Cosmeceuticals 1

CHAPTER 1
COSMECEUTICALS
Y. Madhusudan Rao1, Y. Shravan Kumar2, D. Sathish1
1
Center for Biopharmaceutics and Pharmacokinetics, University College of Pharmaceutical
Sciences, Kakatiya University, Warangal-506 009, Andhra Pradesh, India.
2
Vaagdevi College of Pharmacy, Ramnagar, Hanamkonda, Andhra Pradesh, India.

1.1 History and Background
Cosmeceuticals have become the fastest-growing segment of the personal
care industry. About 25 years ago Dr. Albert Kligman of the University
of Pennsylvania originally coined the term ‘cosmeceutical’, describing a
hybrid category of products found on the spectrum between drugs and
cosmetics that exert a pharmaceutical therapeutic benefit but not
necessarily a biological therapeutic benefit.1
The difference between a drug and a cosmeceutical is that the former
is defined by having a biological effect on living tissue. Another
important distinction is that cosmeceuticals are not regulated by the U.S.
Food and Drug Administration (FDA) and, thus, are not subject to
premarket requirements for proof of safety or efficacy. Cosmeceutical
products often are tested through in vitro studies using silicone replicas of
skin and, at best, clinical trials are small, open-label studies usually
supported by the cosmetic companies themselves. The rigorous testing
required for pharmaceuticals is not mandatory for cosmeceutical
products.2
There are approximately 400 cosmeceutical manufacturers, including
companies that supply the cosmeceutical chemicals and/or manufacture
the products in the U.S. market. The largest companies in the industry for

1
2 Cosmeceuticals

finished products are Procter & Gamble, Johnson & Johnson, L’Oréal,
Estée Lauder, Avon and Allergan, which together represent nearly one-
half of the U.S. market.

1.1.1 Skin Protection
The efficacy of a cosmetic product depends not only on the active
ingredients but also on the delivery system to improve its efficacy. We
have to remember that skin is more than an assembly of several layers of
cells as corneocytes, keratinocytes, fibroblasts and complementing each
other. Chemical products, pollution, stress, irradiation from infrared (IR)
and ultraviolet (UV) sources, and abrasion are involved in skin aging.
The consequences can be visible or invisible: inflammation, burns, edema,
long-term illness, actinic damage, and premature aging. The aging of the
skin manifests itself in many ways: drying out, loss of elasticity and
texture, thinning, damaged barrier function, appearance of spots,
modification of surface line isotropy, and finally, wrinkles.
Most of the cosmeceuticals have been developed with claims of
antiwrinkle and firming, moisturizing and lifting, skin toning and
whitening activity; the antiaging category of skin care products shows
presently the highest growth rates.

1.2 Regulations
In India, a well defined Drugs and Cosmetics Act (1940) operates the
regulations of cosmetics under the authority of Central Drugs Standard
Control Organization (CDSCO). For the manufacture of cosmetics for
sale or distribution the manufacturer should build the factory premises
according to the Schedule M-II. Rapid growth of Pharmaceutical Industry
has revamped and modernized the regulatory set-up of the country. Many
areas including the production and distribution of healthcare products are
brought under the same ambit of regulatory framework.
Bioproducts, food additives and medical devices are all been regulated by
regulating committee. Conducive environment in India also encourages
substantial growth in all departments. With the introduction of Patent Act
2005, many new manufacturers are able to patent their products and
market them effectively. The new regulatory guidelines have facilitated
Research and Development activities to ensure the standard and quality
of new drugs. It has also given an opportunity for the new players to
invest in the emerging market of drugs and cosmetics manufacturing.
Market friendly changes in the policies have also boosted up the market
of Pharmaceutical Industry.
Cosmeceuticals 3

