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SUBMITTED BY: DEEP DAS

ROLL NO: 11121EN007

CLASS: B.PHARM, PART II, SEMESTER V

DEPARTMENT OF PHARMACEUTICSINDIAN INSTITUTE OF TECHNOLOGY (BHU)

COURSE: PHARMACOGNOSY II, PH-3102

COURSE INSTRUCTURE: A. N. SAHU

DATE: 29/10/2013

Cosmeceuticals



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CONTENTS

A. Introduction ………………………….……..…2

B. Classification of cosmeceutical products……......3

1. Moisturizers…………………………………….5

1.1 Occlusive moisturizers…………………...6

1.2 Humectant moisturizers………………….7

2. Photoprotection……...…………………………7

2.1 Luffa cylindrica…….......................…….8

2.2 Portulaca oleracea……………….…...…9

2.3 Terminalia chebula............,.........……….9

2.4 Piper longum………………......………..9

2.5 Aloe Ver a………………………...……10

2.6 Emblica officinalis…………………….10

2.7 Crocus sativus………………...……….10

2.8 Peumus boldus Molina……….….…….11

3. Sunscreen Agents…….…..……………,,,,....…11 3.1 Vitamins...…………...………………..12

3.2 Vitamin A…………………,,,….……..13

3.3 Vitamin E…………………….……….13

3.4 Vitamin C…………………...……...…14

4. Skin Lightening Agents…….………...…...…..14

4.1Ascorbic acid…………….……………15

4.2 Licorice extract………………...……..15

4.3 Alpha-lipoic acid…………….……….16

4.4 Kojic acid…………,…………...……..16

4.5 Aleosin………,……………...………..16

4.6 Arbutin……….……………………….16

4.7 Hydroquinone….……………....……..17

5. Antioxidants………………………….….…….17

5.1 Carotenoids……………,…………….18

5.2 Astaxanthin………....…………….…18

5.3 Lutein………………………………..18

5.4 Lycopene……...………,…...…….….18

5.5 Retinol………………,……………....19

5.6 Flavonoids…………………………..19

5.7 Soy…………………,….………...….20

5.8 Curcumin…………,…..….…………20

5.9 Silymarin…………,….......……..…..20

5.10 Pycnogenol………,...…………..….21

5.11 Ginkgo……………,……………….21

5.12 Green tea…………,,……………….22

5.13 Pomegranate……….………….....22

6. Other antioxidants used in post

resurfacing……………...……………………...23

6.1 Aloevera………………………….23

6.2 Ubiquinone…………………….…23

7. Depigmentation agents……..…...……...…..24

7.1 Phenolic Compounds……………..24

7.2 B Nonphenolic Compounds……...25

7.2.1 Azelaic Acid…………………....25

7.2.2 Tretinoin……………………......26

7.2.3 L-ascorbic Acid………………...26

7.2.4 Kojic Acid……………………...26

7.2.5 Arbutin…………………...…….27

8. Hydroxy Acids………………………...….…27

8.1 α-Hydroxyacids…………..……..278.2 β-Hydroxyacids…………..……..28

8.3 Polyhydroxy acids..............……..28

8.4 Bionic acids………………..……29

9. Retinoids……………………….………….....29

9.1 Tretinoin……………….……….30

9.2 Retinol…………………..….…..31

9.3 Retinyl-palmitate…………….....31

9.4 R etinaldehyde……….………….31

9.6 Alitretinoin……………...….......31

9.7 Tazarotene………………….…..31

9.8 Adapalene………………...……32

10. Peptides………………………………….….32

10.1 Antimicrobial peptides………..32

10.2 Defensins……………………..33

10.3 Psoriasin………………….…..33

10.4 RNase 7……………..….....….34

10.5 Dermicidin 1L………………..34

11. Peptides involved in wound healing……....35

11.1 RGD Peptides………….…….35

11.2 Copper Peptides…………...…35

11.3 Interleukins (IL)………….…..36

12. Growth Factors…………………..………...36

13. Conclusion…………………………...….….37

14. R eferences……..……………………….…..37



A. INTRODUCTION

Cosmeceuticals are cosmetic products with biologically active ingredients purporting to have medical or drug

like benefits. A cosmeceutical is an ingredient with medicinal properties that manifests beneficial topical

actions and provides protection against degenerative skin conditions. The word "Cosmeceuticals" was

popularized by Albert M. Kligman in the late 1970s. It encompasses cosmetic actives with therapeutic, disease

fighting, or healing properties, serving as a bridge between personal care products and pharmaceuticals. Like

cosmetics, cosmeceuticals are topically applied, but they contain ingredients that influence the biological

function of the skin.1 Cosmeceuticals improve appearance by delivering nutrients necessary for healthy skin.

Cosmeceuticals typically claim to improve skin tone, texture, and radiance, while reducing wrinkling.

Cosmeceuticals are the fastest‐growing segment of the natural personal care industry.

For cosmetic labels, no division between active ingredients and other ingredients is required; they are all listed

together. The most important botanicals pertaining to dermatologic uses such as cosmeceuticals include teas,

soy, pomegranate, date, grape seed, pycnogenol, horse chestnut, German chamomile, curcumin, comfrey,

allantoin, and aloe; only green and black tea, soy, pomegranate, and date have been studied to the extent that

clinical trials for the treatment of parameters of extrinsic aging have been published. Few botanical‐ based

cosmeceuticals have uses that are supported by evidence‐ based science. Chemoprevention by oral or topical

use of dietary or pharmacologic agents to inhibit or reverse the development of cancer is a possibility. Potential

cosmeceutical agents in this category include green tea, grape seed extract, vitamin E, and beta‐carotene.

Cosmeceuticals being cosmetic products having medicinal or drug‐like benefits are able to affect the biological

functioning of skin owing to type of functional ingredients they contain. There are skin‐care products that go

beyond coloring and adorning the skin.

These products improve the functioning/texture of the skin by encouraging collagen growth by combating

harmful effects of free radicals, thus maintaining keratin structure in good condition and making the skin

healthier. Most of the eminent multinational companies engaged in cosmetics productions have introduced a

wide range of products having therapeutic effects by addition of a single or more active drug like component

to enhance the efficacy of products which later on was found to be beneficiary for the required purpose.

These products have also mended some flaws associated with existing products leading consumers to

discontinue the use of that product due to allergic reactions or excessive skin drying. Many companies add

humectants like glycerin as a soothing agent which increases the skin moisture level and keeps it hydrated.

Commonly used substances included in cosmeceutical formulations are described as follows.



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B. CLASSIFICATIONOF COSMECEUTICAL PRODUCTS

The cosmeceuticals are mainly divided into seven categories. In choosing an effective Cosmeceuticals

regimen it is critical to match patients and their problems with the appropriate products. Most patients have

multiple needs, and they should be matched with products that offer ingredients with multifunctional benefits.

CLASSIFICATION OF COSMECEUTICALS

Also It can be broadly classified into following categories according to their daily life uses.

SL. NO CATEGORIES

1 Creams, emulsions, lotions, gels and oils for the skin (hands face, feet, etc.).

2 Face masks (with the exception of chemical peeling products).

3 Tinted bases (liquids, pastes, powders).

4 Make-up powders, after-bath powders, hygienic powders, etc.



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5 Toilet soaps, deodorant soaps, etc.

6 Perfumes, toilet waters and eau de Cologne.

7 Bath and shower preparations (salts, foams, oils, gels, etc.).

8 Depilatories.

9 Deodorants and anti-perspirants.

10 Hair care products:

Hair tints and bleaches,

Products for waving, straightening and fixing,

Setting products,

Cleansing products (lotions, powders, shampoos),

Conditioning products (lotions, creams, oils),

Hair dressing products (lotions, lacquers, brilliantine).

11 Shaving products (creams, foams, lotions, etc.).

12 Products for making-up and removing make-up from the face and the eyes.

13 Products intended for application to the lips.

14 Products for care of the teeth and the mouth.

15 Products for nail care and make-up.

16 Products for external intimate hygiene.

17 Sunbathing products.

18 Products for tanning without sun.

19 Skin-whitening products.

20 Anti-wrinkle products.



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Mechanisms of current cosmeceutical agents. Alpha-hydroxyacid (AHA), post-inflammatory hyperpigmentation

(PIH), ultraviolet light (UV).

1. Moisturizers

The main cutaneous function of cosmeceuticals is to enhance the barrier

function of the skin following a resurfacing procedure. Enhancing the barrierdecreases stinging and burning from a sensory standpoint and improves the

look and feel of the skin. Moisturizers can smooth down desquamating

corneocytes and fill in the gaps between the renaming corneocytes to create the

impression of tactile smoothness. This effect is temporary, of course, until the

moisturizer is removed from the skin surface by wiping or cleansing. From a

functional standpoint. Moisturizers can create an optimal environment for

healing and rninirnize the appearance of lines of dehydration by decreasing transepidermal water loss. Trans

epidermal water loss increases when the brick-and-mortar organization of the protein -rich corneocytes held

together by intercellular lipids is damaged. A well-formulated cosmeceutical moisturizer can decrease the water

loss until healing occurs following a resurfacing procedure. There are two cosmeceutical ingredient categories

that can reduce transepidermal water loss post-resurfacing: occlusive and humectants. The most common method



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for reducing transepidermal water loss is the application of occlusive ingredients in combination with humectant

ingredients in a thin moisturizer film.

1.1 Occlusive moisturizers

Occlusive moisturizers contain oily substances that create a barrier to water evaporation. The most popular and

effective occlusive ingredient used following resurfacing is petrolatum. Petrolatum is effective because it blocks

99% of water loss from the skin surface. This remaining 1% transepidermal water loss is necessary 10 provide

the cellular message for barrier repair initiation following wounding. If the transepidermal water loss is

completely halted. The removal of the occlusion results in failure to repair the barrier. And water loss quickly

resumes at its pre-application level. Tubs the occlusion does not initiate barrier repair. Petrolatum does not

function as an impermeable barrier. Rather it permeates throughout the interstices of the stratum corneum

allowing barrier function to be re-established.

1.2Humectant moisturizers

Another concept in rehydrating the stratum corneum is the use of humectants.

