Examples of association between vitamin E and other active molecules.
Vitamins are part of the antioxidant system of human skin, and are detectable in different layers, so the topical application can be an alternative to maintain the functionality of the system. The capacity of the antioxidant gradient of keratinocytes is associated with attenuation of the action of related free radicals in both esthetics and health. These problems arise from extrinsic aging and are related to the risk of cancer. Vitamin E has been proven to have antioxidant and moisturizing properties in the skin and can protect against the damage of UVB radiation, with emphasis on the reduction of acute erythema and photoaging. The choice for the use of topical vitamin E, compared to the oral is given by the safety as mild irritation and it has potential for multifunctional topical formulations. The purpose of the chapter is to review the topical use of formulations with vitamin E, addressing the development, safe use and evaluation of effectiveness.
- vitamin E
Vitamin E is the most well-known fat-soluble non-enzymatic antioxidant, mainly for its ability to inhibit the activity of pro-oxidant agents generated by reactive oxygen species (ROS). Vitamin E can eliminate free radicals induced by endogenous and/or exogenous agents such as ultraviolet radiation, drugs and pollution agents, avoiding their deleterious effects. The antioxidant activity of vitamin E is directly linked to its ability to inhibit the lipid peroxidation in unsaturated fatty acids, incorporating itself into cell membranes, which effectively inhibits lipid peroxidation [1, 2].
The antioxidant activity of vitamin E (alpha-tocopherol) has its property due to its ability to react mainly with the peroxyl radical (HOH•) and singlet oxygen (1O2), which favors lipid peroxidation. The free radical scavenging reaction occurs through the formation of a stable, low-energy radical, tocopheroxyl, which does not have the capacity to react with the free radical-forming agent . Alpha-tocopherol is the main agent capable of removing peroxyl radicals from lipid membranes, such as membranes or low-density lipoproteins (LDL) .
It is a classic dermatological ingredient used alone in its purified form, alpha-tocopherol or by its derivatives. However, the conversion to the purified (isolated) form is required in skin to obtain the desired effects. Topical applications are designed for treating melasma, protecting against ultraviolet radiation (UVR) and improving aging damages [5, 6], The association of vitamin E with other antioxidants increase the effects in skin .
Some studies suggest that a poor diet of vitamin E could be related with skin disorders. Oral supplementation of vitamin E is recommended in many skins’ therapies, such as: yellow nail syndrome, epidermolysis bullosa, cutaneous ulcers, pressure ulcers and burns, sub corneal pustular dermatosis, scleroderma, morphea, calcinosis cutis, Raynaud’s phenomenon, and inflammatory diseases. The oral supplementation of vitamin E could reduce the pigmentation in melasma and contact dermatitis lesions, too demonstrated remission of atopic dermatitis, prevention of sunburn reaction as well as the subsequent chronic skin damage . Vitamin E combined with other antioxidants has shown positive results topically in the photoprotection, as well as delay the growth of the melanoma by promoting the apoptosis of tumor cells and inhibiting VEGF-mediated angiogenesis. Other results with alpha-tocopherol: improvement in periorbital fine lines, roughness, radiance, skin tone, elasticity, density, collagen production and overall appearance by clinical evaluations of skin. Topical application of tocopherol acetate significantly reduces the severity of erythema, edema and skin sensitivity associated with sunburn by UVB . It is difficult to determine the
2. Topical products (cosmetics x medicines)
Skin products can be classified as medicines, cosmetics and cosmeceuticals, however, the teaching line between the categories is tenuous, being widely discussed by dermatologists, pharmacists and beauticians. Medicines and cosmetics are already widely discussed and accepted by world regulatory agencies; however, the term cosmeceutical is used as a marketing appeal and is not recognized as an official legal category. Skin products considered to be cosmetics are generally defined as products to clean, beautify, promote attractiveness, or change appearance, while medicines are intended for the diagnosis, cure, mitigation, treatment or prevention of diseases, which can affect the structure or any function of the skin. Regulatory agencies in different countries seek to organize the offer of products to ensure the safety for users.
Topical products that contain vitamin E can be classified as medicines or cosmetics, depending on their purpose. If the product is intended to lubricate the skin, it will be considered cosmetic and if it has therapeutic use as a healing agent, it will be a medicine. There are legal limits on the daily consumption of vitamin E as a supplement, however, for most international regulatory agencies, such as the NHS, FDA, Health Canada the limits for topical use are not described .
3. Types of vitamin E for topical applications
The antioxidant alpha-tocopherol acetate is the most common form of vitamin E in skin care products. In 2001, the Scientific Committee on Cosmetic and Non-Food Products for Consumers (SCCNFP) presented its opinion during the 18th Plenary Meeting. At the time, SCCNFP believed that alpha-tocopherol acetate did not pose a threat to consumer health and therefore did not propose any restrictions or use conditions .