According to Drugs and Cosmetics Act (1940), “cosmetic” means any
article intended to be rubbed, poured, sprinkled or sprayed on, or
introduced into, or otherwise applied to, the human body or any part
thereof for cleansing, beautifying, promoting attractiveness, or altering
the appearance, and includes any article intended for use as a component
of cosmetic.
In 1938, the U.S. Congress enacted a statue that officially defined
cosmetics and drugs in detailed terms, setting up formal criteria for
classifying a product as either a drug or a cosmetic. No intermediate
category exists, although it was appreciated that a topical could be both a
cosmetic and a drug at the same time. This remains the law to this very
day. It defined a cosmetic, in pertinent part, as an ‘‘article intended for
beautifying and promoting attractiveness.’’ In contrast, a drug was
defined as a substance for use in the diagnosis, cure, treatment, or
prevention of disease, intended to affect the structure and function of the
body. This last clause legally determines whether a formulation is a drug
or a cosmetic. Most skin care products lie somewhere in between drugs
and cosmetics.
They comprise a continuous spectrum of substances intermediate
between the two polar categories defined by Congress. Some traditional
cosmetics are more drugs like in their beneficial effects and some drugs
impact principally on appearance. It is this intermediate, broad-spectrum
range of substances that consists of both drugs and cosmetics which
justifies the fusion term cosmeceuticals. This is simply a biological
concept that recognizes the new realities of skin care products.3
Cosmeceutical is a pragmatic term that enables us to state without
pretense the benefits of a product. It is not an invitation to pass new laws.
There are three main trading blocks, the United States, Europe, and Japan.
Obviously globalization as an integrated free-trade network cannot work
if each block classifies and regulates skin care products differently.
Unfortunately, no international consensus currently exists, inevitably
sparking disputes and trade practices that may place some producers at a
grave disadvantage. The situation is more complex and far more
demanding in Europe. This is made obvious in the European Economic
Cosmetic (EEC) Directive of 1993. The requirements for labeling
cosmetics are formidable and daunting.4 The product information that
must be made available to officials encompasses the following:
qualitative and quantitative composition of the product: specifications of
raw materials; methods of manufacture; safety assessments; and proof of
effectiveness.
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In the United States, manufacturers are not required to demonstrate
either safety or efficacy prior to marketing, as is the case for drugs. On
top of all this, the EEC has prohibited testing on animals after January
1998. Japanese authorities have created their own laws in response to the
problem that many skin care products are neither pure drugs nor pure
cosmetics in the traditional sense, but mixtures of the two. The category
we call cosmeceuticals they call ‘quasi drugs.’ They allow cosmetics to
include pharmacologically active ingredients, provided that the medicinal
effects are mild and the products have been demonstrated to be safe. The
legal wording leaves a lot of room for ambiguities and ad hoc
interpretations that some perceive as a trade restraint.
In the United States, the following agents are regulated as drugs while
in Europe (according to the European commission on cosmetics) they are
sold as cosmetics.
1. Antiperspirants
2. Antidandruff shampoos
3. Sunscreens
This classification is detrimental to industry in the United States,
especially in the case of sunscreens, which are more advanced and more
effective in Europe because there is greater choice of ingredients.
Paradoxes also abound in the United States. For example, retinol (vitamin
A) can be sold as a cosmetic, but its oxidation product, retinoic acid, is
regulated as a drug. However, the product is still only available by
prescription. On the other hand, minoxidil, a drug that purports to grow
hair and improve attractiveness, satisfies the basic definition of a
cosmetic and is available without a prescription. New insights about the
function of the skin, as well as the development of new products for skin
care, make it necessary to question or redefine the definitions of
cosmetics and drugs. Moreover, in the United States, Europe, and Japan,
different definitions of cosmetics are used. The definition of a drug is
more or less equivocal on these countries.
According to the Food, Drug and Cosmetic (FDC) Act, a drug is
defined as an article intended for use in the diagnosis, mitigation,
treatment, or prevention of disease or intended to affect the structure or
any function of the body. In the United States, according to the FDC act
of 1938, a cosmetic is defined as an article intended to be rubbed, poured,
sprinkled, or sprayed on, introduced into, or otherwise applied to the
human body or any part thereof for cleansing, beautifying, promoting
attractiveness, or altering the appearance without affecting structure or
function.6 It is noteworthy that in this definition the cosmetic is not
Cosmeceuticals 5

allowed to have any activity (i.e., without affecting structure or function).
In Europe, the definition of a cosmetic was re-evaluated and described by
the council directive 93/35/EEC of June 14th, 1993.7 The cosmetics
directive contains 15 articles. The definition of a cosmetic is described in
article 1 and is as follows:
A ‘cosmetic product’ shall mean any substance or preparation
intended to be placed in contact with the various external parts of the
human body epidermis, hair system, nails, lips and external genital organs
or with the teeth and the mucous membranes of the oral cavity with a
view exclusively or mainly to cleaning them, perfuming them, changing
their appearance and/or correcting body odours and/or protecting them or
keeping them in good condition.
According to the pharmaceutical affairs law, the Japanese definition of
a cosmetic is as follows:
The term cosmetic means any article intended to be used by means of
rubbing, sprinkling or by similar application to the human body for
cleansing, beautifying, promoting attractiveness and altering appearance
of the human body, and for keeping the skin and hair healthy, provided
that the action of the article on the human body is mild.
The Japanese definition is only slightly different from the definition of
a cosmetic within Europe. Both definitions allow a cosmetic to have mild
activity and possess pharmaceutical activity. This is in sharp contrast to
the definition of a cosmetic in the United States. The introduction of the
term ‘‘cosmeceutical’’ enables to classify more precisely a product with
an activity that is intended to treat or prevent a (mild) skin (abnormality).
In order to avoid introducing new definition criteria, cosmeceuticals are
only regarded as a subclass within the domain of a cosmetic or drug. In
Europe and Japan, cosmeceuticals can be regarded as a subclass of
cosmetics; however, in the United States cosmeceuticals can only be
regarded as a subclass of drugs. Cosmeceuticals could be characterized as
follows:
1. The product has pharmaceutical activity and can be used on normal
or near-normal skin.
2. The product should have a defined benefit for minor skin disorders
(cosmetic indication).
3. As the skin disorder is mild the product should have a very low-risk
profile (see Table 1.1).
6 Cosmeceuticals