Humectants have been used in cosmetics for many years to increase shelf life

by preventing product evaporation and subsequent thickening due to variations

in temperature and humidity. Humectants are a necessary in a11oil-in-water

creams to maintain the required water content. Substances that function as

humectants include glycerin, honey, sodium lactate. urea. propylene glycol,

sorbitol, pyrrolidone carboxylic acid, gelatin, hyaluronic acid, vitarnins and

some proteins. Following resurfacing, the barrier has been injured, and water

must be drawn to the wounded skin to prevent desiccation, which slows healing. Desiccation of the facial skin

also leads to an undesirable sensation of pulling and drawing. Humectants attract water from the deeper epidermal

and dermal tissues to rehydrate the stratum corneum. This water is trapped by the occlusive moisturizing

ingredients in a thin film on top of the stratum comeum . Humectants mayalso allow the skin to feel smoother by

filling holes in the stratum eerneum through swelling. Therefore a good moisturizer should combine both

occlusive and humectant ingredients. There is no doubt that most anti-aging cosmeceuticals are primarily well

constructed moisturizers containing occlusive and humectant ingredients. Furthermore most of the claims

associated with cosmeceuticals are moisturizer claims. Keep in mind that the moisturizer is really the vehicle for

transporting the special ingredient to the skin surface but the vehicle may actually be the active ingredient in many

cosmeceutical formulations. Thus. cosmeceuticals can be used to aid healing and maintain an excellent result

following skin resurfacing.



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2. Photoprotection

Many new developments have occurred in the photoprotection cosmeceutical market to increase both efficacy

and cosmetic acceptability. Higher sun protection factor (SPF) formulations are more popular as new sunscreen combinations arise that provide better ultraviolet B (UVB) protection. New methods of increasing the longevity

of UVA photoprotectants provide better broad-spectrum protection. These advances have improved the ability of

sunscreens to prevent post-inflammatory hyperpigmentation following resurfacing.

Sunscreen filters can be classified into two major categoties. Chemical and physical. Chemical sunscreens also

known as organic filters, undergo a chemical transformation known as resonance delocalization to absorb UV

radiation and transform it to heat. This reaction occurs within the phenol ring, which contains an electron-releasing

group in the ortho and/or para position, and is irreversible, rendering the sunscreen inactive once it has absorbed

the UV radiation. Physical sunscreens, also known as inorganic filters, are usually ground particulates that reflect

or scatter UV radiation absorbing relatively little of the energy. For this reason they have longer activity on the

skin surface.

The most important protection following facial resurfacing is from UVA radiation which is directly responsible

for pigment production. Two important UVA filters include oxybenzone and avobenzone. Oxybenzone provides

weak UVA photoprotection below 320 nm. It is commonly combined with avobenzone. Avobenzone is also

chemically incompatible with other commonly used inorganic filters, such as zinc oxide and titanium dioxide.

Another important UVA photoprotection in facial resurfacing is ecarnsule, better known as Mexoryl". Mexoryl

(L'Oreal) was originally developed to stabilize avobenzone. It is used in combination with oxybenzone and

octocrylene to provide excellent proteetion from post-inflammatory hyperpigmentation following resurfacing. Itis available in two forms: Mexoryl SX and Mexoryl XL. Mexoryl SX is a water-soluble form that is suitable for

daywear sunscreen formulations.

The inorganic UVA/UVB filters titanium dioxide and zinc oxide are also important in preventing post-

inflammatory hyperpigmentation following resurfacing. Titanium dioxide is usually micronized to contain

particles of many sizes to provide optimal UV scattering abilities. Unfortunately, it leaves a white film on the skin

and is used mainly for beachwear sunscreens and not cosmeceuticals. Zinc oxide is usually available in a

microfine forrn, meaning it contains small particles of one size making it appropriate for day wear. A newly

introduced colorless zinc oxide with extrernely small particles is finding its way into many post-resurfacing

cosmeceuticals, but there is concern that the nanoparticles may enter the skin through appendageal structures

creating a permanent reservoir. The cosmeceutical industry has placed a voluntary hold on nanoparticle inorganic

filters and pigments until the penetration issues are better understood.



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Effect of ROS on skin

2.1 Luffa cylindrica

L. cylindrica (Linn) M. Roem. is a climber with a slender, slightly hairy stem

with little furrowing. The seeds of L. cylindrica contain oil in which the fatty

acids are stearic and linoleic acids - are unsaturated fatty acids. It has been

reported that naturally occurring unsaturated fatty acids and phenolic

compounds have free radical scavenging properties In a study by Yoganandam

et al , it was concluded that the fixed oil isolated from the seed kernels of the

plant not only scavenges off the free radicals but also inhibits generation of free

radicals.



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2.2 Portulaca oleracea

Portulaca oleracea (Common Purslane; also known as Verdolaga, Pigweed,

Little Hogweed or Pusley) is an annual succulent in the family Portulacaceae,

which can reach 40 cm in height. It is found throughout India and the Middle

East, but is naturalized elsewhere, and in some regions, is considered an

invasive weed. The whole plant is considered antiphlogistic (takes the heat

out), a bactericide, antidiabetic, anaphrodisiac (opposite to aphrodisiac),

emollient, calmative, diuretic, and refreshing agent. Sanja et al has proved the

antioxidant activity of the methanol extract using methods such as DPPH free radical scavenging, reducing power

estimation by FeCl3, nitric oxide free radical scavenging superoxide scavenging activity. The extract has a

tendency to scavenge the free radicals involved in the ageing process and skin wrinkling and thus may provide

some photoprotective action rejuvenate the skin. The fresh gel, juice or formulated products have been used for

medical and cosmetic purposes and to enhance general health. 2.3 Terminalia chebula

Terminalia chebula, also called Harde, belongs to the family Combretaceae. It

is used commonly in many Ayurvedic preparations as laxative, diuretic and

cardiotonic, as well as in some health supplements. Its chemical constituents

include ascorbic acid, gallic acid and ellagic acid, which are well known to exert

free radical scavenging properties.

2.4 Piper longum

Piper longum L. belonging to the family Piperaceae, is commonly found in

Indonesia, India and the Phillipines. It consists of a spike of fruits forming a

structure about 4 cm long and 6 mm in diameter. The fruit (pepper) contains 1 -

2.5 % volatile oil, 5 – 95 % of crystalline alkaloid piperine and piperettine, and

a resin. Piperine extracted from this plant has been used as an ingredient in

Ayurvedic formulations because of its antioxidant potency both in vitr o and in

vivo in mice. Piperine, due to this antioxidant property, is used topically in a

cream base to treat sunburn diseases.



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2.5 Aloe Vera

The leaves of Aloe vera ( A. barbadensis) (Fam. Liliaceace) are the source of aloe

vera gel. The gel does not include the sap of Aloe vera, which contains

anthraquinones. Aloe vera gel is widely used in cosmetics and toiletries for its

moisturizing and revitalizing action. The whole leaf of Aloe vera is known to aid

cellular repair as well as digestion, assimilation of foods, vitamins, minerals and

other vital nutrients to rejuvenate the skin. The fresh gel, juice or formulated

products have been used for medical and cosmetic purposes and to enhance

general health.

2.6 Emblica officinalis

Emblica officinalis Gaertn., commonly known as amla, is a rich dietary source

of vitamin C, minerals and amino acids. It also contains various phenolic

compounds. Amla extract is known to exhibit potent antioxidant properties and

to provide protection for human dermal fibroblasts against oxidative stress and

therefore, it is assumed to be useful for natural dermal care. Recently, it was

reported that amla extract has effect on human skin fibroblasts, especially

production of procollagen and matrix metalloproteinases (MMPs). The water

extract from dried amla powder contains 2 % ascorbic acid and 29.4 % polyphenols including gallic acid and

elaeocarpusin. Amla extract elevates the mitochondrial activity of human skin fibroblasts and promotes

production of procollagen. Therefore, due to its potential mitigative, therapeutic and cosmetic applications, amla

has been used for skin treatment since ancient times.

2.7 Crocus sativus

Saffron, the dried stigma of the plant Crocus sativus L, popularly used as a spice

and food colorant, has been used in traditional medicine for the treatment of

many diseases including tumors. The chemical constituents of saffron include

the colored carotenoids - crocin and crocetin - and the monoterpene aldehydes -

picrocrocin and saffranol. Salomi et al reported the anti-promoting and non-

mutagenic activity of saffron extract. Lin et al showed that crocins can protect

from the adverse effects of hepatocarcinogenic compounds and that crocetin, the

deglycosylated crocin derivative, can inhibit intracellular nucleic acid synthesis. The anticarcinogenic effect of

the aqueous infusion of saffron, administered orally, using a two-stage skin carcinogenesis model in mice, has



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been evaluated; the protective role of saffron against carcinogenic exposure was attributed to its action on the

physiological detoxification processes and this proved that saffron can prevent chemically-induced skin

carcinogenesis in Swiss albino mice.

2.8 Peumus boldus Molina

Peumus boldus belonging to the family Monimiaceae ( a tree whose leaves

have been traditionally employed in folk medicine) is now widely

recognized as an herbal remedy by a number of Pharmacopoeias. Its leaves

are rich in several aporphine-like alkaloids, among them, boldine, which is

the most abundant one. Research conducted during the early 1990s claimed

that boldine is one of the most potent natural antioxidants. Its

pharmacological actions, which arise from its antioxidant properties, includes cytoprotective, anti-tumor

promoting, antiinflammatory, anti-diabetic and antiatherogenic actions; it has also shown some actions which do

not seem to be associated with these activities, e.g., vasorelaxing, anti-trypanocidal, immuno- and neuro-

modulator, cholagogic and/or choleretic actions. Free radicals are known to participate in either the aetiology or

the development of most UV-induced skin lesions. Through the experiments conducted on boldine, it has been

proved that boldine has a UV light-filtering property relevant to a photoprotective action. In fact, Hidalgo et a

showed boldine to be photo-unstable when irradiated at wavelengths up to 300 nm and to display a photo-protector

effect against UV-B, both in vitro and in vivo in mice. Photo-protection was evidenced by the prevention of UV-

induced increase in the skin temperature of rodents.

