Clinics in Dermatology (2009) 27, 469–474

Cosmeceuticals vitamins
Mônica Manela-Azulay, MD, PhD a,⁎, Ediléia Bagatin, MD, PhD b
a
Department of Medical Clinics (Dermatology), Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
b
Department of Dermatology, Federal University of São Paulo, São Paulo, Brazil

Abstract The term cosmeceutical was created over 25 years ago to define products with active
substances that cannot be considered cosmetics or drugs. Cosmeceuticals are increasingly popular, with
sales representing one of the largest growing segments of the skin care market. These products are found
in many forms, including vitamins, peptides, growth factors, and botanical extracts. Cosmeceuticals that
contain topically applied vitamins have an increasing role in skin care.
© 2009 Elsevier Inc. All rights reserved.

Introduction stability, penetration, and retention within the skin. Although

The term cosmeceutical was created over 25 years ago by
Albert Kligman of the University of Pennsylvania to define
products with active substances that cannot be considered
cosmetics or drugs. A cosmeceutical is a logical evolutionary
concept, given the advances in skin anatomy and physiology.
Contemporary belief is that almost all compounds applied to
skin have the ability to penetrate and exert changes to skin
structure.1 Currently, cosmeceuticals are very popular, with
sales representing one of the largest growing segments of the
skin care market, especially for products that are designed to
help in the prevention and the treatment of aging skin.
The demand for products that reduce the cosmetic effects
of aging continues to grow because people wish to remain
looking youthful as long as possible. These products are
found in many presentations and are represented by vitamins,
peptides, growth factors, and botanical extracts.2 There are
still many controversial points about the drugs presented in
cosmeceutical products; among them, mechanisms of action,
optimal concentration, biologically active form, formulation
⁎ Corresponding author.
E-mail address: m.azulay@msm.com.br (M. Manela-Azulay).
tests are available to answer some of these questions, we can
speculate that at times there is little interest in such data,
given that cosmeceutical products are not regulated and are
usually well-accepted by consumers.3
For these reasons, dermatologists should be aware of
cosmeceutical products and have access to accurate scientific
theory with validated data—if any exists—to support
cosmeceutical claims. For some products, in vitro evidence
shows that these ingredients do have antiaging activity. The
question remains whether it is possible to deliver adequate
doses to the skin in vivo and to produce clinical or histologic
effects. It is important to evaluate these new products with a
critical and careful methodology, giving consideration to
intended product use and the design of available studies
supporting product use. Then, one can decide if the product
is useful as a main or adjuvant treatment for aging skin.2
Vitamins are essential compounds for many functions of
the human organism. Some vitamins can be synthesized, but
others need to be obtained by an adequate diet. The most
important are vitamins A, B, C, D, E, and K, as well as folic
acid. Scientific evidence shows that, in addition to their
specific functions, certain vitamins are useful for prevention,
as well as for topical and systemic treatment of photoaging
and chronologic skin aging. They are also effective in the

0738-081X/$ – see front matter © 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.clindermatol.2009.05.010
470
management of acne vulgaris. Various vitamins are used as
drugs or cosmeceutical products are also of great interest for
topical treatment.
It is postulated that molecular mechanisms of photoaging
are the same for chronologic skin aging, which also occurs in
all others organs.4 The difference is that skin is in direct
contact with the environment and undergoes the influence of
other factors, such as the cumulative effect of ultraviolet
(UV) A and B irradiation. Skin damage related to sun
exposure may accelerate its intrinsic aging process; there-
fore, photoaging represents the superposition of the biologic
effects of sun irradiation over the intrinsic aging that occurs.
Two important pathways are related to chronologic aging.
One is the progressive telomere shortening and finally its
disruption that is caused by low-grade oxidative damage.
This also affects other cellular structures and is a
consequence of aerobic cellular mitochondrial metabolism.5
Damage is initiated by the generation of reactive oxygen
species (ROS), also called free radicals. This reaction is an
inherent part of the cellular metabolism related to energy
production. Cells have enzyme processes that keep the
oxidative damage at a minimum; nevertheless, it is
progressive. Over time, the consequences are damage to
DNA, resulting in mutations, reduction in protein functions,
and peroxidation of membrane lipids affecting the transport
and transmembrane signaling.6
In skin, these mechanisms are accelerated by UV
irradiation that activates protein kinases, up-regulating
expression and activation of the nuclear transcription factor
AP-1, which then stimulates genes for matrix-degrading
enzymes such as matrix metalloproteinases 1, 3, and 9. These
matrix metalloproteinases degrade skin collagen and thereby
impair the structure of the dermis. The AP-1 also interferes
with types I and III collagen gene expression in human dermal
fibroblasts, down-regulating its synthesis. Elevated levels of
degraded type I collagen within the dermis, especially the
larger fragments, may also negatively regulate its synthesis.4
The knowledge of these mechanisms provides the basis
for the three most important approaches for prevention and
treatment of aging skin, mainly the photoaging process.