The Cosmetic Ingredients Review Panel (CIR) in 2002 has assessed the safety of 14 tocopherols and tocotrienols and concluded that these ingredients are safe when used in cosmetics. The Panel further reviewed data from clinical and animal studies to determine the safety of tocopherols and tocotrienol ingredients and considered it appropriate to extrapolate existing information to conclude on the safety of all tocopherols and tocotrienols .
Since vitamin E can absorb ultraviolet light to produce free radicals, there is a possibility that strong exposure to sunlight after topical application may cause skin reactions. However, vitamin E concentrations between 0.1–1.0% are generally considered to be safe and effective for increasing vitamin E levels in the skin, but higher levels of α-tocopherol have been used with no apparent side effects . Vitamin E as alpha-tocopherol or tocopherol acetate is used in over-the-counter products in concentrations ranging from 1.0 to 5.0% [13, 14, 15].
Vitamin E is the main fat-soluble antioxidant in the body with biological activity and it is the collective name for the eight mains naturally occurring substances such four tocopherols and four tocotrienols. The eight analogues of vitamin E share similar chemical antioxidant activity, however, they are distinguished by their individual physico-chemical and biological effects at the molecular level in humans and higher animals. Alpha tocopherol is the most active, being considered an important asset in protecting cell membranes from lipid peroxidation promoted by free radicals [13, 14, 15].
Alpha-tocopherol is practically insoluble in water and this characteristic can difficult the development of topical products with high water content. In addition, this molecule is easily oxidized by atmospheric oxygen. Vitamin E acid acetate and succinate esters are applicable for clinical use due to their high oxidation stability but require the use of surfactants to improve the water solubility. Alpha-tocopherol is solubilized by large amounts of surfactants, but the hydrolysis of acetate is the limiting step in terms of its concentration during bioavailability .
The antioxidant properties of vitamin E are attributed to its free aromatic hydroxyl group; thus, the esters of vitamin E need to be hydrolyzed during absorption by the skin to exhibit this activity. In the biologically inactive esterified form, vitamin E acetate is more used because of its greater stability, acting as a prodrug, being hydrolyzed in active free vitamin E (alpha-tocopherol) after penetration into the skin. The bioconversion of vitamin E into the active form can be influenced by the technology involved in the development of formulations, by the target layer of the skin and exposure to ultraviolet rays. The stratum corneum seems to have less efficiency in the bioconversion of esters of vitamin E when compared to the nucleated epidermal layers. Thus, alpha-tocopherol should provide more efficient antioxidant protection for skin surface lipids and skin barrier constituents than vitamin E esters. However, in the nucleated epidermis the bioconversion of vitamin E acetate to active free form occurs at a much higher rate. In this sense, the choice of which vitamin E molecule to be used must consider the target layer of the skin and include product development strategies so that the activity of vitamin E is fully utilized [15, 16].
4. Vitamin E in skin damage
Vitamin E, more specifically alpha tocopherol, is considered one of the main fat-soluble and non-enzymatic antioxidant agents of natural origin, due to its advantages in terms of the protective activity against physical and chemical damage promoted by free radicals (FR). Vitamin E is an antioxidant capable of binding to the membrane in various tissues [17, 18]. Therefore, it is involved in several oxidative mechanisms in epidermis and dermis, catalyzed by ultraviolet radiation (UVR) and pollutants (Figure 1).
4.1 Oxidative stress: lipid peroxidation and free radicals’ formation
The first studies related to the damage caused by the formation of FR on the skin, promoting lipid peroxidation, date from the 1950s and 1960s. To avoid the damages, the use of natural and synthetic substances was suggested in order to prevent the formation of FR [19, 20].
Reactive oxygen species (ROS) such as superoxide (O2−•), hydroxyl radicals (OH•), peroxyl (HOH•) and singlet oxygen (1O2), can be formed by endogenous (physiological) processes such as inflammation, physical activity in excess, nutritional disorder, hereditary issues, neoplasms, and even, by processes related to exogenous sources such as UVR and pollution agents. In the skin, the main damage related to lipid peroxidation generated by FR from exogenous sources is the activation of melanogenesis and damage to collagen fibers [19, 21, 22].
The lipid peroxidation of the epidermis cells occurs through the action of the ROS, which has the ability to bind to the unsaturated bonds present in the polyunsaturated fatty acids of the cell membrane phospholipids [22, 23]. The process starts between polyunsaturated fatty acids (PUFA) and the oxygen radical, obtaining a lipid radical, which causes a rearrangement process in the presence of molecular oxygen, becoming a peroxy lipid radical. The lipid peroxyl radical is also capable of attacking unsaturated lipids, generating new radicals, such as the lipid radical as in the first stage of the reaction and the lipid hydro peroxide radical, thus promoting a cyclic reaction. Thus, it is necessary to use substances capable of interacting with cell membranes and to extinguish the free radicals formed, such as vitamin E [24, 25].