3. Sunscreen Agents

Use of sunscreen agents and limiting the exposure to sun prevents early wrinkling

and skin cancer. Sunscreen agents are used to prevent sunburns. There are two kinds

of sunscreen agents: chemical and physical. Chemical sunscreen agents protect the

skin from the sun by absorbing the ultraviolet (UV) and visible sun rays, while



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physical sunscreen agents reflect, scatter, absorb, or block the rays. Sunscreen agents often may comprise more

than one ingredient. For example, products may contain an ingredient that provides protection against the

ultraviolet A (UVA) sun rays and another ingredient that protects from the ultraviolet B (UVB) sun rays, which

are more likely to cause sunburns than the UVA sun rays. Ideally, coverage should include protection against

both UVA and UVB sun rays. The sun protection factor (SPF) that is present on the label of these products reflects

the minimum amount of UVB sunlight that is needed with that product to produce redness on sunscreen protectedskin as compared with unprotected skin. Sunscreen products with high SPFs provide more protection against the

sun. The following sunscreen agents have been recommended by the U.S. Department of Health:

Cycloform (isobutyl p‐amino benzoate)

• Propylene glycol p‐amino benzoate

• Monoglyceryl p‐amino benzoate

• Digalloyl trioleate

• Benzyl salicylate and benzyl cinnamate (2% each)

Besides these, chemical sunscreens mainly based on para‐amino benzoic acid, its deivatives, cinnamates, various

salicylates and benzophenones, dibenzoylmethanes, anthraline derivatives, octocrylene and homosalate are

frequently employed as sun blocking agents. Direct physical blockers include metal containing compounds such

as iron, zinc, titanium, and bismuth. Zinc oxide and titanium dioxide are highly reflective white powders, but

submicron zinc oxide or titaniumdioxide powder particles transmit visible light while retaining their UV blocking

properties, thus rendering the sun block invisible on the skin.

3.1 Vitamins

Exposure to the UV radiations accelerates the aging effect of the skin. The

progressive telomere shortening and finally its disruption by low‐grade oxidative

damage are related to the aging. Damage is initiated by the generation of reactive

oxygen species (free radicals). It is a progressive process whose consequences are

damage to DNA. The topical treatment of acne vulgaris with vitamin A, is very

well supported by evidence. 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. Activation of toll‐like receptors may also

be involved in the scarring process by activating the metalloproteinases the retinoids arem 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 minimizing the formation of comedones and



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inflammatory lesions. 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.

3.2 Vitamin A

The human epidermis contains significant amounts of vitamin A (alltrans‐

retinol). It has been observed that both UVB and UVA can damage the

metabolism and transport of vitamin A. This may lead to vitamin A deficiency

in the skin.13 Small amounts of retinol in the body gets converted to all‐trans

retinoic acid also called tretinoin (active form) & rest of the retinol is converted

into retinyl ester (storage form). Topical retinoids have successfully been used

to treat acne. The efficacy of topical tretinoin in the treatment of photoaged and

intrinsically aged skin is sufficiently established. The effects are believed to be mediated through its binding to

the nuclear retinoid acid receptors. It induces type I and type III procollagen gene expression in human skin,

resulting in increased deposition of collagen fibrils in the dermis. The effects result in an improvement in the

clinical and histologic skin appearance. 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 moderate to severe skin irritation

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.16 Photosenstivity is another problem to be dealt in case of tretinoin.

The useful concentration of topical retinol ranges 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. Vitamin A (retinol) is the prototype of all other retinoids and is necessary for proper growth, bone development, and integrity of mucosal and epithelial surfaces. In vitamin A deficiency, the

eyes and the skin are severely affected. The conjunctiva and the cornea develop metaplasia and keratinization,

leading to night blindness. Vitamin A exists in three isomeric forms among which beta form found to be more

active than alpha & gamma isomer. Its deficiency may lead to dry rough skin. The advent of synthetic analogs of

vitamin A in the 1970s brought new interest into their biological activity, especially on the skin. Since then,

vitamin A and its derivatives have been useful in the treatment of many skin disorders, including ichthyosis, acne

and psoriasis.

3.3 Vitamin E

The physiological function of vitamin E, if applied dermally is to contribute to the

antioxidant defense of the skin, because of its tendency to absorb UV light in the

solar spectrum region that is responsible for most of the harmful biologic effects of



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the sun18. Vitamin E blocks lipid peroxidation in cells & tissues & it is a good antioxidant. It helps to enhance

the performance of UV filters, softens skin & moisturizes within. Vitamin E is the body's major lipid‐soluble

antioxidant, if oxidized, vitamin E can be regenerated back to its reduced form by L ‐ascorbic acid. Vitamin E as

alphatocopherol or tocopherol acetate is used in topical OTC (over ‐the counter) products in concentration (1% ‐

5%). Alphatocopherol has been found to be beneficial in reducing minimal erythema and the number of epiderma

sunburn cells, which marks skin damage related to oxidative stress caused by UVB19. The effect of vitamin Eafter sun exposure seems to have no benefit. Vitamin E can reduce UV‐induced erythema and edema when it is

applied before UV exposure. Topical application of vitamin E may increase stratum corneum hydration and

enhance water binding capacity. Alpha‐tocopherol also shows synergistic effect with vitamins A (retinol) and C

(ascorbic acid) in combined products, providing an appreciable photo protection and antioxidant action that

suggests a potential effect in the protection against photo aging and skin cancer. Nanoemulsions have been

formulated containing palm oil esters in water with vitamin E and are promising potential nanocosmeceuticals.

3.4 Vitamin CThe increase of vitamin C in skin concentration is limited even with huge oral

supplementation. Vitamin C has become a popular topically applied

cosmeceutical because topical application of Lascorbic acid is the only way to

further increase skin concentration. Free radical scavengers have grabbed the

attention of researchers on vitamin C. L‐ascorbic acid is the active form of

vitamin‐C, which was first used as cosmeceutical creams. Previous formulations

(L‐ascorbic acid) were very unstable due to the oxidation of the vitamin exposed to air. So to overcome this

problem, esterified derivatives of L‐ascorbic acid in topical formulations have been used to improve stability. The

most commonly used derivatives are ascorbyl‐ 6‐ palmitate and magnesium ascorbyl phosphate. Skin‐lightening

effect has been observed by the demonstration of Magnesium ascorbyl phosphate.

4. Skin Lightening Agents

Hyperpigmentation is the changing of colour intensity of the skin to darker hue,

which is due to an increased amount of melanin in the epidermis, the dermis, or

both. This change can be due to 2 pathophysiologic processes: melanocytosis

(increased number of melanocytes) and melanosis (increased amount of melanin).

Skin lightening agents work best when melanosis or melanocytosis is confined to

the epidermis. Patients with Fitzpatrick skin types III have advantage over type‐

IV such as type I‐III benefit from local pigment lightening for the treatment of



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hormonally induced melasma and postinflammatory hyperpigmentation caused by acne and trauma, whereas

those with Fitzpatrick skin types IV and darker may also seek therapy for pigmentary changes that occur around

the eyes, in the intertriginous areas, following dermatitis, or with acne and trauma. Standard dermatologic agent

for skin lightening is hydroquinone but its safety is questionable, leading to the use of alternative agents such as

retinoids, mequinol, azelaic acid, arbutin, kojic acid, aleosin, licorice extract, ascorbic acid, soy proteins, and N

acetyl glucosamine.

4.1Ascorbic acid

Ascorbic acid, also known as vita min C, is used in cosmeceuticals for the

treatment and prevention of hyperpigmentation because it interrupts

melanogenesis by interacting with copper ions to reduce dopaquinone and block

dihydrochinindol-2-carboxyl acid oxidation. Ascorbic acid, an antioxidant, is

rapidly oxidized when exposed to air, with limited stability. For this reason. Many

cosmeceuticals are using the more stable magnesium ascorbyl phosphate. Which

is metabolized to ascorbic acid in the skin. High concentrations of ascorbic acid

must be used with caution, however, as the low pH can be irritating to the skin.

Pigment-lightening cosmeceuticals may contain ascorbic acid as a pH adjustor or

to function as an antioxidant preservative. It is important to recognize that

ascorbic acid is a multifunctional ingredient with very minimal pigment-

lightening capabilities.

4.2 Licorice extract

Licorice extracts are found in cosmeceuticals to decrease facial redness and reduce

pigmentation. The extract contains liquiritin and isoliquertin. Which are glycosides

containing flavonoids, which induce skin lightening by dispersing melanin. To see

clinical results. The liquiritin must be applied in the dose of 1 g per day for 4 weeks.

Irritation is not a side effect, as is so frequently observed with hydroquinone and

ascorbic acid, but efficacy is Minimal.



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4.3 Alpha-lipoic acid

Alpha-lipoic acid is found in a variety of anti-aging cosmeceuticals ramfunction as an

antioxidant, but it mayalso have very lirnited pigmentlightening properties. It is a

disulfide derivative of octanoic acid that is able to inhibit tyrosinase. However, it is a

large molecule and cutaneous penetration to the level of the melanocyte is

challenging, significantly reducing its efficacy.

4.4 Kojic acid

Kojic acid, chemically known as 5-hydroxymethyl-4H-pyrane-4-one, is one of the

most popular cosmeceutical skin-lightening agents found in cosmetic-counter skin-

lightening creams distributed worldwide. It is a hydroph.ilic fungal derivative

obtained from Aspergillus and Penicillium species. It is the agent most commonly

employed in vast Asia for the treatment of melasma, but it is highly unstable. Newer

formulations have incorporated kojic dipalmitate but the efficacy of this derivative

has not been well studied. Some research indicates that kojic acid is equivalent to hydroquinone in pigment-

lightening ability. The activity of kojic acid is attributed to its ability to prevent tyrosinase activity by binding to

copper.

4.5 Aleosin

Aleosin is a low-molecular-weight glycoprotein obtained from the aloe vera plant. It is a natural

hydroxymethylchromone functioning to inhibit tyrosinase by competitive inhibition at the DOPA oxidation site.

In contrast to hydroquinone, it shows no cell cytotoxicity, but it has limited ability to penetrate the skin due to its

hydrophilic nature. The effects of aleosin have been largely demonstrated in pigmented skin equivalents. Not

human-use studies. It is sometimes mixed with arbutin to enhance its

Skin-lightening abilities.

4.6 Arbutin

Arbutin. Chemically known as 4-hydroxyphenyl-beta-glucopyranoside, isobtained from the leaves of the Vaccinium vitis-idaea and other related plants. It

is a naturally occurring gluconopyranoside that causes decreased tyrosinase

activity without affecting messenger RNA expression. It also inhibits melanosome

maturation. Arbutin is not toxic to melanocytes and is used in a variety of pigment-

lightening preparations in Japan at concentrations of 3%. Higher concentrations



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are more efficacious than Jower concenrrauons, but a paradoxical pigment darkening may occur. Arbutin-beta

glycosides have been produced that are less cytotoxic than arbutin.