Although primarily an aesthetic problem, photoaging con-
stitutes the background for the development of precancerous
and cancerous skin lesions. Clinical and histologic evidence
indicates that certain structural changes induced by excessive
sun exposure can be reversed, to some extent, by an adequate
treatment regimen. The most important measure to prevent
photodamage lies in the daily and continuous use of
sunscreen that blocks both UVB and UVA.7 Another
approach is the potential effect of topical and systemic
antioxidants that enhance ROS neutralization.6 The last is the
use of compounds that help to repair DNA and collagen
damage, as well as stimulate collagen synthesis.
Topical vitamins, α-hydroxy acids, and growth factors
can provide some of these effects. The results are better when
these products are used before and maintained after the
execution of procedures available in cosmetic dermatology.
M. Manela-Azulay, E. Bagatin
There are substances with benefits documented with
sufficient scientific background, and many more that lack
such data.8 Many products are being introduced in daily skin
care antiaging cosmeceuticals or cosmetic products based on
hypothetical in vitro mechanisms of action, without
confirmation by controlled clinical trials.
It is accepted that cosmeceutical products must be as safe
as a cosmetic and should not act as a drug. They have
performance characteristics that suggest pharmaceutical
action, but they are registered (where necessary) and sold
as a cosmetic.8,9 The skin care industry is marketing a huge
number of new agents promising results that have not yet
been proven. In our opinion, this is one of the serious side
effects of these antiaging products: They sell the fantasy of
the eternal beauty, they have minimal or no effects, and
usually, they are very expensive.
On the other hand, the treatment of acne vulgaris with
topical vitamins, mainly vitamin A, is very well supported by
evidence. Vitamin A is more frequently used in pharmaceu-
tical than in cosmeceutical products. Vitamin B3, commonly
known as nicotinamide or niacinamide, is available in
cosmetic and cosmeceutical products and can be used as a
complementary agent for some types of acne, as well as
aging skin.
Acne is a multifactorial disease involving excessive
sebum production by the sebaceous glands related to an
increase in the androgen levels in the onset of puberty, ductal
hypercornification of the follicles, and proliferation of Pro-
pionibacterium acnes and other bacteria that activate the toll-
like receptors, resulting in attraction of lymphocytes,
neutrophils, and macrophages. Other factors are production
of proinflammatory cytokines such as interleukin (IL)-1, IL-
8, IL-12, and tumor necrosis factor-α. This is the base for the
inflammation and immune response, which is extremely
variable in different sites of the affected skin and individuals,
perhaps on an inherited basis. P acnes can also induce
follicular keratinocytes to release IL-1α, which causes
keratinocytes proliferation and contributes to the formation
of the preclinical lesion of acne, which is the microcomedo.
Activation of toll-like receptors may also be involved in the
scarring process by activating the metalloproteinases.10-12
The retinoids are vitamin A derivatives constituting the
most effective comedolytic agents. They function by
normalizing desquamation of the follicular epithelium,
preventing the formation of new microcomedo, and mini-
mizing the formation of comedones and inflammatory
lesions.10-12 Nicotinamide is useful as a complementary
drug because of its mild anti-inflammatory activity and its
possible action in the reduction of sebum production and
improvement of the skin barrier.13-15
Vitamin A
The human epidermis contains significant amounts of
vitamin A (all-trans-retinol), enzymes responsible for its
Cosmeceuticals vitamins
metabolism, binding proteins for its protection and transport,
and the nuclear receptors involved in the respective induced
gene activity modulation. Data have shown that this complex
system can be a direct target for UVB and UVA, as part of the
adaptive response to UV irradiation. This mechanism may
lead to a vitamin A deficiency in the skin.16
Vitamin A cannot be synthesized; it must be obtained
through dietary means. The ingestion of vitamin A depends
on the presence of retinoids (animal sources) and carotenoids
(vegetable sources) in the diet. In the body, a small
percentage of retinol is converted to its biologically active
form, all-trans retinoic acid (tretinoin), through an inter-
mediary, retinaldehyde. Most of retinol is converted to
retinyl ester, its storage form.
Topical retinoids have successfully been used to treat
acne for nearly 4 decades. Initially, a retinoid was a
compound of similar structure and action to retinol.