In a more detailed way, the mechanism involved in the lipid peroxidation process occurs through a chain reaction of the polyunsaturated fatty acids (PUFA) of biological membranes, which due to the large amount of unsaturation, become extremely susceptible to attack by free radicals. The process begins with the activity of the free radical like OH*, which extracts H from PUFA resulting in the radical PUFA*. After the molecular rearrangement of a conjugated diene, the molecule is susceptible to attack by O2, resulting in a peroxyl radical (PUFAOO*). PUFAOO* can extract H from the adjacent PUFA, thus propagating a chain reaction. Self-oxidation occurs continuously, which can seriously affect the functionality of the tissue .
The action of pollutants and UV radiation (UVR) on the skin has already been studied, but the mechanisms involved are still uncertain, knowing that the damage is initially related to the composition of the skin’s sebum and the quality of the stratum corneum, which may lead to the formation of wrinkles, hyperchromies (spots), wrinkles and accelerated extrinsic aging and dermatological diseases such as atopic dermatitis, related to lipid peroxidation [27, 28, 29].
The chronic and acute damage to the skin caused by UVR (UVB and UVA) are related to the direct absorption of rays and indirectly through photosensitization reactions. Mostly (> 95%), UVA radiation, more specifically UVAI (340–400 nm), has the major ability to penetrate the skin and it causes deeper damage. The aggression of UVA radiation targets collagen and supporting fibers, in addition to cellular DNA. The DNA damage is related to the mutagenic power of UVA radiation, which can act directly or indirectly through photosensitization reactions .
Studies prove the mutagenic power of UVA through direct oxidation reactions of DNA nucleic acids with ROS, which can lead to simple disruptions of the DNA strands or to disruptions in symmetrical positions in the two strands. Several studies (
As the UVR, polluting agents have harmful effects on the skin by increasing the oxidative stress and decreasing the physiological enzymatic and non-enzymatic antioxidant capacity. With the formation of FR and ROS, an interaction occurs with the lipid layer membrane, initiating the cascade reactions of lipid peroxidation and the release of pro-inflammatory mediators, which result in the accumulation of neutrophils and phagocytic cells, that also generate radicals free, thus promoting a cyclical reaction. Oxidative stress initiates a series of quite complex biological processes that result in DNA damage, activation of transcription factors such as activating protein 1 (AP1) and the nuclear factor Kappa-B (NF-KB) and even some pathways of signaling involved in cell growth and differentiation and degradation of dermal connective tissue. Pollutants are also capable of inducing functional changes in lipids, DNA, skin proteins, favoring the acceleration of skin aging, inflammatory processes and dermatological pathologies [33, 34].
4.2 Free radicals and the activation of melanogenesis
Melanogenesis can be considered as the first skin defense, being directly influenced by the skin phototype and, consequently, by the amount and type of melanin present. Melanocytes are particularly vulnerable to excessive oxidative stress from ROS due to their pro-oxidant state and the melanin synthesis involves oxidation reactions and generation of superoxide anion (O2−) and hydrogen peroxide (H2O2), promoting oxidative stress. The initiation of melanin synthesis occurs by a single route, with the conversion of tyrosine to dopa by the catalytic activity of the enzyme tyrosinase, releasing O2−, which also oxidizes dopa to dopaquinone with the release of O2−. From the obtaining of dopaquinin, a specific orthoquinone, capable of reacting with nucleophilic compounds, the synthesis follows two distinct pathways, eumelanogenesis and pheomelanogenesis, which respectively produce the darkest and lightest melanin monomers (red-yellow) [35, 36].
The homeostasis of human melanocytes in the epidermis is maintained mainly through a complex paracrine network, involving growth factors and cytokines synthesized by epidermal keratinocytes and dermal fibroblasts and modulated by UV radiation. Keratinocyte-derived endothelin-1 is a potent mitogen and a melanogenic factor capable of reducing H2O2 generation and apoptosis in human UV-irradiated melanocytes . The α-MSH melanocortin and adrenocorticotropic hormone (ACTH) are synthesized by keratinocytes and melanocytes and stimulate the synthesis of eumelanin, as well as the survival and proliferation of melanocytes by binding and activating the melanocortin 1 receptor (MC1R). The MC1R is a receptor located on the surface of melanocytes with the ability to bind to protein G. Studies show that the treatment of human melanocytes in culture with α-MSH, results in a decrease in the generation of H2O2, due to exposure to UV rays .
With the production of ROS, oxidative stress formed can interrupt melanocyte homeostasis, compromising their survival or even leading to malignant pathogens. Thus, the balance between the pro and antioxidant properties of melanin in the skin is mainly determined by the proportions of eumelanin and pheomelanin, the levels of melanin intermediates and the concentrations of reactive metals in the melanosome microenvironment. The generation of H2O2 in response to the action of UV radiation is inversely proportional to the constitutive pigmentation, suggesting a natural antioxidant effect of melanin [35, 38]. The inhibition of melanogenesis occurs in several stages, such as the inhibition of the enzyme tyrosinase that acts in several phases of the melanin production cascade, and also influences the post-transcriptional concentration of tyrosinase and other enzymes related to melanogenesis, such as tyrosinase-related protein 1 (TRP1) and DOPA chrome tautomerase (TRP2) .