4.7 Hydroquinone

The gold standard for the treatment of hyperpigmentation in the USA remains

hydroquinone. This substance is actually quite centroversial having been removed

from the aTC markets in Europe and Asia. Concern arose because oral

hydroquinone has been reported to cause cancer in mice fed large amounts of the

substance. While oral consumption probably is not related to topical application.

Hydroquinone remains controversial because, it is toxic to melanocytes. Hydroquinone, a phenolic compound

chemically known as lA-dihydroxybenzene, functions by inhibiting the enzymatic oxidation of tyrosine and

phenol oxidases. It covalently binds to histidine or interacts with copper at the active site of tyrosinase. It also

inhibits RNA and DNA synthesis and may alter melanosome formation. Thus selectively damaging melanocytes

These activities suppress the melanocyte metabolic processes. Inducing gradual decrease of melanin pigment

production. Hydroquinone is still the best option for lightening post-inflammatory hyperpigmentation following

resurfacing.

5. Antioxidants

Antioxidants form one of the most popular categories of cosmeceutical ingredients. This is due tGthe fact that the

major cause of cutaneous aging is oxidation of skin structures from highly reactive oxygen molecules present in

our oxygen-rich environment. It is amazing tG think that the life-giving oxygen required to survive is also the

same oxygen responsible for aging the human body. The primary souree of cosmeceutical antioxidant ingredients

is botanical extracts, since all plants must protect themselves from oxidation following UV exposure. Antioxidant

botanieals function by quenching singlet oxygen and reactive oxygen species, such as superoxide anions

hydroxyl radicals fatty peroxy radicals and hydroperoxides. There are many botanical antioxidants available. Both

from raw-material suppliers and from the cosmeceutical industry and they can be classified in three categones

Carotenoids, flavonoids and polyphenols. Carotenoids are chemically related to retinoids, while flavonoids

possess a polyphenolic structure that accounts for their antioxidant, UVprotectant, and metal chelation abilities

Lastly, polyphenols represent a chemical subset of flavonoids. Antioxidants are found in many skin lines for use

following resurfacing procedures. They are typically placed in moisturizing vehicles that may aid in healing

through the prevention of transepidermal water loss. Whether Cosmeceuticals the antioxidant formulation extends

the effect of a resurfacing procedure has never been documented, yet their frequent use demands a thorough

understanding of their function.



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5.1 Carotenoids

Carotenoids are derivatives of vitamin A and have found widespread use in

cosmeceuticals due to the established topical anti-aging benefits associated with

the prescription retinoid tretinoin. The carotenoids are a large family of orange,

red, and yellow substances that perform vital antioxidant roles when ingested

and are less well established as topical antioxidants. The carotenoids are

discussed in detail here.

5.2 Astaxanthin

Astaxanthin is a pink carotenoid found in high concentration in salmon accounting for the

characteristic pink color of the fish. This is the rationale for anti-aging diets recommending

the ingestion of a serving of salmon fivemtimes weekly. For topical application purposes.

Astaxanthin is obtained from the marine rnicroalgae Haematococcus pluvialis. The efficacy

of astaxanth in is attributed to its cell mernbrane composed of two external lipid layers,

which has been touted to possess stronger antioxidant abilities than vitamin E. Few studies

exist to confirm the topical effect of astaxanthin, but it has been studied extensively as an oral supplement

Astaxanthin in concentrations of 0.03-0.07% produces a pink-colored cream. This limits the concentration that

can be used, but no topical adverse reactions have been associated with this carotenoid. The topical antioxidant

benefits of astaxanthin have not been established.

5.3 LuteinAnother carotenoid found in topical cosmeceuticals is lutein. It is naturally found in green

leafy vegetables. Such as spinach and kale. Lutein is an antioxidant in the plant kingdom, also

being used for blue light absorption, in the animal kingdom, lutein is found in egg yolks,

animal fats and the corpus luteum. It is a lipophilic molecule, not soluble in water,

characterized bya long polyene side chain composed of conjugated double bonds. These

double bonds are degraded by light and heat, a universal characteristic of carotenoids to a

greater or lesser degree. The topical value of lutein in wound healing has never been evaluated.

5.4 Lycopene

Lycopene is a potent carotenoid found in most fruits and vegetables with .a red color

including tornatces, waterrnelon, pink grapefruit, papaya, gac, red beli pepper and

pink guava. Lycopene is a highly unsaturated hydrocarbon containing 11 conjugated



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and two unconjugated double bonds which makes it a longer molecule than any other carotenoid. This makes its

absorption into the skin doubtful. It undergoes cis-isomerization when exposed to sunlight. Even though lycopene

was the new oral supplement added to many commercial multivitarnins this year its topical value has never been

documented. It is safe for skin application, but may stain the skin in high concentration.

5.5 Retinol

Of all the topical carotenoids retinol is the best understood. Since it is necessary

for vision and possesses a weli-characterized skin receptor. It is theoretically

possible to interconvert the retinoids from one form to another. For exarnple.

retinyl palmitate and retinyl propionate. Chemically known as retinyI esters, can

become biologically active following cutaneous enzymatic cleavage of the ester

bond and subsequent conversion to retinol. mRetinol is the naturally occurring

vitamin A form found in red, yellow, and orange fruits and vegetables. It is the pigment responsible for vision but

is highly unstable. Retinol can be oxidized to retinaldehyde and then oxidized to retinoic acid, also known as

prescription tretinoin. It is this cutaneous conversion of retinol to retinoic acid that is responsible for the biologie

activity of some of the new stabilized OTC vitamin A preparations designed to irnprove the appearance of benign

photodamaged skin. Unfortunately, only small amounts of retinyl palrnitate and retinol can be converted by the

skin, accounting for the increased efficacy seen with prescription preparations containing retinoic acid. The main

problem with prescription retinoids is their irritancy. Unfortunately, as the biological efficacy of the retinoid

increases, so does the irritancy. This is also the case with the OTC retinoids. Retinol is more irritating than the

retinyl esters and also more unstable. It is for this reason that cosmeceutical formulations not manufactured understrict oxygenfree conditions prefer to add retinyl palrnitate to moisturizing creams. However, the retinyl palrnitate

may act as an antioxidant for the lipids present in the moisturizer. The topical benefit of retinol has been

documented by weU-controlled studies. It is commonly felt among dermatologists that retinol is of benefit, but it

is difficult in moisturizer studies that do not include vehicle control to separate the retinol benefit from the

moisturizer benefit. Nevertheless of all the carotenoids available for Iermulation. Retinol has the most evidence

to support topical application efficacy following resurfacing.

5.6 FlavonoidsFlavonoids are aromatic compounds, frequently with a yellow color that occur

in higher plants. Five thousand flavonoids have been identified with a sirnilar

chemical structure, possessing 15 carbon atoms and a variety of biologie

activities. Flavonoids can be divided into flavones. Flavonols, isoflavone and

flavones. Each with a slightly different chemical structure. Currently, the most



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common isoflavone incorporated into cosmeceuticals are daidzein and genistein, derived from soybeans. Other

sourees of flavonoids include curcumin, silyrnarin. pycnogenol, and gingko.

5.7 Soy

The soybean-derived isoflavones genistein and daidzein function as

phytoestrogens when orally consumed, and have been credited with the

decrease in cardiovascular disease and breast cancer seen in Asian women.

These isoflavones are present when the soy is fermented. Some of the

cutaneous effects of soy have been linked to its estrogenic effect in

postmenopausal wornen. Topical estrogens have been shown to increase skin

thickness and promote collagen synthesis [35]. It is interesting to note that gemsrein increases collagen gene

excressicn in cell culture, out there are no published reports of this collagen-stimulating effect in topical human

trials. Genistein has also been reported to function as a potent antioxidant, scavenging peroxyl radicals and

protecting against lipid peroxidation in vivo.

5.8 Curcumin

Curcumin is a popular natural yellow food coloring used in everything from

prepackaged snack foods to rneats. It is sometimes used in skin-care products as

a natural yellow coloring in products that claim to be tree of artificial ingredients.

Curcumin comes from the rhizome of the turmeric plant and is consumed orally

as an Asian spice, frequently found in rice dishes to color the otherwise white

rice yellow. However, this yellow color is undesirable in cosmetic preparations.

Since yellowing of products is typically associated with oxidative spoilage. Tetrahydrocurcumin, a hydrogenated

form of curcumin, is off-white in color and can be added to skincare products not only to function as a skin

antioxidant but also to prevent the lipids in the moisturizer from becoming rancid, the antioxidant effect of

tetrahydrocurcumin is said to be greater than vita min E by cosmetic chemists. It is said to provide antioxidant

skin benefits by quenching oxye-gen radicals and inhibiting nuclear factor-KB.

5.9 SilymarinSilymarin is an extract of the milk thistle (Silybum marianums, which belongs to the

aster family of plants including diasies, thistles. and artichokes. The plant is named

milk thistle because the oldest recorded use of the extract was to enhance human

lactation, and because the plant produces a white milky sap. The extract consists of

three flavonoids derived from the fruit, seeds, and leaves of the plant. These



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flavonoids are silybin, silydianin, and silychristin. Homeopathically, silymarin is used

to treat liver discase. But it is a strong antioxidant, preventing lipid peroxidation by

scavenging free radical species. Its antioxidant effect have been Cosmeceuticals

demonstrated topically in hairless mice by a 92% reduction in skin tumors Icllowing

UVB exposure. The mechanism for this decrease in tumor production is unknown but

topical silymarin has been shown to decrease the formation of pyrimicline dimers in amouse model. It has also been found to improve the healing ofburns in albino rats,

which is the rationale for its incorporation into some wound-healing and postresurfacing preparations. Silymarin

is found in a number of high-end moisturizers for benign photoaging to prevent cutaneous oxidative damage and

to re duce facial redness. A double-blind placebo-controlled study in 46 subjects with stage I-UI rosacea found

improvement in skin redness, papules, itching, hydration and skin color. This was felt to be due to its direct

activity on modulating cytokines and angiokines.