Table 1.1 Cosmeceuticals as a Subclass of Cosmetics (Europe and Japan)
and as a Subclass of Drugs (U.S.).
Cosmetic Cosmeceutical Drug
Pharmaceutical activity + + +
Intended effect in skin disease – + +
Intended effect in mild skin disorder – + +
Side effects – + +
The procedure for registration of a cosmeceutical should not be as
cumbersome as for drugs. The intended activity of the cosmeceutical for
treatment of a minor skin disorder should be demonstrated by clinical
studies within the framework of good clinical practice. Moreover, it
should be shown that safety requirements are optimal and that no side
effects can be expected.8 The safety evaluation is mandatory for
cosmetics in Europe, according to articles 2, 12, and 13. In the United
States, this would mean that a subclass of drugs (cosmeceuticals) are
registered in a similar manner as over-the-counter products.9 It would be
beneficial if these countries could agree on the definitions of cosmetics
and drugs and, in so doing, define cosmeceuticals as a subclass of
cosmetics. This would prevent the current situation in which certain
products are registered as drugs in the United States (sunscreens) and as
cosmetics or cosmeceuticals in Europe and Japan. Clearly cosmeceuticals
are the fastest growing segment of the skin care market and are currently
the driving force in the field of skin care research.
Table 1.2 Summary of cosmetic regulations- USA, EU and INDIA10.
CONTENTS USA EU INDIA
Authority FDA EMEA CDSCO
Rules and Food Drug and Council Directive Drugs and Cosmetic
regulations Cosmetic Act 76/768/EEC Act
Pre-market Not required Not required by Required under state
approval Cosmetic Directive govt. licensing
Labelling Should comply Based on Council Should comply with
with the FD&C Directive part XV of the D&C
and FP&L 76/768/EEC rules 1945
Expiry date No date required Date of minimum Indicated as ‘use
durability if before date’
durability is <30
months. Period after
opening if durability
is >30 months
Post marketing Yes (voluntary N/A N/A
reporting cosmetic
system registration
programme)
Cosmeceuticals 7

Table 1.3 Regulations specifically prohibit or restrict the use of the following
ingredients in cosmetics11.
Ingredient Activity
Bithionol Because it may cause photo-contact
sensitization.
Halogenated salicylanilides (di-, Because they may cause photocontact
tri-, metabromsalan, and sensitization.
tetrachlorosalicylanilide)
Chloroform Because of its animal carcinogenicity and
likely hazard to human health.
Vinyl chloride As an ingredient of aerosol products,
because of its carcinogenicity
Zirconium-containing complexes In aerosol cosmetic products, because of
their toxic effect on lungs, including the
formation of granulomas.
Methylene chloride Because of its animal carcinogenicity and
likely hazard to human health.
Chlorofluorocarbon propellants The use of chlorofluorocarbon propellants
(fully halogenated chlorofluoroalkanes) in
cosmetic aerosol products intended for
domestic consumption is prohibited.