4.3 Role of vitamin E in skin’s oxidative stress
The mechanism of action of vitamin E (Figure 2) regarding the antioxidant activity in the skin is directly related to the chemical mediation of the phenolic hydroxyl (OH) of its structure, capable of donating H to the peroxyl radical (PUFAOO*), resulting in the formation of a stable lipid species (PUFAOOH). Thus, when donating the hydroxyl H, vitamin E becomes a relatively non-reactive free radical, as the unpaired electron moves to the aromatic ring. Thus, with electronic displacement, incorporation occurs in biological membranes, being located awfully close to the polyunsaturated fatty acids of the cell membrane phospholipids, interrupting the chain reaction. Vitamin E stops the reaction by the ability to donate hydrogen from the OH group to the unsaturated lipid or to the lipid peroxyl radical (PUFOO *), forming the low-energy tocopheroxyl stable radical (VE-O *), which in turn does not present the ability to act as a free radical forming agent [40, 41]. Vitamin E also has antioxidant activity involving other lipid radicals, acting directly on the radical’s singlet oxygen and superoxide anion .
Studies have shown the activity of vitamin E in the modulation of damage caused by FR mediated by the action of UVR on the skin, such as lipid peroxidation, photoaging, immunosuppression and photocarcinogenesis . Vitamin E is able to reduce the inflammatory reactions of the skin, attenuating the production of prostaglandin involved in the process, pro-inflammatory cytokines, cyclooxygenase-2 (COX-2) and NADPH oxidase [43, 44, 45].
In addition to its anti-inflammatory capacity, vitamin E is also able to modulate the protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3-K) signaling pathways and to reduce the increase in collagenase expression. PKC modulation may be representative in terms of cell growth control, however, the interaction between vitamin E (alpha-tocopherol) and PKC protein does not occur directly, assuming that it occurs preventively to its action at the cellular level [45, 46].
Vitamin E has the ability to significantly suppress collagen degradation by inhibiting metalloprotein 1 (MMP-1), involved in the initial process of collagen hydrolysis . It can be identified in deeper layers of the skin, supposing its activity to minimize the photocarcinogenesis process, being considered as one of the main antioxidants of the human epidermis. Another characteristic of vitamin E is its use as an early and very sensitive marker for oxidative damage promoted by the environment [47, 48]. Thus, vitamin E prevents the lipoperoxidation of cell membranes and the degradation of fatty acids that are essential for the proper functioning of the body and skin [8, 49, 50].
Vitamin E can eliminate FR induced by UVA radiation, protect endogenous antioxidants from degrading processes, prevent lipid peroxidation and reduce immunosuppression caused by UVR. To increase protection against erythema and sunburn, the association of vitamins E and C is indicated, presenting potential against skin aging and skin cancer. Another activity of vitamin E on the skin is its application before sun exposure, avoiding the formation of the cyclobutane pyrimidine dimer (CPD) induced by UVB .
In general, exposure excessive to pollution and ultraviolet radiation promotes a greater production of free radicals, thus requiring an oral and/or topical supplementation of antioxidant substances, such as vitamin E, thus, the endogenous mechanism is not sufficient to prevent deleterious skin damage .
5. Topical treatments with vitamin E
After vitamin E depletion, oral intake is the best way to replenish the stock of this antioxidant in skin. In fact, oral supplementation brings cosmetic effects after 8–12 weeks. For alpha-tocopherol alone, a photoprotection effect by reduction of human skin malondialdehyde concentration was observed . The combination of vitamin E with other antioxidants is very beneficial for skin treatments. Alpha-tocopherol in combination with ascorbic acid increased UVB photoprotection in the human epidermis [53, 54]. The same combination showed a reduction in UV-induced inflammation . Good outcomes for treating chloasma were seen with the same mixture during double blinded clinical trials . When more antioxidants act together, strong outcomes are seen, such as reduction of UVB-induced wrinkle and increased collagen synthesis  and treatments of melasma [58, 59]. Despite the benefits to skin appearance, oral intake is not considered cosmetic treatment for its systemic effects.
Topical delivery also plays an important role in restock vitamin E. It is widely used in its purified forms or indirectly using vegetable seed oils . It is a classical ingredient in dermatology and still used in cosmetics worldwide in a recent growth tendency. Cosmetics containing vitamin E are most valuable in the USA, UK and France. The top cosmetic claims used in labels and the categories are in Figure 3 .