5.10 PycnogenolPycnogenol is an extract of French marine pine bark iPinus pinasters. The extract is a

water-soluble liquid containing several phenolic constituents, inelucling taxifolin,

catechin, procyanidins. It also contains several phenolic acids inelucling p-

hydroxybenzoic. Protocatechuic, gallic, vanillic, p-couric, caffeic, and ferulic. It is a

trademarked ingredient, a potent tree radical scavenger that can reduce the vita min C

radical returning the vitamin C to its active form (VI, C). The active vita min C in turn

regenerates vitamin E to its active Iorrn, maintainlng the natural oxygen-scavengingmechanisms of the skin intact. Pycnogenol is the ideal anti-aging additive since it demonstrates no chronic toxicity

no mutagenicity, no teratogenicity, and no allergenicity. In B16 melanoma cells. It was shown to inhibit tyrosinase

activity and melanin biosynthesis. Many discussions of antioxidant flavonoids include a mention of pycnogenol

but few high-quality data are presented.

5.11 Ginkgo

Ginkgo biloba, also named the maidenhair tree, is the last member of Ginkgoaceae

family which grew on earth some 200-250 million years ago. For this reason,

ginkgo contains flavonoids not found in other botanieals. In possesses bilobalide

(a sequiterpene), ginkgolides (diterpenes with 20 carbon atoms), and other

aromatic substances such as ginkgol, bilobdol, and ginkgolic acid. It is a plant with

numerous purported benefits and has been a common part of homeopathic

medicine in East Asia for 4000 years. The plant leaves are said to contain unique polyphenols such as terpenoids



20 | P a g e

(ginkgolides. bilobalides) flavinoids and flavonol glycosides that have antlinflammatory effects. These anti-

inflammatory effects have been linked to anti-radical and anti-lipoperoxidant effects in experimental fibroblast

models. Ginkgo flavonoid fractions containing quercetin, kaempferol, sciadopitysin, ginlegetin, and isoginkgetin

have been demonstrated to induce human skin fibroblast proliferation in vitro. Increased collagen and

extracellular fibronectin were also demonstrated by radioisotope assay. Ginkgo extracts are therefore added to

many cosmeceuticals to function as antioxidants and promoters of collagen synthesis following resurfacing, basedon non-human mode Is of oxidative damage. Polyphenols Polyphenols are a subset of flavonoids used in many

cosmeceuticals. Two main sourees of polyphenols are teas and fruits. This section presents green tea and

pomegranate as examples of the evidence available to support polyphenol biologie activity.

5.12 Green tea

Tea (Camellia sinensis) is botanical popular in East Asia for 5000 years. Used both

topically and orally. There are several different types of teas: green, black, oolong

and white. The different teas come from the same plant, but different processing

imparts different properties. Green tea is made from unfermented tea leaves and

contains the highest concentration of polyphenol antioxidants. Green tea can be

easily added to topical creams and lotions designed to combat the signs of

photoaging but it must be stabilized itself with an antioxidant, such as butylated hydroxytoluene. A topically

applied green tea Cosmeceuticals extract containing GTP ((-)-epigallocatechin- 3-gallate) was found to reduce

UVB-induced inflammation as measured by double skin-Iold swelling. They also found proteetion against UV-

induced edema, erythema, and antioxidant depletion in the epidermis. This was further investigated by applyingGTP 10 the back of humans 30 minutes prior 10 UV irradiation, which resulted in decreased myeloperoxidase

activity and decreased infiltration of leukocytes as compared to untreated skin. The application of topical green

tea polyphenols prior to UV exposure has also been shown to decrease the formation of cyclobutane pyrimidine

dimers. These dimers are critical in initiating UV-induced mutagenesis and carcinogenesis which represent the

end stage of the aging process. Thus green tea polyphenols can function topically as antioxidants

antiinflammatories, and anti-carcinogens, making them a popular cosmeceutical additive.

5.13 PomegranatePomegranate iPunica granatum) is a deciduous tree bearing a red fruit native to

Afghanistan, Pakistan, Iran, and northern India. It was brought to California by the

Spanish settlers in 1769 and is commercially cultivated for its juice. Pomegranate

juice commonly consurned in the Middle East, provides about 16% of the adult

requirement of vitamin C per 100 mg serving. It also contains pantothenic acid,



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also known as vita min B5, potassium. And antioxidant polyphenols. These substances have been demonstrated

to proteet against UVA- and UVB-induced cell damage in SKU-1064 human skin fibroblasts. Pomegranate juice

has also been purposed to reduce oxidative stress and to affect low-density lipoprotein (LDL) and platelet

aggregation in humans and apolipoprotein E-deficient mice. It has also been studied for improving hyperlipidemia

in diabetic patients. It is found in some wound-healing preparations to promote healing, but its value has never

been demonstrated. 6. Other antioxidants used in post-resurfacing

Other antioxidants are commonly found in commercial preparations for use after resurfacing procedures. These

ingredients are used to promo te healing, and they include aloe vera and ubiquinone.

6.1 Aloevera

Probably the most widely used cutaneous botanical anti-inflarnmatory is aloe vera.

The mucilage is released from the plant leaves as a colorless gel containing 99.5%

water and a complex mixture of mucopolysaccharides, amino acids hydroxy

quinone glycosides and minerals. Compounds isolated from aloe vera juice inelude

aloin, aloe emodin, aletinic acid, choline, and choline salicylate. Reponed cutaneous

effects of aloe vera inelude increased blood flow, reduced inflammation, decreased skin bacterial colonization

and enhanced wound healing. The anti-inflarnrnatory effects of aloe vera may result from its ability to inhibit

cyclooxygenase as part of the arachidonic acid pathway. Studies have evaluated the effect of aloe vera on burn

wounds and acne. Aloe vera cream was found to show no tanning or sunburn proteetion and no efficacy in sunburn

treatment as compared to placebo. Rueter and colleagues studied a 97.5% concentration of aloe vera for its anti-

inflammatory effect and demonstrated positive results in a sunburn cell assay as compared to 1% hydrocortisone

These data provide evidence for the anti-inflammatory effect of pure aloe vera gel. However, most products sold

over the counter for under $10 do not contain a high enough percentage of aloe vera to induce clinically relevant

inflammation reduction.

6.2 Ubiquinone

An endogenous antioxidant that has been incorporated into anti-

aging moisturizers is ubiquinone, also known as Coenzyme Q10 or

CoQ10. For a topical I antioxidant to be clinically effective, it must

penetrate into the skin. Hoppe and colleagues from Beiersdorf

demonstrated the topical penetration of ubiquinone into the viable

epidermis and a reduction in oxidation as measured by weak photon emission. They were also able to show a



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significant decrease in the expression of collagenase in human dermal fibroblasts following UVA radiation and

improvement in orbital wrinkling. However, oral supplementation had no effect on the main antioxidant defenses

or pro-oxidant generation in tissues in mice. It also did not affect the life span in mice, according to Shoal and

colleagues. In a .human study, Passi et al. administered 50 mg vitamin E, 50 mg Coenzyme Q10, and 50 mg

selenium. An increase in stratum corneum Coenzyme QI0 was noted after 15 and 30 days of ingestion, but the

significance of this finding was not evaluated. Other evidence suggests that topical Coenzyme QI0 may provideadditive antioxidant benefits when combined with the colorless carotenoids phytoene and phytofluene. This effect

was demonstrated in fibroblast cultures.

7. DEPIGMENTATION AGENTS

Since the introduction of hydroquinone as a skin lightening agent in 1961,

several products with bleaching properties have been used for the

treatment of pigmentary disorders of the skin. The most important medical

indications for the use of these agents are melasma and postinflammatory

hyperpigmentation, although they have also been used as alternative

options for the treatment of ephelides, solar lentigenes, nevi, and lentigo

maligna. This article reviews the most commonly used bleaching agents, discusses their mechanism of action

and focuses on their efficacy and safety in treating unwanted skin pigmentation. Based on our current knowledge

the ideal bleaching agent has to fulfill certain pharmacologic criteria. It should have a potent bleaching effect with

a rapid time of onset (less than 2 to 3 months), carry no short- or long-term side effects, and lead to a permanent

removal of undesired pigment. Most of the currently available bleaching or depigmenting agents cause atemporary removal of hyperpigmentation, which usually recurs after discontinuation of therapy. Presently, there

are three categories of bleaching agents, phenolic compounds, nonphenolic compounds, and combination

formulas.

7.1 Phenolic Compounds

These chemical compounds contain a phenol group. The most important agent of this group is hydroquinone

(HQ), which is considered the most commonly prescribed bleaching agent today. HQ derivatives are the

monobenzyl ether of hydroquinone, the 4-methoxyphenol, the 4-isopropylcatechol, the 4-hydroxyanisol, and the

N-acetyl-4-S-cystaminylphenol. Hydroquinone HQ, a hydroxyphenolic chemical compound, inhibits the

conversion of dopa to melanin by inhibiting the tyrosinase enzyme. These cytotoxic compounds are responsible

for the destruction of pigment cells, which results in skin depigmentation. However, cells are capable of protecting

themselves against cytotoxic agents by intracellular glutathione (GSH). This protection takes place under the

enzymatic action of the detoxification enzyme glutathione S-transferase (GST), which is responsible for the



23 | P a g e

conjugation of toxic species to GSH. The depigmenting effect of hydroquinone is shown to be potentiated by

buthionine sulfoximine (BSO) and cystamine as the result of the reduction of intracellular levels of GSH by these

two agents. Additionally, BSO and cystamine are shown to inhibit the activity of GST. The combination of all-

trans-retinoic acid (tretinoin, TRA) with hydroquinone or 4-hydroxyanisole is also known to produce synergetic

skin depigmentation. TRA serves as a potent inhibitor of mammalian GSTs and is known to make cells more

susceptible to the cytotoxic effect of chemicals by inhibiting the activity of this enzyme. This agent is also shownto reduce the level of intracellular GSH in certain cells. We have proposed that the mechanism of action of TRA

to synergistically enhance the melanocytotoxic effect of chemicals involves the inhibition of GST and the

impairment of glutathione-dependent cytoprotection against melanocytotoxic agents.