Variations of this molecule have resulted in three genera-
tions of topical and systemic retinoids: the nonaromatics
(retinol, tretinoin, and isotretinoin), the monoaromatics
(etretinate and acitretin), and the polyaromatics (arotinoid,
adapalene, and tazarotene).17
The efficacy of topical use of tretinoin in the treatment of
photoaged and intrinsically aged skin is sufficiently evidence
based. The effects are believed to be mediated through its
binding to the nuclear retinoid acid receptors (RARs), RAR
and RXR that exist as three distinct gene products: alpha,
beta, and gamma. It induces type I and type III procollagen
gene expression in human skin, resulting in increased
deposition of collagen fibrils in the dermis. It also reduces
collagen breakdown by inhibiting the metalloproteinases. An
overall thickening is observed in the epidermis, a compaction
of the stratum corneum, and deposition of a mucinous
material (glycosaminoglycans) in the stratum corneum and
intercellular spaces. The effects result in an improvement in
the clinical and histologic skin appearance. It is still the gold
standard topical treatment for this purpose.18-21 A few
benefits have been reported for two other topical retinoid
compounds, isotretinoin and tazarotene, but a lower level of
evidence is available.21
Tretinoin cream in the appropriated concentrations of
0.025%, 0.05%, and 0.1%, as well as 0.1% isotretinoin and
0.1% tazarotene, frequently produce a moderate to severe
skin irritation. Also, because they remain as prescription
drugs, there is an increased interest in achieving the same
effects with other retinoids (retinol, retinaldehyde, retinyl
propionate, and retinyl palmitate), permitted allowed as
components of cosmeceutical products.21,22 Retinaldehyde
(0.05%) is another useful topical agent for the treatment of
photoaged skin. It has a lower frequency of irritation but less
efficacy than tretinoin. Unfortunately, few clinical trials have
studied this interesting compound.23,24
There has been considerable confusion and doubt about
the benefits of retinol and retinyl cosmeceutical products
marketed as “antiaging” formulations. They have varying
low concentrations, and usually there are few clinical trials
471
demonstrating efficacy. It seems that the useful concentration
of topical retinol should range from 0.3% to 1%. Most of the
over-the-counter products available usually contain lower
levels of retinol (about 0.08% or less), compared with the
concentration used in the few clinical studies available.2,25
These forms are not biologically active until enzymatic
conversion to the active metabolite, retinoic acid, occurs in
vivo. It has not been proven yet, if the skin has adequate
levels of these enzymes to make a clinical difference. Most of
the studies are in vitro and do not explain these aspects.
Retinal is speculated to be 20-fold less effective than
tretinoin, and the cutaneous concentration of tretinoin is
1000-fold less with topically applied retinol than with the
proper drug. A small quantity of retinol appears to be
converted into tretinoin in human skin.25 It is possible that a
much higher concentration would be required, increasing
risk of irritation that could be similar to what is observed with
the use of tretinoin and other retinoids.22
Another problem with retinol compounds is that they are
easily degraded by oxygen and light exposure. A new
synthesized retinol derivative with higher photostability,
named retinyl N-formyl aspartamate, was described as
effective in a recent very small, uncontrolled study.26
For treating acne, topical retinoids are useful in all cases,
because they interfere with the precursor lesion, the
microcomedo. They can reverse the abnormal desquamation
process, and in addition, they have anti-inflammatory
properties, including suppression of toll-like receptor
expression. The main retinoids used in treatment of acne
are pharmaceutical products. Most of the studies are related
to tretinoin in older formulations as well as in newer vehicles
that provide less irritation. Other studies have investigated
isotretinoin, adapalene, and tazarotene. 12 Only in vitro
studies have addressed the comedolytic and antibacterial
effects of retinaldehyde.27,28 Retinol or retinyl cosmeceu-
ticals are not indicated in the treatment of acne. Current
research on receptor selectivity holds the promise of the
development of new retinoid molecules with improved
benefits and safety.29,30
Vitamin E
Vitamin E, like vitamin A, is present in mammalian skin.