1.3 Types of Cosmeceuticals
Based on their function cosmeceuticals are classified as follows-
 Skin-whitening and/or depigmenting cosmeceuticals
 Moisturizing cosmeceuticals
 Antiwrinkle cosmeceuticals
 Sunscreen cosmeceuticals
 Antiphotoaging cosmeceuticals
Based on various products presently on the market, cosmeceuticals
can be divided into the following broad categories:
 Antioxidants
 Growth factors
 Peptides
 Metals
 Anti-inflammatories/botanicals,
 Polysaccharides
 Pigmentlightening agents.
8 Cosmeceuticals

1.3.1 Antioxidants12
Oxidative stressors create inflammatory molecules that lead to the
formation of free radicals species. These free radicals are highly reactive
molecules with unpaired electrons, and they can cause cellular damage to
cell membranes, lipids, proteins, and DNA. Damage to DNA eventually
results in collagen breakdown. Free radicals also play a role in 3
additional detrimental processes: inflammation, photodamage, and
carcinogenesis. Antioxidants neutralize damaging free radicals by
quenching reactive molecules and, thus, protecting cells from both
endogenous stress (by-products of cellular energy) and exogenous
stressors (ultraviolet light, pollution, cigarette smoke).
Antioxidants comprised a group of diverse molecules including, but
not limited to, vitamins (A, B, C, and E), alpha lipoic acid (ALA),
Coenzyme Q-10 (CoQ-10), idebenone, polyphenols, and kinetin. They
vary in their abilities to protect against inflammation, photodamage, and
carcinogenesis.

1.3.1.1 Vitamin A
Forms
Several forms of vitamin A are used cosmetically, in particular retinol,
retinyl esters (e.g., the acetate, propionate, and palmitate esters of retinol),
and retinaldehyde. Through endogenous enzymatic reactions, these are all
ultimately converted to trans-retinoic acid, which is the functional form
of vitamin A in skin.
Mechanisms
Interaction of trans-retinoic acid with nuclear receptor proteins leads to
interaction with specific DNA sequences to affect transcription, resulting
in either increased or decreased expression of specific proteins/enzymes.
Among the many gene expression changes induced by retinoids, some
specific ones that are likely relevant to skin antiaging effects are those
leading to thicker skin, which likely contributes to diminish fine lines and
wrinkle appearance, for example, increased epidermal proliferation and
differentiation (epidermal thickness increase), increased production of
epidermal ground substance (glycosaminoglycans [GAG] that bind water,
thus increasing epidermal hydration and thickness), and increased
production of extracellular dermal matrix components such as collagen
(dermal thickness increase). In addition to stimulatory effects, retinoids
also have inhibitory effects. For example, retinoids are reported to reduce
production of collagenase and inhibit production of excess ground
Cosmeceuticals 9

substance in photoaged dermis, an important mechanism because
reduction in excess GAG is associated with reduced skin wrinkling.
Retinoids also reduce expression of tyrosinase, a key enzyme in the
conversion of tyrosine to melanin. Because the epidermal effects of a
topical retinoid such as trans-retinoic acid (e.g., epidermal thickening)
occur within days after initiation of treatment, skin effects such fine line
reduction can begin to appear quickly. In general, retinoids are very
potent, so topical doses of less than 1% are typically sufficient to obtain
significant effects.
Working with retinoids presents two substantial challenges. The first
is their tendency to induce skin irritation. Choice of retinoid can reduce
this issue. Retinol is better tolerated by skin than trans-retinoic acid, 2-
retinaldehyde has irritation potential similar to retinol and retinol esters
are better tolerated than retinol. The second key concern is instability,
especially in the presence of oxygen and light. To increase retinoid
stability in finished product, formulation and packaging should ideally be
done in an environment with minimal exposure to oxygen and light.

1.3.1.2 Vitamin B3
Forms
The primary forms of vitamin B3 that have been used in skin care
products are niacinamide (nicotinamide), nicotinic acid, and nicotinate
esters, such as tocopheryl nicotinate, myristoyl nicotinate, and benzyl
nicotinate.
Mechanisms
Vitamin B3 is an essential vitamin. It is a precursor to a family of
endogenous enzyme cofactors, specifically nicotinamide adenine
dinucleotide (NAD), its phosphorylated derivative NAD(P), and their
reduced forms NAD(H) and NAD(PH), which have antioxidant
properties. These cofactors participate in many enzymatic reactions in the
skin and thus can potentially influence many skin processes. The
diversity of processes in which these cofactors participate may be the
mechanistic basis for the diversity of cosmetic effects observed from the
topical use of a precursor such as niacinamide. Fairly high doses (2% to
5%) of vitamin B3 have been used to achieve these desired effects like
improved skin color, skin barrier improvement, reducing skin sensitivity
and responsiveness to environmental insult, such as from surfactant
exposure.
10 Cosmeceuticals

The key challenge for working with niacinamide and nicotinate esters
is avoiding hydrolysis to nicotinic acid. Nicotinic acid, even at low doses,
can induce an intense skin reddening (flushing response). Formulating in
the pH range of 4 to 7 is preferred to avoid hydrolysis. Most of the esters,
unfortunately, induce a skin flushing response, some within seconds or
minutes of topical application even at very low concentrations of less
than 1%. Some of the esters, such as tocopheryl nicotinate and myristoyl
nicotinate, apparently are less prone to cause this flush response and thus
appear to be more suitable for aesthetic use topically.

