded in formulations for skin
health promotion are reviewed. Conventional and nanoparticle-based formulations
enable vitamin E chemical stabilization, and they are suitable vehicles for its release
on the skin. Further, nano-sized carriers can increase vitamin E content in formula-
tions as well as favor its skin penetration.
Keywords: antioxidant, tocopherols, tocotrienols, skin, health
. Introduction
Neurodegenerative and metabolic diseases progression is related to oxidative
stress [1, 2], a condition where there is a lower ability of endogenous antioxidants to
scavenge free radicals [3] resulting in free radicals increase. Most frequent free radicals
are the reactive oxygen species (ROS) such as singlet oxygen, hydrogen peroxide
and hydroperoxide. ROS are formed endogenously [4] and its production is raised
by some environmental factors [3]. Major internal sources are mitochondrial oxida-
tive reactions, phagocytosis by macrophages and xenobiotics metabolization [4].
Environmental factors include pollution, ultraviolet radiation and smoking [3]. Free
radicals damage DNA, protein and lipids [4] and their increase is involved in diabetes
progression [1] and in Alzheimer and Parkinson’s diseases onset [2]. In addition, cystic
fibrosis patients are more prone to oxidative stress owing to vitamin E deficiency [3].
Some endogenous antioxidants are glutathione peroxidase, vitamin C and vitamin
E [4]. Vitamin E is a non-enzymatic endogenous antioxidant [4] preventing athero-
sclerosis due to reduction of low density lipoprotein (LDL) oxidation. Beyond from
antioxidant, it has a fundamental role in neurological and immune system function

Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects

[4]. Accordingly, oral intake of vitamin E would be an interesting alternative treat-
ment to oxidative related diseases to improve patients quality of life [5, 6]. Apart
from oral intake, natural sources of this vitamin are the vegetable oils. Wheat germ
oil, sunflower oil, rice bran oil, canola oil and palm oil are some representants rich in
vitamin E. Nuts and fresh foods contain vitamin E, but in smaller amounts [4].
. Vitamin E isoforms and derivatives
A sum of 4 tocopherols isomers and 4 tocotrienols isomers compose vitamin E.
Isomers are named as alpha, beta, gamma and delta and their chemical structures
are shown in Figure . Tocopherols and tocotrienols differ only in their side chain.
Tocotrienols have an unsaturation on its side chain. In respect to isomers, the
nomenclature is due to substitutions in R1 and R2 positions. Alpha isomers have a
methyl group both at R1 and R2 while delta isomers do not have any methyl group.
Instead, beta and gamma isomers have one single methyl group, in R1 or in R2.
Regardless of the source, vegetables contain a mixture of isoforms and one of them
is predominant [7, 8]. Isoforms are obtained through extraction from vitamin E- rich
vegetables such as wheat (shown in Figure ) whose principal isoform is alpha-
tocopherol [7]. Chemical synthesis is employed to obtain alpha-tocopherol [7, 8].
Commercially, vitamin E is available mainly as alpha-tocopherol [9, 10] or tocoph-
eryl acetate [11–13] which are used above all to oral [14, 15] and skin [10, 12, 16] applica-
tions, respectively. Among vitamin E derivatives are tocopheryl acetate, tocopheryl
glucoside and tocopheryl phosphate. Tocopheryl acetate is the most used vitamin E
derivative [17] also named as tocopherol acetate or vitamin E acetate [18]. It is obtained
through tocopherol modification to improve stability since tocopherol is a labile form.
However, tocopheryl acetate is biologically inactive and it must be converted to tocoph-
erol in skin and intestine. Often, there is no mention about tocopheryl acetate isomer as
alpha-tocopheryl acetate is the most used [8].
Regarding human use, there is no standardization about vitamin E dose neither
in oral intake [14, 15] nor in skin formulations [10, 19, 20]. Although its deficiency
in adults is unusual [4], its oral intake may be recommended in cystic fibrosis
Figure 1.
Extraction of vitamin E isoforms, chemical structure of Tocopherols, Tocotrienols and Tocopheryl acetate.
Created in BioRender and ACD/ChemSketch.