7.2 B Nonphenolic Compounds

7.2.1 Azelaic Acid

Azelaic acid (AZA) is a naturally occurring 9-carbon dicarboxylic acid that was

isolated recently from cultures of Pityrosporum ovale and was associated with

the hypomelanosis seen in tinea versicolor. It has been shown to have beneficial

therapeutic effects in acne vulgaris and certain pigmentary disorders, such as

melasma and lentigo maligna. AZA interferes with the function of tyrosinase in

vitro and may also inhibit DNA synthesis and mitochondrial oxidoreductase. It does not appear to affect normal

melanocytes, and treatment of constitutively pigmented normal skin, freckles, lentigenes, and nevi with AZA did

not produce a significant therapeutic result. The drug, however, appears to exert an antiproliferative and cytoxic

effect on hyperactive and abnormal melanocytes and may halt the progression of lentigo maligna to lentigo

maligna melanoma. AZA has been used at concentrations of 15 – 20% for the treatment of melasma and

postinflammatory hyperpigmentation. In double-blind comparative studies, topical AZA achieved a good-to-

excellent response in 60 – 70% of melasma patients, and was found to be more effective than 2% HQ and of

equivalent efficacy to 4% HQ. A combination regimen of AZA with topical tretinoin 0.05% for the treatment of

melasma produced similar results after 6 months compared with AZA monotherapy (approximately 73% of good-

to-excellent improvement), although the addition of tretinoin was associated with an earlier and more pronounced

lightening of melasma pigmentation and a greater percentage reduction of lesion size during the early phase of

treatment. These results suggest that tretinoin augments the efficacy of AZA. In another clinical study, the

addition of 15 – 20% glycolic acid lotion to AZA cream 20% was as effective as 4% HQ cream for the treatment

of facial hyperpigmentation in darker-skinned individuals. At the usual concentrations, AZA is well tolerated in

humans. Adverse reactions such as pruritus, transient erythema, scaling, and irritation are usually mild and subside



24 | P a g e

within 2 to 4 weeks. Allergic sensitization and phototoxic reactions can occur, but are rare. No systemic toxicity

has been reported.

7.2.2 Tretinoin

The use of tretinoin for the treatment of cutaneous hyperpigmentation was

introduced by Kligman in 1975, stemming from his observation that acne

patients receiving tretinoin developed lighter skin after months of treatment.

Tretinoin has been shown in vitro to inhibit both constitutive and induced

melanin formation in melanoma cell lines. In vivo, tretinoin enhances the

epidermal cell turnover, decreasing the contact time between keratinocytes

and melanocytes and promoting the rapid loss of pigment through epidermopoesis. Tretinoin has been used in

concentrations from 0.025 – 0.1% to treat a variety of pigmentary disorders. The bleaching action is usually very

protracted and occurs anywhere within 12 to 44 weeks of continuous daily application. Comparative studies in

melasma patients have shown a 68 – 73% degree of improvement by tretinoin at 40 weeks of treatment compared

with a control group. Moderate cutaneous side effects, such as erythema and desquamation, are observed in the

majority of patients, and in some cases a more severe dermatitis as well as distressing hyperpigmentation have

been reported. When prescribing tretinoin, the use of sunscreen is rather important to counteract the possibility o

sunburn and photo damage.

7.2.3 L-ascorbic Acid

Vitamin C, or L-ascorbic acid (AsA), interferes with pigment production at

various oxidative steps of melanin synthesis, for example 5, 6 dihydroxyindole

oxidation. AsA has a reducing effect on o-quinones and oxidized melanin and

it can alter melanin from jet black to light tan. A disadvantage of AsA is its

chemical instability in aqueous solution where it becomes quickly oxidized and denatures. AsA esters have been

tested in an effort to overcome this problem. A stable derivative of AsA, magnesium L-ascorbyl-2-phosphate

(VC-PMG), was used in a 10% cream base and produced a significant lightening effect in 19 of 34 patients with

melasma after 3 months of twice daily application.

7.2.4 Kojic Acid

Kojic acid (5-hydroxy-2-hydroxymethyl-4-H-pyran-4- one) is a fungal metabolic product that is structurally

related to maltol. It is a potent tyrosinase inhibitor and functions by chelating copper at the active site of the

enzyme. It also acts as an antioxidant and prevents the conversion of the o-quinones of DL-DOPA

norepinephrine, and dopamine to their corresponding melanin. Kojic acid is used in a 1 – 4% cream base, alone or



25 | P a g e

in combination with tretinoin, hydroquinone, and/or a corticosteroid. It appears to act synergistically with glycolic

acid. The addition of 2% kojic acid in a gel containing 10% glycolic acid and 2% HQ was superior to the same

gel without kojic acid in improving the epidermal melasma of 40 women after 12 weeks of treatment. Compared

with 2% HQ, kojic acid alone appears to be less effective. There are scant data from the literature with regard to

its long-term side effects, al-though some investigators have reported a high frequency of contact sensitivity to

this product.

7.2.5 Arbutin

Tyrosinase is the enzyme for conversion of the substrate tyrosine to melanin in melanocytes, providing

pigmentation to skin. Various compounds that bind to the active site of tyrosinase to inhibit its activity have been

developed as agents to lighten skin and ameliorate unwanted pigmentation. These agents include hydroquinone

kojic acid, and arbutin, amongst others. Arbutin is derived from the leaves

of bearberry, cranberry, mulberry or blueberry shrubs, and also is present in most types of pears. It can

have melanin-inhibiting properties. Arbutin and other plant extracts are considered safe alternatives to commonly

used depigmenting agents to make the skin fairer. Medical studies have shown the efficiency of Arbutin for skin

lightening. There are patents controlling its use for skin lightening. Arbutin actually exists in two conformations

alpha and beta. The alpha conformation offers higher stability over the beta conformation and is the preferred

form for skin lightening indications.

8. Hydroxy Acids

Hydroxy acids are organic carboxylic acids classified into alphahydroxy acids (AHA), beta‐hydroxy acids (BHA)

polyhydroxy acids, and bionic acids on the basis of their molecular structure. Hydroxy acids are found in most of

the marketed cosmetic preparation but are used in very low concentration.

8.1 α-Hydroxyacids

The AHAs are organic carboxylic acids with one hydroxyl group attached to the α-

position of the carboxyl group. The hydroxyl and carboxyl groups are both directly

attached to an aliphatic or alicyclic carbon atom. The hydroxyl group in the AHA is

neutral, and only the carboxyl group provides an acidic property. Many AHAs are

present in foods and fruits and, therefore, are called fruit acids. Glycolic acid, the

smallest AHA, occurs in sugar cane and is the most widely used HA in skin care.

Lactic acid, the next smallest AHA, is also widely used in topical formulations to exfoliate and provide antiaging

effects. Some AHAs contain a phenyl group as a side-chain substituent. This changes the solubility profile of the

http://en.wikipedia.org/wiki/Arbutin

http://en.wikipedia.org/wiki/Bearberry

http://en.wikipedia.org/wiki/Cranberry

http://en.wikipedia.org/wiki/Mulberry

http://en.wikipedia.org/wiki/Blueberry

http://en.wikipedia.org/wiki/Pear

http://en.wikipedia.org/wiki/Melanin

http://en.wikipedia.org/wiki/Depigmenting_agents



http://en.wikipedia.org/wiki/Depigmenting_agents

http://en.wikipedia.org/wiki/Melanin

http://en.wikipedia.org/wiki/Pear

http://en.wikipedia.org/wiki/Blueberry

http://en.wikipedia.org/wiki/Mulberry

http://en.wikipedia.org/wiki/Cranberry

http://en.wikipedia.org/wiki/Bearberry




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AHA, providing increased lipophilicity over conventional water-soluble AHAs and can be used to target oily and

acne-prone skin. Examples include mandelic acid (phenyl glycolic acid) and benzilic acid (diphenyl glycolic

acid).

8.2 β-Hydroxyacids

The BHAs are organic carboxylic acids having one hydroxyl group attached to the

β-position of the carboxyl group. The hydroxyl group in the BHA is neutral in

nature and the carboxyl group provides the acidic property. Some BHAs, such as

β-hydroxybutanoic acid, are present in body tissues as metabolic intermediates and

energy sources; however, they have not yet been commercialized in dermatologic

formulations. Some molecules are both an AHA and BHA because they contain a hydroxyl group in the α-position

to one carboxyl group and in the β-position to another carboxyl group. Malic acid (apple acid), for example

contains one hydroxyl and two carboxyl groups, and citric acid contains one hydroxyl and three carboxyl groups

making both molecules an AHA and a BHA. Citric acid is widely used in topical formulations as an antioxidant

and pH adjustor, and its antiaging benefits are well established.5 Although some have termed salicylic acid a

BHA, we do not consider it to be a BHA; for that reason, it is not included in this discussion. Salicylic acid

behaves differently on skin than other HAs, presumably due to its phenolic hydroxyl attachment that renders the

hydroxyl acidic rather than neutral.

8.3 Polyhydroxy acids

The PHAs are organic carboxylic acids with two or more hydroxyl groups in the

molecule attached to carbon atoms of an aliphatic or alicyclic chain. All the hydroxyl

groups in the PHA are neutral, and only the carboxyl group provides its acidity. To

be both an AHA and PHA, also known as a polyhydroxy AHA, it is essential that at

least one hydroxyl group be attached to the α-position. Many PHAs are naturally

occurring, endogenous metabolites, or intermediate products from carbohydrate

metabolism in body tissues. For example, gluconic acid and gluconolactone are

important metabolites formed in the pentose phosphate pathway from glucose during the biosynthesis of ribose

for ribonucleic acid. Gluconolactone is the most commercialized PHA in skin care products, because it is readily

available and delivers the antiaging benefits of HAs, in addition to strengthening skin barrier function and being

a gentle, moisturizing, antioxidant/ chelating substance. For example, an in vitro cutaneous model of photoaging

demonstrated that gluconolactone protects against ultraviolet (UV) radiation. These findings were attributed to

the ability of gluconolactone to chelate oxidation-promoting metals and trap free radicals. In addition,

pretreatment of skin with gluconolactone does not lead to an increase in sunburn cells after UVB irradiation, as



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has been shown to occur with glycolic acid; this is thought to be due to its antioxidant effects. Gluconolactone

can also be formulated with oxidative drugs, such as benzoyl peroxide, to help reduce irritation potential and

erythema caused by the oxidative drug.

8.4 Bionic acids

The BAs are chemically classified as aldobionic acids. They consist of one

carbohydrate monomer chemically linked to an aldonic acid PHA; examples

are lactobionic acid, maltobionic acid, and cellobionic acid. BAs are

commonly obtained from their disaccharide through chemical or enzymatic

oxidation; for example, lactobionic acid is obtained from lactose, maltobionic

acid from maltose, and cellobionic acid from cellobiose. Although the BAs

are larger molecules than traditional AHAs, they are small enough to penetrate

skin at approximately 358 daltons, and their pKa is roughly equivalent to

smaller AHA molecules; for example, the pKa of lactobionic acid is 3.8, which matches that of glycolic acid.