1.3.1.3 Panthenol
Form
Panthenol, or provitamin B5, is also known as pantothenol and
pantothenyl alcohol. The D optical isomer of panthenol is termed
dexpanthenol. It is a precursor to pantothenic acid (vitamin B5).
Mechanisms
Because panthenol is a precursor to pantothenic acid, its skin effects may
derive from this precursor role. Pantothenic acid is a component of
coenzyme A, which is critical in cellular metabolism, including in acyl
group transfer during fatty acid biosynthesis and gluconeogenesis. By
increasing synthesis of stratum corneum lipids, improved barrier could
result. Panthenol also promotes fibroblast proliferation and epidermal
reepithelialization in vitro, effects that might promote wound healing.
Because panthenol is water soluble and hydroscopic, it has skin
moisturization potential, especially when combined with the widely used
moisturizing agent glycerol.
High temperatures must be avoided when formulating with D-
panthenol, which is the active form of the material, to avoid conversion to
DL-panthenol. The only other challenge in working with this water-
soluble material can be product stickiness if high levels are used.

1.3.1.4 Vitamin C
Forms
There are many forms of this vitamin. Some commonly used ones are
ascorbic acid, ascorbyl phosphate (magnesium or sodium salt), ascorbyl
palmitate, and ascorbyl glucoside.
Cosmeceuticals 11

Mechanisms
Vitamin C has been used as a skin lightener because of its antioxidant
activity and tyrosinase inhibition effect. It has also been described as an
anti-inflammatory agent because it reduces the erythema associated with
postoperative laser resurfacing. In addition, ascorbic acid serves as an
essential cofactor for the enzymes lysyl hydroxylase and prolyl
hydroxylase, both of which are required for posttranslational processing
in collagen (types I and III) biosynthesis. Thus, by stimulating these
biosynthetic steps, ascorbic acid has potential to increase collagen
production for wrinkle appearance reduction. Ascorbate compounds have
been reported to have skin anti-aging effects in the topical doses range
from 3% to 17%.
The primary challenge with vitamin C and derivatives is stability
(oxygen sensitivity), particularly with ascorbic acid, where loss of nearly
half of the ascorbic acid in a month can occur. This is accompanied by
rapid product yellowing, which is likely an aesthetic negative for the
consumer. Various stabilization strategies can be attempted to address the
issue, such as exclusion of oxygen during formulation, oxygen-
impermeable packaging, encapsulation, low pH, minimization of water,
and inclusion of other antioxidants. Despite these strategies, ascorbate
stability remains a challenge, and some of these approaches, such as very
low pH, can lead to unwanted aesthetic skin effects. One family of
ascorbic acid derivatives is the ascorbyl phosphate salts (Mg and Na).
The stability of these salts is substantially better than for ascorbic acid.
Another challenge is skin delivery. Penetration of ascorbic acid across
skin is generally poor, and typically less than 1% of the topical dose
enters the skin. For the phosphate derivatives of ascorbate, skin
penetration can be an even greater challenge due to the negative charges
on the phosphate moiety. Thus, the use of approaches to enhance skin
penetration is desired.

1.3.1.5 Vitamin E
Forms
In addition to the more commonly used forms of vitamin E, in particular
tocopherol and tocopheryl acetate, several other esters, for example,
succinate, nicotinate, linoleate, and phosphate, are used in the cosmetic
arena. Natural tocopherol also has several isomers (alpha, beta, gamma,
and delta) that differ in some of the side chains and have somewhat
different potency. The more cost-effective among these is synthetic
alpha-tocopherol.
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Mechanisms
Vitamin E is an oil-soluble antioxidant. Because oxygen radicals are
involved as a factor in many skin problems, both acute and chronic,
vitamin E has the potential to prevent and improve skin problems caused
by these radicals, in particular, those caused by UV exposure such as
sunburn, skin photoaging (wrinkling), and hyperpigmentation. Topical
vitamin E is effective in presenting UV-induced skin redness. Vitamin E,
at relatively high doses, provides significant effects.
Because tocopherol and tocopheryl acetate are oil soluble, using high
levels can present some challenge in developing an aesthetically elegant
(nongreasy) formulation. There is some oxidative stability concern with
tocopherol; thus, tocopheryl acetate is often used to avoid this issue.
Tocopheryl acetate appears to be less effective, however, due to
apparently slow hydrolysis to the functional free tocopherol.