Vitamin E and Derivatives in Skin Health Promotion
DOI: http://dx.doi.org/10.5772/intechopen.99466
patients [21]. Oral supplementation is equally used to reduce ultraviolet damage to
skin [14, 15]. Furthermore, its combination with other antioxidants is a common
approach. Vitamin C is the most used one [15, 19, 20] because it regenerates oxi-
dized vitamin E [22]. Oxidized vitamin E if not properly regenerated may promote
lipid peroxidation instead of preventing it [4]. The association of several antioxi-
dants is then extremely important to reduce oxidative stress.
. Benefits on skin health and dermatological diseases
The knowledge about vitamin E effects is essential to guide its use in dermatologi-
cal treatments. Table  shows some skin effects and mechanisms of action to vitamin
E isoforms and derivatives. Photoprotection was approached mostly in earlier studies
[23, 27, 28] while current ones approach mostly skin diseases [31, 35]. The antioxi-
dant activity accounts for many skin effects including photoprotection [23–25], skin
aging reduction [36, 37] and pyrimidine dimers reduction. The latter effect is impor-
tant to prevent cancer onset [30]. Moreover, as reactive oxygen species are involved
in the pathogenesis of psoriasis and atopic dermatitis [38–40], the topical application
of vitamin E isoforms would be likewise beneficial in these diseases.
In relation to isomers, earlier researches were directed mainly to alpha-
tocopherol whose action is lipid peroxidation reduction [24]. Nowadays, research is
focused on tocotrienols [31] and tocotrienol-rich fraction [35–37] which are able to
reduce melanoma progression [31, 32], melanogenesis [35] and skin aging [36, 37].
Tocotrienol-rich fraction (TRF) is a mixture of tocotrienols and alpha-tocopherol
[41] allowing to combine the pharmacological benefits of several isomers. Further
studies over tocotrienols and TRF are required to prove their efficacy in skin
diseases treatments.
. Vitamin E in skin care formulations
Conventional formulations [42] and nanotechnological-based formulations
[16, 43] have been used to deliver vitamin E and its derivatives into the skin due
Skin effect Mechanism of action References
Photoprotection Lipid peroxidation reduction [23–25]
Endogenous antioxidants protection [24–26]
Erythema decrease [27, 28]
Inflammation reduction [29]
Cancer prevention Pyrimidine dimers reduction [30]
Reduction of melanoma progression Apoptosis induction [31, 32]
Cell cycle arrest [32]
Improvement of melasma Reduction of tyrosinase activity [33, 34]
Down-regulation of TYRP-2 expression [34]
Down-regulation of TYR, TYRP-1, TYRP-2* [35]
Reduction of Skin Aging Increased collagen expression [36, 37]
Decrease metalloproteinases expression [37]
*TYR: Tyrosinase, TYRP-: tyrosinase-related protein-, TYRP-: tyrosinase-related protein- .
Table 1.
General skin effects and mechanisms of vitamin E isoforms and derivatives.

Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects

to its moisturizing, photoprotective, antioxidant [44, 45] and anticancer proper-
ties [46]. Some formulations applied to skin care are summarized in Table .
Mainly sunscreens and anti-aging commercial products contain this vitamin [42].
Additionally, some cosmetic brands have explored the “anti-pollution” claim
in their labels. As pollution triggers oxidative stress, the “anti-pollution” effect
prevents skin damage induced by pollutants [19].
Nevertheless, several limitations impact vitamin E isoforms and derivatives
bioavailability. Their bioactivity in different target sites, such as the skin is affected.
Vitamin E is an unstable molecule because it undergoes oxidation, especially
the light-triggered phenomena [60]. In this sense, novel drug delivery systems
have been extensively investigated to improve vitamin E bioavailability, solubil-
ity, stability and biodistribution. Consequently, a better skin penetration can be
accomplished [61, 62].
. Conventional formulations
Emulsions and hydroalcoholic gel are the most common conventional formula-
tions bearing either tocopherol, tocopheryl acetate or other esters (succinate,
nicotinate, linoleate, and phosphate). The isoform α-tocopherol is the one with the
best cost–benefit ratio [42]. One single α-tocopherol molecule is capable of neutral-
izing 2 peroxidil radicals which is responsible for lipid oxidation initiation. Then,
a delay in the development of several oxidation-based disorders could be achieved
[38]. Despite being less effective than tocopherol, tocopheryl acetate is widely used
in formulations intended to skin delivery [42].
In sunscreens formulations, vitamin E and its derivatives increase the sun
protection factor [47] and contribute to the photostabilization of chemical filters
[49]. After skin permeation, they can minimize the oxidative stress harmful effects
Skin formulation Skin care
application
Vitamin E isoform or
derivative
Reference
Conventional formulations Photoprotection α-tocopherol [10, 47]
Tocopheryl acetate [48, 49]
Tricotrienol-rich
fraction
[25]
Melasma Tocopheryl acetate [50]
Anti-pollution α-tocopherol [19]
Skin aging Tocopheryl acetate [51]
Acne vulgaris Tocopheryl phosphate [52]
Nanotechnology-based systems Photoprotection Tocopheryl acetate [43, 53]
α-tocopherol [54, 55]
Wound healing Tocopheryl acetate [56, 57]
Dermatitis α-tocopherol [58, 59]
γ-tocotrienol [59]
Skin aging α-tocopherol [9]
Moisturization Tocopheryl acetate [16]
α-tocopherol [9]
Table 2.
Vitamin E isoforms and derivatives in conventional forms and nanotechnology-based systems.