The probable physiologic function of epidermal vitamin E is
to contribute to the antioxidant defense of the skin. Owing to
its physical properties, vitamin E absorbs UV light in the solar
spectrum region that is responsible for most of the deleterious
biologic effects of the sun.31 Although human skin possesses
various intrinsic defense systems that help to minimize the
oxidative damage, excessive and long-term exposure to free
radicals can deplete the body's own endogenous antioxidants,
with the consequence of disruption of normal biomolecules
such as lipids, proteins, and nucleic acids.22
The available literature concerning the efficacy of
systemic and topical antioxidant substances such as
472
carotenoids and vitamins, specifically C and E, is very
extensive, but the results are often contradictory. Positive as
well as strongly negative results have been reported by
different investigators. Skin treatment with these topical
products for cosmetic purposes in these studies resulted in a
range of observations from improvement in appearance to no
effect at all. Almost no adverse reactions have been reported
in most studies. 32
Vitamin E is the body's major lipid-soluble antioxidant
represented, by 8 molecular forms, 4 tocopherols, and 4
tocotrienols. Alpha-tocopherol is the most active and is
important in protecting cellular membranes from lipid
peroxidation by free radicals. Once oxidized, vitamin E
can be regenerated back to its reduced form by vitamin C or
L-ascorbic acid. Vitamin E is available in dietary sources, and
its concentration is highest at the lower levels of the stratum
corneum, where it is released by sebum. Vitamin E as alpha-
tocopherol or tocopherol acetate is used in topical over-the-
counter products in concentrations ranging from 1% to 5%.
In vitro studies have demonstrated the effects of alpha-
tocopherol in reducing minimal erythema dose and the
number of epidermal sunburn cells, which are markers of
skin damage related to oxidative stress caused by UVB.5
Some human studies, however, have showed no evidence of
conversion of tocopherol acetate or succinate to the
biologically active form, alpha-tocopherol, despite its
adequate absorption by the skin. Further, the metabolism of
tocopherol acetate was highly dependent on the delivery
system, emphasizing the importance of formulation of
cosmetic preparations.22
Vitamin E can reduce UV-induced erythema and edema
when it is applied before UV exposure. Use of vitamin E after
sun exposure seems to have no benefit.31 Topical application
of vitamin E may increase stratum corneum hydration and
enhance water-binding capacity. Alpha-tocopherol also acts
synergistically with vitamins A (retinol) and C (ascorbic
acid) in combined products, providing an appreciable
photoprotection and antioxidant action that suggests a
potential effect in the protection against photoaging and
skin cancer.33,34
A recent study35 analyzed an interesting new formulation
with the association of vitamin E (tocopheryl acetate),
vitamin A (retinyl palmitate), vitamin C (ascorbyl tetra-
isopalmitate), and bioflavonoids from Ginkgo biloba. The
authors presented it as a “biological filter” against UV
damage. They demonstrated that this formulation possesses a
higher in vitro antioxidant activity, due to its free radical
scavenging properties (almost 100% of inhibition of free
radical production) compared with the separate use of the
components. When they tested it in vivo, using hairless mice
skin, the photoprotective effect (reduction in UV-induced
erythema) was not observed. The authors concluded that this
result was possibly related to the formulation vehicle, which
influences the cutaneous penetration, as well as to the
concentration of vitamins. They further hypothesized that
these substances together may act on the epidermis by
M. Manela-Azulay, E. Bagatin
different mechanisms and can be a promising new concept in
antiaging and photoprotection cosmeceuticals.
These combinations are very unstable, and it is
important to achieve an ideal way to avoid chemical
instability. One recent published proposal was the incor-
poration of ferulic acid into a solution of 15% ascorbic acid
and 1% alpha-tocopherol, which doubles the photoprotec-
tive effect of the formulation.36
Although topical application of vitamin E demonstrates
promising photoprotective effects, specifically when it is
combined with other antioxidants, controlled studies in
humans are needed before it can be recommended as an
effective cosmeceutical agent for the treatment of both
intrinsic and extrinsic aging.2,31
Vitamin B3 (niacinamide or nicotinamide)
Vitamin B3, or nicotinamide or niacinamide, is a
derivative of niacin obtained through diet from meat, fish,
milk, egg, and nuts. Its deficiency is one of the causing
factors of pellagra. Niacin has been used in medicine, most
commonly to lower cholesterol. Nicotinamide is part of the
coenzymes nicotinamide adenine dinucleotide (NAD), NAD
phosphate (NADP), and its reduced forms are NADH and
NADPH. These molecules are important in many cellular
metabolic enzyme reactions.2,22 The reduced forms may act
as antioxidants.