1.3.1.6 Alpha lipoic acid
Alpha lipoic acid (ALA) is a lipoamide synthesized in the mitochondria
of plants and animals. It is a scavenger of reactive oxygen species and a
metal chelator. ALA regenerates endogenous antioxidants such as
vitamins C and E, glutathione and ubiquinol. ALA is both water and lipid
soluble, allowing it to penetrate lipophilic cell membranes and enter the
aqueous intracellular matrix. The molecule prevents lipid peroxidation,
has anti-inflammatory properties, and acts as an exfoliant. ALA does not
protect against UV-induced erythema or reduce the number of sunburn
cells.

1.3.1.7 Ubiquinone
CoQ-10, or ubiquinone, is a fat-soluble antioxidant located in the inner
mitochondrial membrane of nearly all living cells that is necessary for
steps in adenosine triphosphate (ATP) production for cellular energy. It
acts by downregulating MMPs. CoQ-10 also inhibits lipid peroxidation in
plasma cell membranes. There is good in vitro evidence that CoQ-10 can
decrease periorbital wrinkles. Idebenone is a more potent synthetic
analog of CoQ-10 that is a powerful antioxidant. Idebenone shows
highest anti-inflammatory properties, photoprotective effects, and
prevention of UV immunosuppression. It may repair mitochondrial DNA
and decrease nuclear thymine dimer photoproducts. Like other
antioxidants, idebenone downregulates MMP expression. Overall, it may
improve roughness, dryness and fine lines, and increase hydration.
Cosmeceuticals 13

1.3.1.8 Polyphenols
Polyphenols are plant-derived antioxidants that have anti-inflammatory,
photoprotective, and anticarcinogenic properties. Flavonoids are a
subgroup of polyphenols that are popular ingredients in many
cosmeceuticals. They include grape seed extract, green tea extracts, and
soy isoflavones. Grape seed extract can induce vascular endothelial
growth factor expression on keratinocytes to enhance dermal wound
healing. Green tea extracts such as epigallocatechin 3-allate have been
shown to decrease levels of UVB damage, DNA damage, sunburn, and
erythema.

1.3.2 Growth Factors
Growth factors comprise a large group of regulatory proteins that attach
to cell surface receptors to mediate inter- and intracellular signaling
pathways. Wound healing relies on a complex interaction of various
cytokines and growth factors.
Growth factors relevant to wound healing may induce new collagen,
elastin, and glycosaminoglycan formation and mediate angiogenesis.
One human growth factor presently used in cosmeceuticals is
transforming growth factor-1, which is derived from cultured fibroblasts
harvested from neonatal foreskin. Advances in biotechnology have lead
to further products such as processed skin cell proteins (PSPTM)
harvested from fetal cell lines. Other growth factors include placental
extract, recombinant epidermal growth factor, and platelet- derived
growth factor.

1.3.3 Peptides
Forms
With variations in amino acid sequence, number of amino acids, and use
of derivatives of these acids, the array of possible peptides is limitless. A
few peptides with known sequences have been of particular interest to the
cosmetic industry, such as palmitoyl-lysine-threoninethreonine- lysine-
serine (pal-KTTKS; Matrixyl), acetyl-glutamate-glutamate-methionine-
glutamine-arginine-arginine (Ac-EEMQRR; Argireline), and the
tripeptide copper glycine-histidine-lysine (Cu-GHK).
14 Cosmeceuticals

Mechanisms
The peptide pal-KTTKS is a fragment of human dermal collagen that
stimulates new collagen production and has been proposed for wound
healing. The synthetic pal-KTTKS is also functional in stimulating
collagen production in vitro. In addition, at extremely low levels (parts
per billion) in culture, pal-KTTKS reduces excess dermal GAGs which
contribute to an antiwrinkle appearance effect. Like KTTKS, GHK is also
a fragment of dermal collagen. Copper is a required factor for activity of
lysyl oxidase, an enzyme involved in collagen synthesis. Ac-EEMQRR is
described as a mimic of botulinum neurotoxin (Botox), which functions
by inhibiting neurotransmitter release, thus “relaxing” the muscles
involved in defining facial wrinkles.
An important challenge is delivery into skin because peptides are
poorly penetrating, especially as the number of amino acid residues
increases. An approach to that problem is the addition of a lipophilic
chain (e.g., palmitate), which can increase skin penetration several fold
over the underivatized peptide. An additional challenge is the cost. As the
number of amino acid residues increases, the cost of the peptide can
increase dramatically. The consequences are that only low levels of a
peptide can be used in the product, which is acceptable if the peptide is
potent or the finished product cost to the consumer must be high.