Vitamin E and Derivatives in Skin Health Promotion
DOI: http://dx.doi.org/10.5772/intechopen.99466
caused by UV radiation [48, 63]. In the latter case, an adequate vehicle is important
since it can influence its permeation. In this regard, especially o/w (oil- in-water)
emulsions have been used as the vehicle of choice [64]. From this perspective,
a report showed that o/w emulsion containing vitamin E prevented erythema
induction and reduced inflammatory damage caused by UV exposure in healthy
volunteers [48].
In anti-aging formulations, vitamin E and its derivatives act as antioxidants,
scavenging free radicals, the principal accelerators of skin aging [65]. As regards
to α-tocopherol, it decreased expression lines, wrinkles, and freckles induced by
photoaging in a study performed in vivo [66]. In addition, α-tocopherol smooths the
skin, increases the stratum corneum ability to maintain its humidity and accelerates
the epithelialization process [67]. For these purposes of use, most commercially
available formulations are emulsions o/w, both in creams and lotions.
Furthermore, the association of vitamin E and its derivatives with other ingre-
dients increased the effectiveness of different dermocosmetic treatments [45]. In
this sense, the application of a lotion combining α-tocopherol phosphate, ascorbyl
2-phosphate 6-palmitate, and glyceryl-octyl-ascorbic acid reduced the complica-
tions of acne vulgaris [52]. On the other hand, in a randomized controlled trial,
a cream containing hydroquinone, buffered glycolic acid, vitamins C and E, and
sunscreen was safe and effective in melasma treatment [50]. Recently, a serum
containing vitamin C, tocopheryl acetate and raspberry leaf cell culture extract had
anti-aging and brightening effects on the skin, with significant improvement of
skin color, elasticity, and radiance. The smoothness, scaliness, and wrinkles were
also improved by topical use of the product once a day, during eight weeks [51].
. Nanotechnology-based formulations
Bioactives molecules and lipophilic vitamins release on or into the skin by
topical products comprise a challenging task owing to the characteristics of the
stratum corneum barrier. Thereby, the drug accumulates on the skin surface.
Besides, vitamin E low stability by its direct exposure to UV radiation can limit
conventional formulations effectiveness [58]. Therefore, when it comes to topical
administration, nanostructured drug vehicles have shown advantages over conven-
tional delivery systems. The most investigated nanostructured carriers for vitamin
E comprise liposomes, nanoemulsions, polymer nanoparticles and lipid-based
nanoparticles [54].
Liposomes are self-assembled vesicles composed by one or more hydrophobic
bilayers constituted by amphiphilic phospholipids which originate an aqueous core
domain. Phospholipids contain phosphorus in their composition [68]. Diversely,
nanoemulsions are thermodynamically unstable surfactant-stabilized systems com-
posed of nano-sized micelles bearing an oily nucleus [69]. Polymer nanoparticles,
whether nanocapsules or nanospheres, are colloidal artificially prepared spherical
carriers surrounded by a polymer membrane. Nanocapsules contain an oily core
and nanospheres contain a polymeric matrix [70]. Besides, chitosan obtained from
shrimp and crab shells [71] is employed to form polymeric nanoparticles. In these
nanoparticles, there is a matrix formed by chitosan and tripolyphosphate. The latter
is used as a crosslinking agent [58]. Elseways, lipid nanoparticles either solid lipid
nanoparticles (SLN) or nanostructured lipid carriers (NLC) have a lipophilic bioac-
tive entrapped. SLN are formed by a solid lipid-based core while NLC are formed
by a mixture of solid and liquid lipids [72]. Figure  shows the general structures of
some nanocarriers used to deliver vitamin E into skin.
Concerning liposomes, an optimized composition [73], a proper selection of
preparation methods and a suitable particle size range [74] are essential as skin