Nicotinamide is one of the newest vitamin-based
components of cosmeceutical products. Most of the studies
available have focused on its anti-inflammatory and antiacne
actions.13 It is also believed that its anti-inflammatory effect
may improve skin appearance by reducing leucocyte
peroxidase systems that may lead to localized tissue damage
as well as by ameliorating the cutaneous barrier.12 In a
comparative study, the anti-inflammatory effect of 4%
nicotinamide gel in the management of acne vulgaris was
as good as the benefits of 1% clindamycin gel.37 This anti-
inflammatory effect is also useful to reduce cutaneous
erythema in various disordes.15
The possible utility of topical nicotinamide in the
improvement of skin appearance may be related to its action
in the synthesis of sphingolipids, free fatty acids, cholesterol,
and ceramides, thus decreasing transepidermal water
loss.12,38,39 The improvement of facial dyspigmentation is
also likely mediated by the suppression of melanosome
transfer from melanocytes to keratinocytes.40 Nicotinamide
increases collagen production in fibroblast culture, and this
effect may be responsible for the improvement of skin
elasticity and reduction of fine wrinkles.15 All of these
effects may help to reverse some of the aging skin signs, and
for this purpose, it has been used in cosmeceutical products
in concentrations ranging from 3.5% to 5%.15,41
Because it is nonirritating to facial skin, easily formulated,
chemically stable, and compatible with other formulation
components, niacinamide has been considered an ideal
Cosmeceuticals vitamins
cosmeceutical agent; nevertheless, it is from one-third to
one-fifth as effective as topical 0.025% tretinoin.15 There is
certainly opportunity and interest to optimize use of this
agent to achieve a higher performance.
Vitamin C
Vitamin C, or L-ascorbic acid, is the most plentiful
antioxidant in human skin. Most animals and plants have the
capacity to synthesize vitamin C. Humans are an exception,
because we have lost the ability to produce L-gulono-
gamma-lactone-oxidase, the enzyme necessary for its
production.42 Vitamin C must be obtained from dietary
sources. Even with massive oral supplementation, the
increase of vitamin C in skin concentration is limited.43
Topical application of L-ascorbic acid is the only way to
further increase skin concentration, and therefore, vitamin C
has become a popular topically applied cosmeceutical.
Much of the recent research on vitamin C has focused on
its role as a free radical scavenger. Vitamin C is water-soluble
and functions in the aqueous compartment of the cell by
donating electrons, neutralizing free radicals, and protecting
intracellular structures from oxidative stress.44 L-ascorbic
acid is essential for collagen biosynthesis. It serves as a
cofactor for prolyl and lysyl hydroxylases, enzymes that
hydroxylate proline and lysine in collagen, stabilizing its
triple helical structure. Recent studies have demonstrated that
vitamin C also influences collagen synthesis independently
of hydroxylation by activating its transcription and stabiliz-
ing procollagen messenger ribonucleic acid.45 Ascorbate
also inhibits elastin biosynthesis, further supporting treat-
ment of photoaged skin.46
The first cosmeceutical creams used vitamin C in its
active form, L-ascorbic acid. Early formulations of L-ascor-
bic acid were very unstable due to the oxidation of the
vitamin exposed to air. For this reason, esterified
derivatives of L-ascorbic acid in topical formulations have
been used to improve stability. The most common
derivatives are magnesium ascorbyl phosphate and ascor-
byl-6-palmitate.46 Magnesium ascorbyl phosphate demon-
strated a skin-lightening effect in an open study. Studies
with ascorbyl-6-palmitate in hairless mice revealed percu-
taneous absorption but little effectiveness in an UVB
photoaging model.47 In contrast, other studies48 suggest
that delivery of L-ascorbic acid into skin depends on
removing the ionic charge on the molecule. This is
achieved at a pH of less than 3.5 The maximal concen-
tration of the L-ascorbic acid for percutaneous acid was
20%. Higher levels failed to increase absorption.48
Daily application of a 15% solution of L-ascorbic acid
increased ascorbic acid levels 20-fold and tissue levels of the
vitamin were saturated after 3 days.48 Ascorbyl-6-palmitate
is a free radical scavenger and has some advantages over
L-ascorbic acid.49 Despite these discussions, all the research-
ers agree that topically applied vitamin C has many benefits,
473
such as promoting collagen synthesis, lightening hyperpig-
mentation, and anti-inflammatory and photoprotective prop-
erties.6,48,49 data confirming these benefits and its diverse
biologic activity in the skin makes topical vitamin C a
valuable and useful agent for the dermatologist practice.
Conclusions
Cosmeceuticals containing topically applied vitamins
have an increasing place in the dermatologist's armamentar-
ium. The growing demand for combating the signs of aging
has had a profound effect in society. In the dermatologist's
practice, requests have grown considerably for aesthetic
medical treatments, such as chemical peelings, botulinum
toxin, laser, and soft tissue augmentation. The first step to
initiate an aesthetic treatment, no matter the choice, is to
prepare and recommend a daily skin care regimen.
Dermatologists have a responsibility to help achieve a
healthy appearance of their patient's skin through proper skin
care guidance. It is important for us to understand the science
behind cosmeceuticals as they are increasingly being
incorporated into the skin by daily use of skin care products.
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