Sugar amines
Forms
Many materials fall within the broad category of sugar amines, with some
widely known ones being the hexose amines glucosamine and N-acetyl
glucosamine (NAG).
Mechanisms
Glucosamine and NAG are precursors to the biopolymer hyaluronic acid,
which is an important water-binding structural component of skin in the
epidermis and the dermis. Topical use of the hexose compounds thus can
improve skin moisturization and also fine lines/wrinkle appearance by
building skin structural matrix. NAG has been discussed as an exfoliant,
interfering with the cross-linking between corneocytes. Glucosamine has
inhibited protein glycosylation in vitro, inhibiting activation of
protyrosinase to the active enzyme tyrosinase and thus inhibiting the
production of melanin. These materials also have anti-inflammatory
properties.
Cosmeceuticals 15

For glucosamine, the challenge is stability. It readily undergoes a
Maillard reaction leading to a brown polymeric product. This can be
managed to some extent by use of antioxidants and acidic pH. NAG is
substantially more stable and thus lacks this challenge. Both materials at
high doses (e.g., above 2%) can be sticky in formulation, which can
impart aesthetic negatives.

Ceramides
Forms
There are many ceramides and ceramide analogs. This contribution will
not focus on any particular material but rather discuss them as a group.
Mechanisms
Ceramides are lipids essential for a normal stratum corneum water barrier.
The other key lipid components of the barrier are cholesterol and fatty
acids. All three are required and occur in an approximately equimolar
mixture in the intercellular space in stratum corneum, but ceramides have
received more attention. Externally supplied ceramides function by
incorporating into the intercellular lipid of stratum corneum to replace the
depletion that occurs with aging and environmental damage such as from
surfactant exposure. The most effective therapy is described as a mixture
of ceramides with the other two barrier lipid components.
Ceramides are oil-soluble. As long as the dose of ceramide is not high,
it should incorporate into the oil phase of a formulation without difficulty.
Ceramides can be expensive though, such that use of high concentrations
is a cost challenge.

1.3.4 Metals
Forms
Of the many metals, cosmetic products typically contain only a few,
among them zinc, copper, selenium, strontium, magnesium, and
manganese, as salts and complexes with organic compounds. A few
examples are zinc oxide, copper peptide, and selenomethionine.
Mechanisms
Metals have specific functions in the skin, often associated with their role
as required cofactors in the activity of metalloenzymes, and therefore, the
mechanisms associated with individual metals are widely varied. Certain
metalorganic compound complexes such as pyrithione-zinc and selenium
sulfide are antifungal agents that are effective as antidandruff agents.
16 Cosmeceuticals

Zinc is also associated with the antioxidant proteins superoxide dismutase
and metallothionein, so zinc oxide has antioxidant potential as a source of
zinc for synthesis of these proteins. Copper is a cofactor for many
proteins, including lysyl oxidase and prolyl hydroxylase, enzymes that
are important in collagen synthesis. Selenium is a cofactor for the
antioxidant enzymes glutathione peroxidase and thioredoxin reductase.
Some metals and their complexes are colored (e.g., copper is blue-
green), so that can be an aesthetic challenge at higher doses. Metal salts
also can negatively affect product thickeners, requiring substantial
adjustment of the formulation. The presence of zinc, for example, can
complex with materials such as avobenzone, a common UVA sunscreen,
resulting in the avobenzone crystallizing out of solution, causing a
yellowing of the product, and significantly decreasing the sunscreen’s
efficacy.

1.3.5 Anti-inflammatories/Botanicals
Numerous cosmeceuticals have been researched to treat sensitive skin,
skin affected by rosacea, and photodamage to reduce the redness
associated with inflammation. Licochalcone A, from the licorice plant
Glycyrrhiza inflata, has anti-inflammatory properties. The mechanism of
action is thought to be dual inhibition of cyclo-oxygenase and
lipoxygenase, thereby reducing proinflammatory cytokines and UVB-
induced prostaglandin E2 release by keratinocytes. In this book we are
going to discuss about botanicals in individual chapter according to the
topic.