BAs are hygroscopic materials that readily attract and retain water, forming a gel matrix when their aqueous

solution is evaporated at room temperature. The transparent gel contains certain amounts of water, forming a clear

gel matrix. Formation of a gel matrix may add protective and soothing effects for inflamed skin. Indeed

formulations containing BA are well tolerated and help calm skin when applied after cosmetic procedures that

weaken the skin’s barrier, including superficial HA peels and microdermabrasion. One notable protective use of

lactobionic acid, a BA used in some commercial skin care formulations, is as an antioxidant chelator in organ

transplantation preservation solutions. Lactobionic acid reportedly inhibits hydroxyl radical production byforming a complex with the oxidationpromoting metal Fe (II). Furthermore, gluconolactone (a PHA) and

lactobionic acid and maltobionic acid (BAs) inhibit oxidative degradation of hydroquinone and banana peel.

Lactobionic acid also functions as an inhibitor of the matrix metalloproteinase (MMP) enzymes. Excessive

activity of MMPs occurs with age and sun exposure, contributing to wrinkle formation, skin laxity, and visible

telangiectasia. The use of BAs to inhibit MMPs may provide a significant benefit in the prevention of

photodamage.

9. RETINOIDS Vitamin A and its derivatives, both natural and synthetic, have been popular additives in topical for years and are

recognized as the gold standard for the prevention and treatment of photoaging. The following topical retinoids

are recognized as being useful:

Natural retinoids

• Retinol (vitamin A alcohol)



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• Retinyl-palmitate (vitamin A ester)

• Retinyl-acetate (vitamin A ester)

• Retinaldehyde (vitamin A aldehyde)

• Tretinoin (all-trans-retinoic acid)

• Isotretinoin (13-cis-retinoic acid)

•Alitretinoin (9-cis-retinoic acid)

Synthetic retinoids

• Tazarotene

• Adapalene

Tretinoin, isotretinoin, alitretinoin, tazarotene, and adapalene are registered as drugs; the others are

cosmeceuticals (medicinally active cosmetics). Vitamin A and its derivatives exert their action by binding to

specific nuclear receptors. The ligand-receptor complex modulates the expression of the genes involved in cellular

differentiation and proliferation, normalizing cell keratinization. Retinoids might also act independently from the

binding to nuclear receptors. Each of them exerts its own activity, offering a further choice to the dermatologists

who deal with topical retinoids. Although there are several studies proving the efficacy of tretinoin as topical

treatment of photoaging, few studies are available for the other retinoids.

9.1 Tretinoin

Kligman and Willis1 first introduced retinoids for use as photoaging agents. After

its application, the author noticed improvement of skin depigmentation and

rejuvenation. When used on photodamaged skin, tretinoin's clinical effectsinclude improvement of wrinkles, roughness, mottled pigmentation, and skin

appearance as a whole. The histologic changes observed are decreased corneocyte

adhesion (loss of desmosomes, decreased tonofilaments, increased autolysis of

keratinocytes, intracellular glycogen deposition), epidermal hyperplasia,

increased number of Langerhans cells, increased synthesis of collagen and elastin, and angiogenesis. Tretinoin

enhances epidermal cell turnover, decreasing contact time between keratinocytes and melanocytes and promoting

a rapid loss of pigment through epidermopoesis. Tretinoin is available in different concentrations (0.01%, 0.25%

0.5%, and 0.1%) and as different formulations (cream, gel, solution). Creams are generally prescribed for sensitive

skins, whereas gels are prescribed for oily skins. Continuous once-daily application is mandatory to achieve

maximum results, in any case not occurring before a 3-month period. The only clinical improvement that appears

after only 1 month is skin smoothness. To maintain the results, long-term treatment is necessary. There are no

limits to the duration of tretinoin topical use. Moderate cutaneous side effects, especially erythema and





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Tazarotene improves skin roughness, fine wrinkling, and epidermal atrophy. It is available at 0.05% and 0.1%

gel and cream.

9.8 Adapalene

Even if usually indicated for acne, adapalene has also been tested for the

treatment of photoaging. Once-daily application of adapalene 0.1% gel for 4

weeks, followed by a twice-daily application for up to 9 months, significantly

reduced actinic keratoses and lentigines.

10. PEPTIDES

10.1 ANTIMICROBIAL PEPTIDES (AMPS)

Cathelicidins and defensins are the two major groups of epidermal AMPs that possess inherent antimicrobial

activity. Like most AMPs they are positively charged, with the positively charged amino acids localised to oneside of the molecule and opposite to the most hydrophobic groups. Granulysin is also an AMP but whilst it has

action in the skin it is not synthesised in the skin. Other peptides and proteins that exert antimicrobial activity

within the skin are psoriasin, RNase 7, adrenomedullin (AM), antileukoprotease and DCD. Cathelicidins The

expression of cathelicidins and mouse cathelicidin- related antimicrobial peptide (CRAMP) in skin keratinocytes

varies with infection and/or injury. Only one cathelicidin, human cationic antibacterial protein has been identified

in humans, although about 30 cathelicidin members are present in mammalian species. hCAP expression has been

detected in human skin keratinocytes at sites of inflammation in the skin and in specialised keratinocytes of the

nail, neonatal skin and in eccrine glands Cathelicidin peptide (human cathelicidin; LL-37) is produced by the

neutrophils, mast cells and keratinocytes in response to inflammatory processes. LL-37 also acts as a

chemoattractant for neutrophils, monocytes, T cells andmast cells. Mast cells can produce LL-37 thereby leading

to a positive feedback cycle. Elevated levels of LL-37 have been reported in psoriatic skin ( _ 304 mM) and

wounded skin. LL-37 plays an important role in the repair of damaged tissue and wound closure by promoting

wound vascularisation and reepithelisation. It also induces IL-8, IL-18 and IL-20 production by human

keratinocytes through MAP kinase pathway. IL-18, an interferon (IFN)-g inducer, is a proinflammatory cytokine

intracellularly produced from a biologically inactive precursor, pro-IL-18. It is produced by keratinocytes and its

expression is highly enhanced in skin diseases, like psoriasis in which human b-defensins (hbD) and LL-37 are

highly expressed.



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10.2 Defensins

Defensins are cationic peptides (MW 3 – 5 kDa), characterised by six cysteine residues that form characteristic

disulphide bridges. They are divided into alpha, beta and theta subfamilies based on the alignment of the

disulphide bonds. AMPs of the defensin family exhibit broad activity against gram-negative bacteria, fungi,

mycobacteria and enveloped viruses and have been isolated from neutrophil granules, macrophages and some

specialised epithelial cells of the small intestine. a-Defensins Six alpha defensins have been identified, of which

four are known as human neutrophil peptides (HNP)-1, 2, 3 and 4, as they are associated with human neutrophils

The other two are called human defensins (HD)-5 and 6. They are expressed in the paneth cells of the intestine

and in the epithelial cells of the female genitourinary tract.21 Alpha defensins exert their action on both microbes

and the host. They have potent antiviral activity and HNPs 1 – 3 have been shown to increase the expression of

tumour necrosis factor (TNF) a and interleukin-1 in human monocytes activated by Staphylococcus aureus. The

expression of alpha defensins has been studied in squamous cell carcinomas of the human tongue and compared

with autogenous nontumour tissue. HPLC-MS and amino acid sequencing was utilized for separation, structural

identification and quantitation of the HNPs. MALDI-MS analysis of HPLC fractions from both tumour and

nontumour tissue detected peptide masses for HNP-1, HNP-2 and HNP-3 which were confirmed by amino acid

sequencing. When analysis of paired tumour and nontumour tissue samples was performed, the concentration of

defensins in the tumour tissue was about 2 – 12 times higher than in the nontumour tissue. b-Defensins Beta

defensins have been identified in many cell types including epithelial cells and neutrophils. HbD 1 – 4 have been

identified in humans. HbD-1 (MW 3.9 kDa) is constitutively produced by various epithelial tissues including the

urogenital and respiratory tracts.u

-Defensins This is a novel class of defensins isolated from rhesus monkeyneutrophils and named u-defensins for their circular molecular structure.

10.3 Psoriasin

Another peptide discovered in psoriatic skin lesions is psoriasin. Psoriasin is an

AMP (MW 11 kDa) which is constitutively expressed in healthy skin

keratinocytes and is a member of the S100 gene family. Although the

physiological function of S100 proteins is not fully understood, a few studies have

indicated involvement of S100 proteins in innate host defence. Over-expression

of psoriasin may be linked to inflammation which is common in psoriasis. Glaser

et al. also identified psoriasin as the principal Escherichia coli-killing AMP in

healthy human skin, which is present on the skin surface and focally expressed in healthy skin keratinocytes

Psoriasin was induced in vitro and in vivo in keratinocytes by E. coli, indicating that its focal expression in skin



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may be derived from local microbial induction. Zn2þ-saturated psoriasin showed diminished antimicrobia

activity, suggesting that Zn2þ sequestration could be a possible antimicrobial mechanism.

10.4 RNase 7

RNase 7 (MW 14.5 kDa) is a basic protein that is abundant in healthy skin and is believed to be one of the

principal cationic proteins of healthy human skin.40 The RNase A superfamily has been extensively researched

over the last few decades and among the better characterised RNases are RNase 1 and RNase 5. Others include

eosinophil cationic protein (ECP) or RNase 3, and RNases 4, 6, 7 and 8. These were identified by Harder and

Schro¨der40 who showed that crude extracts from stratum corneumcontained antimicrobial activity against E.

coli and S. aureus. RNase 7 may be an inducible peptide since the levels are high in psoriatic skin and gene

expression is increased on contact of keratinocytes with bacteria. Adrenomedullin AM (MW 6 kDa) is a 52 amino

acid peptide which is expressed in keratinocytes of the epidermis and hair follicles, cells of the eccrine, apocrine

sweat glands and secretory ducts of normal skin, and in skin tumours of different histologies. AM is reported to

have numerous physiological roles including vasodilation, renal homeostasis, hormone regulation

neurotransmission and growth modulation. It is also thought to be involved in the wound repair process. Martinez

et al. characterised adrenomedullin receptor (AM and AM-R) expression in human skin in order to understand its

potential functions in the skin. The presence of AM and its receptor in normal and neoplastic skin were confirmed

by RT-PCR and Western blot analysis performed on cell extracts from human skin cell lines. Immunoreactivity

for AM and in situ hybridization signal for AM-R was found in all epithelial components of the skin. Many

specimens corresponding to the major histological types of skin cancer showed a positive staining for AM and

AM-R. Antileukoprotease Antileukoprotease (ALP), also called mucous protease inhibitor or secretoryleukoprotease inhibitor, is present in human callus and detected in supernatants of cultured human primary

keratinocytes and in various human body fluids. It is a very potent human serine protease able to inhibit the

neutrophil derived serine proteases polymorph nuclear leukocyte elastase (HLE) and Cathepsin G (CG). Wiedow

et al. described the constitutive production and release of ALP by human keratinocytes and epithelial carcinoma

cell lines (KB grown in Dulbecco’s Modified Eagle and A431 grown in minimum essential medium). When the

antimicrobial activity of ALP was compared with HbD-2, ALP was seen to be constitutively produced and

expressed by the keratinocytes whereas HbD-2 is only expressed after stimulation of keratinocytes with bacteria

Recombinant ALP exhibited microbiocidal activity in a dose-dependent manner.