The lipophilic nature of vitamin E requires an oily or alcoholic phase at the topical formulation. In cosmetics, the main drivers capable of delivering this type of molecule are serums, tonics, oils and especially emulsions. For vitamin E alone, hydro-alcoholic solution of alpha-tocopherol showed a reduction of UV-induced erythema in the epidermis  and the reduction on the number of epidermal sunburn cells. While O/W and W/O emulsions containing alpha-tocopherol acetate increased skin hydration and water-binding capacity in the stratum corneum . Vitamin E is also used as coadjutant in other topical products to improve physical–chemical characteristics or to donate different effects. One of the most studied associations is with vitamin C, due its primary replenisher of vitamin E mechanism in skin. Vitamin C regenerates the oxidized form of vitamin E to its reduced form [64, 65]. A similar mechanism is expected using other antioxidants. Table 1 shows examples of associations of vitamin E and other molecules. The type of molecule and/or type of formulation is chosen depending on the target to address.
|Vitamin E||Combined molecule||Effect||Model||Reference|
|Alpha-tocopherol (1%)||L-ascorbic acid (15%)||Synergic protection against erythema and sunburn cell formation||Aqueous solution applied to pig skin|||
|Tocopheryl acetate (1%)||L-ascorbic acid (20%) + ||Improved the appearance of aging skin (Skin color, elasticity, radiance, smoothness, scaliness and wrinkles)||Commercial serum applied |||
|Tocopheryl acetate||Bioflavanoids from ||Protected the skin from UV damage by reduction on the number of sunburn cells||Emulsion containing 5% of the mixture |||
|Vitamin E||A good antibacterial activity against ||Dressing|||
|Vitamin E 5 IU||vitamin A (10 000 IU) + vitamin D (1000 IU) + vitamin B1 (50 mg) + vitamin B2 (12.7 mg) + vitamin B6 (15 mg) + vitamin C (500 mg) + nicotinamide (100 mg) + dexpanthenol (vitamin B5) (25 mg)||Reduction of age spots and melasma|||
|Vitamin E||Resveratrol + Baicalin||Improvement on the periorbital fine lines, roughness, radiance, skin tone, elasticity, density, and overall appearance|||
|Vitamin E||Photostable filters (octyl methoxycinnamate, avobenzone and 4-methylbenzilidene camphor) + vitamins A (1,700,000 UI/g) and C [2% (w/w) ascorbyl tetraisopalmitate]||The formulation with filters showed better stability comparing with the vitamins alone|
In mouse skin
|Vitamin E||Amniotic membrane mesenchymal stem cell||Decreased the diameter of lesions||In chronic leprosy|||
|Vitamin E||Ferulic acid + Vitamin C||Suggests preventing skin cancer||Topically solution in the skin of white Yorkshire pigs|||
|Vitamin E||Vitamin C||Prevention of inflammation due lipid peroxidation caused by |||
|Alpha-tocopherol||Ferulic acid||Inhibition of melanization||[75, 76]|
|Delta-tocopherol glucoside (0.05%)||Retinaldehyde (0.05%) + glycylglycine oleamide (0.1%)||Improvement on the elastin fiber production and a protection effect of the elastin and fibrillin fiber network against UV-induced alterations|||
The metabolization of derivatives into the active form of vitamin E (alpha-tocopherol) occurs at a far extend in the nucleated epidermis . Therefore, the conversion is highly dependent on the delivery system of cosmetic preparations into controlling skin permeation . To address this issue, several innovations on cosmetic formulations have appeared during the last decade.
The use of chemical permeation enhancers (e.g. alcohol, surfactants, terpenoids) is a good strategy to change stratum corneum polarity and fluidity. Likewise, the use of devices that create micron-scale pores in skin (e.g. iontophoresis, microneedles) is also available in clinics . The benefits of using those techniques is to maintain the original formulation. However, adaptations may be needed to maintain stability in the case of adding chemical agents. Another strategy is to change the formulation completely by using new delivery systems to encapsulate vitamin E.
Micro and nanoemulsions are strong candidates for its permeation capacity. Nevertheless, reduced sizes may have systemic effects, which is not allowed for cosmetics. Regulatory issues must be address in controlling the particle size. Vitamin E microemulsions (256 nm) reach dermis, however with the aid of surfactants . More recently, bigels are a viable cosmetic formulation. These biphasic systems formed by hydrogels and organogels show good spreadability and emollient and moisturizing effect, besides its transdermal capacity . However, bigels containing alpha-tocopherol showed no difference against regular emulsions for hyperpigmentation and inflammatory markers in in vivo tests . More tests are required to evaluate the benefits and safety of new cosmetic formulations.
6. Safety and efficacy of topical products with vitamin E
Many products in the cosmetic market have vitamin E in its composition. The definition of optimal dosage of vitamin E in cosmetics products depends on the derivative molecule and the type of formulation.
6.1 Safety of Vitamin E
Studies with animals to evaluate safety is common in many countries, especially in oral products. In animal experiments, 200 mg/kg was administered orally to frogs, rabbits, cats, dogs, and monkeys, with repeated application to mice over a period of 10–61 days. In food of rats, 4.000 mg/kg of Vitamin E was added and, in these experiments, was not mutagenic, teratogenic nor carcinogenic properties .