1.3.6 Polysaccharides
Polysaccharides include the family of hydroxy acids: alpha hydroxy acids
(AHA), beta hydroxyl acids (BHA), and polyhydroxy acids (PHA). The
AHAs include glycolic acid (grapes), lactic acid (milk), malic acid
(apples), and citric acid (citrus fruits) among others. They are considered
to be keratolytics because they diminish corneocyte adhesion in the lower
levels of the stratum corneum, allowing exfoliation and improvement in
skin dullness. They also function as humectants, possibly by increasing
dermal glycosaminoglycans, as well as improve stratum corneum barrier
function. The exact mechanism of action of AHAs is not known. BHAs,
such as beta-lipohydroxyacid and tropic acid, are exfoliants appropriate
for acne prone and oily skin. Salicylic acid was once thought to be a BHA,
but it is structurally a phenolic aromatic acid. Its lipophilic structure
allows it to penetrate into the sebaceous follicles, thus making it useful
for patients with oily skin. Salicylic acid is available in a wide range of
Cosmeceuticals 17

concentrations. PHAs can hydrate, moisturize, as well as exfoliate the
skin. They include gluconolactone, which may protect against UV
radiation in vitro and lactobionic acid, which is both an antioxidant and a
humectant. Because of their large size, PHAs do not penetrate the skin as
easily and are therefore less irritating to sensitive skin.

1.3.7 Pigment Lightening
The popularity of pigment-lightening cosmeceuticals is because of their
effect on out skin tone. The most commonly used pigmentlightening
agent is hydroquinone, which works by inhibiting tyrosinase activity.
Tyrosinase is the rate-limiting, essential enzyme in the biosynthesis of
melanin. It is available both in over-the-counter and in prescription
strengths, and it is often combined with other agents such as retinol,
AHAs, vitamin C, and topical steroids. Side effects include an irritant
contact dermatitis and, more rarely, exogenous ochronosis. Kojic acid is a
fungal derivative commonly used in Japan that has been shown to
decrease melanin content via tyrosinase inhibition in vitro. It also
decreases melanin content in melanocytes and is an antioxidant. One
disadvantage is that it can be irritating and is known to cause true
hypersensitivity. Like hydroquinone, it is often combined with other
cosmeceutical agents or with topical steroids to reduce irritation.
Glabridin is the main active ingredient in licorice extract and can inhibit
tyrosinase activity. In addition, glabridin has anti- inflammatory
properties attributed to cyclooxygenase inhibition. Ellagic acid is a
polyphenol widely found in plants such as pomegranates, which inhibits
tyrosinase by chelating copper at the active center of this enzyme. It may
selectively inhibit melanin synthesis only in UV-activated melanocytes.
Fatty acids such as linoleic acid act by tyrosinase degradation without
toxic effects on melanocytes.

1.4 Marketed size
According to the study conducted by Indian Cosmetic Sector Analysis the
cosmetic market is around INR 356 billions. Most of the international
companies have introduced their products in India in 1990s. The total
Indian beauty and cosmetic market size currently stands at INR 422.3
Billion in 2010 and showing growth between 15–20% per annum, in the
US it is about $6.5 billions. Skin care products occupy half of the
cosmeceuticals industry through out the world. Among the skin care
products anti-aging market plays major role driven by an aging
population seeking to maintain the appearance of youth. Antioxidants
will remain the largest chemical category while botanicals and enzymes
18 Cosmeceuticals

stay among the best opportunities. Injectables and skin care products will
register the fastest growth.
According to Confederation of Indian Industries (CII) report, US$0.68
per capita is spent for cosmetics, which might be lower than some other
countries, but this indicates a growing awareness among consumers.
There are two major factors that are saying the buying decision among
women here. First obviously is the television and media exposure they
have today. The other not so obvious one is the corporate dressing culture,
which slowly is evolving in the Indian market.

Fig. 1.1 Global Therapeutic Dermatology Marketsplit by Product Class.
[Colour Fig. on page 393]

1.5 Conclusion
The cosmetics industry today holds a unique position. It is characterized
by highly competitive marketing strategies and depends on the ability to
introduce rapidly new innovative products into the market place. On the
other hand, dermatological research may also proceed in the cosmetic
field while in-depth research may be conducted with regard to therapeutic
applications. Cosmetic companies are permitted to create and market
products that are known to have an effect on the structure and function of
skin, with little regulation. Most consumers believe that cosmeceuticals
Cosmeceuticals 19

are regulated and tested as drugs. Consumers trust that ingredients have
been tested for safety and that claims made in advertisements are real.
One can easily conclude that cosmeceuticals will continue to evolve in
parallel with advances in our understanding of skin biology, along with
improved methods of measuring the benefits that may be provided by
well-engineered skin care products. But we have to consider the changes
in the science and technology, so clinicians, scientists and dermatologists
have to update their knowledge in this field to produce high quality
products with safety.

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