Vitamin E in Health and Disease - Interactions, Diseases and Health Aspects

penetration will be affected by these factors. Regarding biological activity, vitamin
E-loaded liposomes inhibited lipid peroxidation more effectively than free vitamin
E [74]. Lately, tocopherol acetate-loaded transferosomes optimized wound healing
process [56]. As transferosomes are elastic liposome-like ultra-deformable vesicles,
a higher diffusion across the stratum corneum can be accomplished [75, 76]. Topical
administration of vitamin E-loaded liposomes are also interesting to enable a high
drug penetration and transdermal release into skin tumors [68].
Lipid nanoparticles ability to increase sunscreens efficacy was previously shown
[53, 55]. Tocopherol acetate-loaded SLN increased sunscreen UV-blocking effect
[53]. Moreover, alpha-tocopherol and sunscreens loaded in NLC and SLN increased
vitamin E photostability. Additionally, nanoencapsulated vitamin E promoted a
better photoprotection than nanoparticle-based formulation without Vitamin E
[55]. Besides, tocopheryl acetate and idebenone loaded in NLC provided a skin
hydration increase because lipids have occlusive properties. Vitamin E loaded in
NLC reduced skin pigmentation which was attributed to the photoprotective effect
of Vitamin E [43].
An innovative nanocomposite dressing for burn wound healing containing
vitamin E- loaded polymer nanoparticles allowed a vitamin controlled release [57].
In another report, α-tocopherol loaded to nanospheres was crosslinked to cellulose
fiber to obtain a novel cosmetic fabric with potential application to atopic dermatitis
patients [58]. As to nanoemulsions, tocopherol-loaded nanoemulsions increased
skin delivery in vitro and they protected vitamin E from UV-triggered degradation
[54]. More recently, α-tocopherol and γ-tocotrienol were loaded in nanoemulsions
to treat dermatitis as an attempt to avoid the use of steroid anti-inflammatory
drugs. This nanotechnological formulation could be in the future an alternative to
dermatitis patients [59].
Lastly, clinical trials are essential to complement in vitro assays. According to
human experiments, different nanosystems could be employed to ensure a more
immediate or a more prolonged skin hydration [16]. Beyond skin moisturization,
lipid nanoparticles improved human skin elasticity and firmness [9]. Importantly,
a protocol clinical trial proposes the use of a formulation containing vitamin
E-loaded NLC to reduce radiodermatitis in breast cancer patients. Since radioder-
matitis is a recurrent radiotherapy side effect, the use of this topical formulation
could improve cancer treatment as there would be lower patients quitting radio-
therapy treatment [77].
Figure 2.
Structure of some vitamin E nanocarriers. SLN: Solid lipid nanoparticles. NLC: Nanostructured lipid carriers.
TPP: Tripolyphosphate. Created in BioRender.


Vitamin E and Derivatives in Skin Health Promotion
DOI: http://dx.doi.org/10.5772/intechopen.99466
Author details
Júlia SchererSantos*, Guilherme DinizTavares and Thaís NogueiraBarradas
Faculty of Pharmacy, Department of Pharmaceutical Sciences, Federal University
of Juiz de Fora, JuizdeFora, Brazil
*Address all correspondence to: julia_scherer_santos@hotmail.com
. Conclusion
Reactive oxygen species are implicated in systemic and skin diseases pathogene-
sis. Hence, topical use as well as oral intake of antioxidants should be encouraged to
reduce stress oxidative effects. Vitamin E isomers and derivatives are widely known
for their antioxidant activity. Tocopherols and tocotrienols isomers are found in
vegetable oils. Elseways, vitamin E derivatives are synthetic forms obtained from
natural isomers. Endogenously, alpha-tocopherol scavanges reactive oxygen species
and owed to this effect, the oral supplementation of vitamin E is beneficial to
prevent the appearance and progression of diseases. In relation to cutaneous effects,
both oral and topical formulations provide a photoprotection against harmful ultra-
violet radiation. Moreover, despite tocotrienols potential application in melanoma
treatment, their skin effects are not fully understood.
Majority of skin care formulations contain alpha-tocopherol isoform or
tocopherol acetate derivative whose effects are mainly due to their scavenging
ROS ability. Therefore, the reduction of skin aging, melasma and cancer preven-
tion can be achieved by different vitamin E pathways on the skin. As conventional
forms and nanotechnology-based systems bearing vitamin E are useful in skin
diseases treatment, their use is essential to skin health promotion and maintenance.
Nevertheless, its therapeutic effectiveness is limited. Vitamin E loaded in nano-
structured delivery systems can significantly increase antioxidant-based therapy
effectiveness. In the future, there will be a need for well-designed controlled trials
to support the benefits of nanotechnology-based products containing this vitamin.
© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License (http://creativecommons.org/licenses/
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

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