The toxicity of vitamin E is very low, because in clinical studies, a daily dosage of 100–300 mg of vitamin E was considered harmless, even when their use extends over a long period of time. Double-blind studies demonstrated that large oral doses of up to 3,200 USP-Units/day led to no consistent adverse effects. They mentioned that the optimal human plasma concentration of vitamin E is between 1.0 and 1.5 mg/dl .
Numerous genotoxicity studies were conducted with tocopherol, tocopheryl acetate, tocopheryl phosphate (MTP), and tocopheryl succinate. The only remarkable result was tocopheryl succinate with only a weak positive in a sister chromatid exchange assay in the presence of metabolic activation .
Tocopherol and tocopheryl acetate are generally recognized as safe food ingredients . According to Brigelius-Flohe et al. , vitamin E supplements for pregnancy usually contain only small doses of vitamin E, although adverse effects have not been observed at higher doses. The original report on tocopherols indicated that tocopheryl succinate, up to 75 mg/d in the diet did not have reproductive or developmental effects in rats. In relation to tocopheryl acetate, 1.6 g/kg/d, generally did not have any reproductive or developmental effects in rabbits, hamsters, rats, or mice . There is no published report documenting adverse fetal effects due to use of topical vitamin products. Topical application of vitamin E can rarely cause contact dermatitis, erythema multiforme, and xanthoma .
Vitamin E and its derivatives are widely used in many cosmetic and dermatologic products, in general, papers with side effects such as allergic or irritant skin reactions are rare. In clinical studies, tocopherol and tocopherol acetate were found to be safe for use in topical skin formulation since irritant or sensitizing reactions were found only in very small percentages . Tocopheryl acetate was not irritating to rabbit eyes in one study, but it produced weak-to-moderate conjunctival irritation in another study . Positive patch test results of alfa-tocopherol are rare and need to be critically reviewed. However, the derivative (alpha-tocopheryl linoleate), demonstrated allergic popular and follicular contact dermatitis in 1000 cases, reported in Switzerland by a line cosmetic in 1992. This compound was easily oxidized under the storage condition . According to Baumann and Spencer , 33% of the patients studied developed a contact dermatitis to the vitamin E. The ingredients considered safe to use in cosmetics were Ascorbyl tocopheryl acetate, Ascorbyl tocopheryl maleate, Dioleyl tocopheryl methylsilanol, Potassium ascorbyl tocopheryl phosphate, Sodium tocopheryl phosphate, Tocopherol, Tocophersolan, Tocopheryl acetate, Tocopheryl linoleate, Tocopheryl linoleate/oleate, Tocopheryl nicotinate, Tocopheryl phosphate, Tocopheryl succinate and Tocotrienols. remembering that the concentrations and conditions of use in the safety tests must be observed .
Tocopheryl acetate, 0.2 mL applied under an occlusive patch for 24 hours prior to irradiation, was not phototoxic in a study in 11 participants . According to ECHA , animal and clinical testing concluded that tocopheryl acetate was not photoallergenic or phototoxic. The dermal LD50 of tocopheryl acetate is >3 g/kg bw in albino rats. Five animals per group were dosed with 1 or 3 g/kg bw undiluted tocopheryl acetate in vegetable oil under an occlusive patch for 24 hours. Slight erythema was observed 24 to 48 hours after exposure. Slight abrasion was observed in one low dose female, two high-dose females, and two high-dose males . The acute dermal toxicity of mixed tocopheryl phosphates (MTPs) was determined in New Zeal and rabbits; the dermal LD50 was greater than 1,130 mg/kg bw MTP in female rabbits .
An aqueous gel containing 1,130 mg/kg bw MTP (918 mg/kg bw a-tocopherol equivalents) was applied to the clipped dorsal skin of 5 male and 5 female rabbits for 24 hours using surgical gauze. At 24 hours, slight-to-well-defined erythema was observed in 4 of 5 males and all females, and slight-to-moderate edema was observed in 2 of 5 males and all females. Signs of irritation were not observed at days 7 and 14 .
6.2 Efficacy of Vitamin E for topical formulations
According to Costa , vitamin E has a wetting action and in an
Topical application of tocopherol acetate significantly reduces the severity of erythema, edema and skin sensitivity associated with sunburn by UVB. Magnetic resonance images showed that there was no increase in skin thickness associated with edema. However, the cytotoxic effects of UV exposure as measured in Chinese hamster embryo cells can also be reversed by the presence of other antioxidants as well as a-tocopherol, ascorbic acid, butylated hydroxytoluene (BHT) and GSH. However, before exposure UV these components do not protect against cytotoxicity. In this study, it was observed that high dietary levels of vitamin E can restore the level of incorporation of thymidine dimers into DNA, in UV-exposed epidermal cells in relation to control non irradiated cells. The DNA was isolated and determined by the method of Gendominico Record et al. 1991 .
Gaspar and Campos , evaluated photoprotective formulations with a combination of photostable (octyl methoxycinnamate, benzophenone-3 and octocrylene or photoinstable filters (octyl methoxycinnamate, avobenzone and 4-methylbenzilidene camphor), both in addition to A, C and E. vitamins The combination of photostable filters showed a better response compared to the others. The filter components and vitamins were quantified by HPLC analysis and spectrophotometry. The formulation containing only vitamins, showed irritation and hairless in mouse skin, this was observed by histopathology.
Ferulic acid, by protecting vitamins C and E, can prevent UV-induced thymine dimer formation when applied topically to skin evaluated by fluorescence microscope coupled with a camera. Studies mentioned a presence of mutations in thymine dimer in keratoses and squamous cell carcinomas of skin, so this result requires that this combination can prevent skin cancer . The photoprotective actions demonstrated by the topical application of alpha-tocopherol in mice may not be restricted to the action of itself . It is likely that the dimers formed from UVB photo-oxidation of alpha-tocopherol, and perhaps the trimers as well, may themselves confer photoprotection, this was observed by similarities in the UV absorbance spectrum. Vitamin E slowed melanoma growth by promoting tumor cell apoptosis and inhibiting VEGF-mediated angiogenesis. The mechanism of the
6.3 Skin disorders
Some studies suggest that a poor diet of vitamin E could be related with skin disorders. Oral supplementation of vitamin E is recommended in therapy of yellow nail syndrome in a dosage of 1000 IU once a day for a period of 6 months; epidermolysis bullosa (300–600 IU/day); in cutaneous ulcers with treatment of pressure sores in doses of 800 IU/L gradually increasing to 1600 IU/L; in wound healing with zinc and vitamin C for pressure ulcers and burns; in subcorneal pustular dermatosis (d-alpha-tocopheryl acetate) 100 IU/day, gradually increasing to 400 IU/day for 4 weeks; in scleroderma, morphea, calcinosis cutis, and Raynaud’s phenomenon respond to vitamin E in a range from 200 to 1200 IU per day; in Hailey–Hailey disease with derivative of vitamin E
Vitamin E has been reported to be effective in inflammatory diseases with attenuation of pro-inflammatory cytokine TNF, evaluated by a section of skin mice by quantitative ELISA kit . In a combination of oral vitamins, A, C, and E with or not proanthocyanidin there was a significant reduction of pigmentation in melasma and pigmented contact dermatitis lesions in two randomized clinical double-bind study [5, 92]. Oral vitamin E (400 IE/day) for 8 months, improvement and near remission of atopic dermatitis and a 62% decrease in serum IgE levels . In oral combination with carotenoids (ß-carotene and lycopene), vitamins C and E, selenium and proanthocyanidins there was decreases the UV-induced expression of Metalloproteinases 1 and 9, that means prevention of sunburn reaction as well as subsequent chronic skin damage, evaluated by clinical trials .
In chronic leprosy a topical combination of vitamin E and with an amniotic membrane mesenchymal stem cell decreased the diameter of these lesions, evaluated by randomized controlled trial and monitored weekly . In a dressing based on the association of Vitamin E and
Studies show that there was an improvement in the healing of wounds in diabetic rats by topical vitamin E . According to Kuriyama et al. , some animal’s studies even suggest that topical vitamin E at a concentration of 20% suppressed allergic and irritant contact dermatitis, exerting a comparable effect to 0.5% prednisone ointment. Those skin conditions are generally self-reported as dry skin .
With the onset of xerosis, several inappropriate situations can arise, such as the release of inflammatory mediators, hyperproliferation of keratinocytes and interruption of epidermal differentiation, in addition to changes in lipid structure and enzymatic activity . Skin aging, specifically after age 65, presents several constitutional and functional changes in all layers of the skin, such as cellular senescence, decreased proliferative capacity, decreased ability to repair cellular DNA, abnormalities related to chromosomes, loss of telomeres, DNA extranuclear related mutations, oxidative stress and genetic mutations, promoting the formation of wrinkles, loss of elasticity and dryness of the skin [98, 99]. According to Rhie et al., 2001, the alpha-tocopherol concentration in the epidermis is negatively affected with aging and especially with photoaging, in this case the levels found are even lower when compared to young skin .
Over the years, the main histological changes occur with the basal cells, which suffer from dyscrasia, presenting an increase in volume and size, which can be accentuated by the action of UV radiation. As for the functionality of the basal cells, there is a decrease in mitotic activity and an increase in the cell cycle time and the cell migration time, which can promote changes in the outermost layer of the skin. The horny extract does not change its thickness, however, the replacement of lipids happens slowly, which significantly affects the function of barrier, protection and maintenance of natural hydration [101, 102].
Thus, the topical use of vitamin E is adequate for its recognized antioxidant and protective activities, favoring the improvement of the skin barrier due to its lipophilic character and also, effectively avoiding lipid peroxidation by protecting cell membranes from the action of free radicals . Gehring et al.  evaluated the hydration capacity of the stratum corneum by the use of vitamin E (5%) in water/oil and oil/water emulsions, demonstrating moisturizing activity in the stratum corneum, in addition to providing indications that indicate retention of water in the stratum corneum. Gonullu and collaborators  also report that the topical use of vitamin E for a period of two to four weeks can improve the ability of water to retain in the skin, favoring hydration.
While aging decreases keratinocyte proliferation, the abnormal hyperproliferation those cells are seen in psoriasis. Psoriasis is a chronic inflammatory process of the skin which affects 1–2% of the population and can affect the quality of life. It is most characterized by the presence of erythematous plaques with silvery scale on various regions of the body including the scalp, extensor regions of the extremities, and intertriginous areas of the skin [19, 105, 106]. Studies on the influence of vitamin E on psoriasis include oral and topical treatment evaluation of the vitamins combination, minerals, among others (vitamins A, C, D, E, B1, B2, B3, B5, B6, B12, magnesium, zinc, selenium, folic acid, copper, lysine and proline), that act on oxidative stress, energy metabolism, the immune system and optimized collagen formation. The consumption of olive oil, a vitamin E source, is also associated with improvement in psoriasis symptoms, acting positively in the suppression of serum levels of metalloproteinase-3 (MMP-3), protein of the cartilage olimeric matrix (COMP) as well as the levels of pro-inflammatory cytokines (TNF-α, IL-1β and IL-17) . Topical treatments include the application of products added with plant extracts containing vitamin E and other derivatives, the results are representative in relieving the symptoms of psoriasis induced in the mouse model, suppressing the levels of Interleukin-22 involved in extensive proliferation of keratinocytes and pathogenesis of psoriasis. The critical importance of the interleukin axis for the pathogenesis of psoriatic disease has resulted in new biological treatments targeting these cytokines, indicating that vitamin E is a component of interest in the treatment of psoriasis [106, 107, 108, 109].
Antioxidants consumed orally or topically may impact several organs in the body and among them, the skin. Systemic or centralized effects of these molecules can be modulated by the administration pathway and cellular machinery involved in their metabolization. When compared with other natural bioactive compounds, vitamin E has a specific mechanism of activation in skin due its lipophilicity. Alpha-tocopherol is the active molecule, but several derivatives are available in the market to address solubility, cost and pharmacotechnical necessities. The acetate and succinate esters exhibit better oxidation stability and are often associated with surfactants to improve water-solubility. The hydrolyzation of those molecules is mandatory to achieve biological effects and is mainly driven by enzymatic complexes in skin. The application of derivatives is an interesting alternative for slow delivery of this vitamin since the necessity of activation may lead to accumulation and a reservoir effect .
The natural lipophilicity of vitamin E impacts also its biological effects in skin. Vitamin E structure forms complexes with lipids in the cellular membrane and therefore acts promptly against the ROS formation due UV or pollution exposure . The reduction/blockage of oxidative stress’ cascade protects skin against several damages visible as wrinkles, melasma and cancer. Besides the lipid peroxidation, vitamin E has an important role in DNA integrity and epigenetic gene modulation . As a natural component of the healthy tissue, vitamin E is associated with impaired skin treatments, such as psoriasis, dry skin, atopic dermatitis and other skin disorders related to oxidative stress and inflammation .
The presence of vitamin E is expected in skin, which makes permeation experiments, bioavailability studies and quantification analysis more challenging. Raman confocal spectroscopy showed good sensibility to evaluate the health benefits and safety of vitamin E in human skin
The cosmetic market is always releasing innovative products despite vitamin E is considered a very classic dermatological active. New delivery systems focused on better absorption, deeper permeation or simpler hydrolysis are the R&D main targets. Since vitamin E is generally recognized as safe (GRASA) food ingredient and used in over-the-counter products with broader concentration range (1.0 to 5.0%), there is little regulatory concern about the exploration of this molecule in cosmetics and supplements. The focus of this chapter is topical applications and therefore, the oral toxicity data was not extensively covered. Safety assessment of alpha-tocopherol and its most used esters showed no phototoxicity, no genotoxicity and no ocular and dermal sensibilization . The use of vitamin E in topical applications is a safe, effective and well accepted worldwide, especially in association with other antioxidants.
Vitamin E, more specifically alpha-tocopherol, can be considered a substance with antioxidant activity with the ability to protect long-chain unsaturated fatty acids. It is also capable of playing an important role in a wide variety of physiological and biochemical functions, mediated by the antioxidant function or by its stabilizing effect on cell membranes, breaking down the peroxyl chain propagation reactions and eliminating the efficient lipid peroxyl radicals. Is has been used for decades and is still a very good a widespread ingredient for dermatological products and formulations, especially when associated with other antioxidants such as vitamin C. However, it is important to emphasize the need for more in-depth studies on the use of its derivatives and associations, regarding the conversion speed and the converted amount of vitamin E in skin. There are few studies related to the topical safety and efficacy of vitamin E in the literature, although it is widely used in cosmetics and dermatologic products. A low incidence of contact dermatitis has been reported. However, more studies would be needed for a conclusive answer regarding its topical safety. The definition of optimal dosage in cosmetics depends on the derivative molecule and the type of cosmetic formulation.