10.5 Dermicidin 1L

DCD-1L is a novel AMP family with a broad spectrum of activity and no similarities to other known peptides. It

is constitutively expressed in eccrine sweat glands and transported to the epidermal surface. DCD expression was

not observed in epidermal keratinocytes of healthy human skin. Immunohistochemistry and RTPCR studies



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showed that DCD-1L expression was not induced in keratinocytes in inflammatory conditions such as psoriasis,

AD and lichen planus. DCD-1L thus functions by modulating the colonisation of the skin rather than responding

to inflammation. Lai et al. further expressed DCD-1L in E. coli as a fusion protein to understand its mechanism

and investigate its antimicrobial spectrum. DCD-1L displayed antimicrobicidal activity against nosocomial

pathogens, but no haemolytic activity against human erythrocytes. The antimicrobial activity of DCD was not

affected by the low pH and high salt concentrations of human sweat. This finding suggests that sweat glands mayhave a function in the innate immune responses of the skin by secreting these antimicrobial agents.

11. PEPTIDES INVOLVED IN WOUND HEALING

Wound healing is a localised process which involves a series of specific and coordinated events such as

inflammation, wound cell migration and mitosis, neovascularisation, and regeneration of the extracellular matrix

(ECM).

11.1 RGD Peptides

Most cells are attached to the ECM through integrins that link the intracellular cytoskeleton with the ECM. Many

of the integrins recognise a tripeptide (arginine-glycine-aspartate) or RGD in target proteins of the ECM. Vigor

et al hypothesised that during the proteolytic remodelling of the ECM, small soluble RGD-containing peptides

were released into the matrix. Soluble RGD-peptides have previously been found to be internalized into a cell in

an integrin-independent manner and are able to directly bind to and activate caspase-3, thus inducing apoptosis

To investigate this hypothesis dermal fibroblasts were embedded into collagen type I or fibrin matrices and

viability was assessed by in situ haematoxylin staining. Results indicate that apoptosis was induced specifically

in response to collagen matrix remodelling. Small soluble RGD containing peptides were produced by enzymatic

cleavage of collagen, which induces apoptosis of dermal fibroblasts through specific caspase-3 cleavage.

11.2 Copper Peptides

Copper peptides have been used in skin care in a similar way to vitamin C, alpha lipoic acid and green tree

extracts. Copper functions as a part of cytochrome c oxidase and superoxide dismutase which are used in energy

production and as antioxidants. It is also essential to the normal growth, development and function of the human

body. Copper is bound to glycine, histadine and lysine which are used to synthesize a copper based peptide

Copper peptide has a positive influence on the growth and regulation of hair follicles and when used on wounds

increases collagen disposition, tensile strength and angiogenesis in healing tissues. A method for stimulating hair-

growth by topically administering or injecting an effective amount of a peptide copper complex has been

described and patented. Buffoni et al. examined the effects of Gly-His-Lys-Cu and of three synthetic analogues

(I, II and III) on wound healing of guinea-pig dorsal skin and on cultured fibroblasts. Hydroxyproline, proteins



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DNA and semicarbazide-sensitive amine oxidase were measured and it was found that both the peptides caused

a decrease in the activity of semicarbazidesensitive amine oxidase but there was no significant difference between

the two peptides .The main effects of these peptide-copper complexes were slower reorganization of the skin and

a delayed activation of fibroblasts.

11.3 Interleukins (IL)

Interleukins are a class of cytokines identified for their role in mediating immunological functions. IL-1 is

produced by keratinocytes in two forms: IL-la and IL-lb. IL-6 (MW 26 kDa) is secreted from the cells in multiple

glycosylated forms. Like TGF-a, the levels of IL-6 are elevated in psoriasis, cultured keratinocytes and skin

tumour cell lines. IL-8, also known as neutrophil activating protein (NAP), mediates both growth stimulatory and

inflammatory processes. It is produced by cultured human dermal fibroblasts and keratinocytes in response to IL-

1 or TNF-a. Rennekampff et al. hypothesised that IL-8 was released from an intracellular preformed pool in

keratinocytes in the presence of psoriasis. Sticherling et al. showed that IL-8 is produced de novo by wound cells

leading to increased reepithelialisation in vitro and in vivo by stimulating keratinocyte proliferation and migration

They investigated in vitro whether IL-8 upregulates the underlying phenotype of keratinocytes with respect to the

expression of integrin subunits a2, a3, a5 and a6. An inverse relationship between IL-8 immunoreactivity and

expression of the a6 integrin was found and loss of intracellular IL-8 immunoreactivity was accompanied by an

increase in a6 expression. Flow cytometry analysis revealed strong expression of integrin subunits a2 and a3 and

weaker expression of a5 and a6 on cultured, unstimulated keratinocytes. IL-8 was shown to be the major bioactive

chemoattractant for PMNs in human blister and skin graft donor site wound fluids. In vitro experiments on the

effect of recombinant human (rh) IL-8 on keratinocytes proliferation revealed a rise in cell number accompanied by an increase in cells in S phase and over-expression of the integrin. Topical application of IL-8 on human skin

grafts in a chimeric mouse model showed enhanced reepithelialisation in IL-8 treated animals over controls.

12. Growth Factors

Growth factors act as regulators in wound healing and on exogenous application can modify the process. Two

peptide growth factors which play a pivotal role in normal wound healing in tissues such as skin, cornea and the

gastrointestinal (GI) tract are the structurally related peptides epidermal growth factor (EGF) and transforming

growth factor alpha (TGF-a). Other peptides such as basic and acidic fibroblast growth factors (bFGF and aFGF)

platelet derived growth factors (PDGF-AA, -AB and -BB) and insulin-like growth factor (IGF-I) have been

identified as potential wound-healing agents. EGF/TGF-a receptors are expressed by many types of cells

including skin keratinocytes, fibroblasts, vascular endothelial cells and epithelial cells of the GI tract. Healing of

a variety of wounds in animals and patients has been enhanced by treatment with EGF or TGF-a. EGF also

increased the tensile strength of skin incisions in rats and corneal incisions in rabbits, cats and primates. Sorensen



35 | P a g e

et al. demonstrated that two of the important growth factors in wound healing, IGF-I and TGF-a, induce the

expression of the AMPs/polypeptides hCAP-18, hbD-3, NGAL and SLPI in human keratinocytes.

Growth hormone (GH) and prolactin (PRL) are produced in the anterior pituitary gland and skin is one of the

target organs for GH and prolactin bioregulation. Dermal fibroblasts in cell culture have been shown to produce

PRL and GH mRNA. Slominski et al.64 investigated whether the epidermis expresses the genes for GHand PRLDetectable levels of GH and PRL were not found in human immortalized keratinocytes or in malignant

melanocytes (basal cell carcinoma) but IGF-1 was expressed in malignant specimens. GHmRNA was detected in

normal human skin but not in cultured human epidermal keratinocytes. Transforming Growth Factor-b

Transforming growth factor-b (TGF-b) can act as a multi-functional regulator of both cell growth and

differentiation. Three isotypes of TGF-bs namely TGF-b1, TGF-b2 and TGF-b3, have been found in human

tissues. TGF-b2 is usually expressed in the intercellular space of all the layers of the epidermis and TGF-b3 is

present in the subepidermal area of the dermis. Falanga et al. could not detect TGF-b1 or TGF-b2 in the epidermis

or epithelial structures of forearm skin from healthy human volunteers. The dermal matrix contained minimally

detectable amounts of the two isoforms. In all cases, the dermal matrix and cells contained greater amounts of

TGF-b1 than TGF-b2.

13. CONCLUSION

The usage of cosmeceuticals has drastically hiked in recent years, which in turn has increased the spectrum of the

physician to broaden their range of products to enhance the comeliness of the patients associated with derma

problems. However, at times, where generations are keenly worried for their beauty, lots of manufacturingcompanies are competing and working hard to provide convincing results to meet requirements of the patients

Claims of effectiveness lack convincing evidence, thus the industry is challenged to provide evidence on the

effectiveness of these compounds. Cosmeceuticals like vitamins, sunscreens, hydroxyl acids & many more have

diseases thus enhancing the skin texture. Clinical trials of cosmeceuticals are important to know the interaction

skin and cosmeceuticals which could even be influenced by environmental fact.

14. REFERENCES

1. Asian Journal of Pharmaceutical and Clinical Research: COSMECEUTICALS FOR THE SKIN: AN

OVERVIEW Vol. 4, Issue 2, 2011 ISSN - 0974-2441

2. Tropical Journal of Pharmaceutical Research June 2011; 10 (3): 351-360 Herbal Cosmeceuticals for

Photoprotection from Ultraviolet B Radiation: A Review AK Mishra1, A Mishra, and P Chattopadhyay

3. Dermatologic Therapy, Vol. 19, 2006, 289 – 296 Printed in the United States ISSN 1396-0296 Retinoids in

cosmeceuticals



4. Thomas C. Tsai, BS and Basil M. Hantash, Cosmeceutical Agents: A Comprehensive Review of the Literature

5. H. Dureja, D. Kaushik, M. Gupta, V. Kumar, V. Cosmeceuticals: An emerging concept Lather Indian JPharmacol | June 2005 | Vol 37 | Issue 3 | 155-159

6. International journal of pharmaceutical sciences and researches, SAHA IJPSR 2012, vol: 3(1):59-65 ISSN:0975-8232, Cosmeceuticals and herbal drugs: Practical uses.

7. Skin Peptides: Biological Activity and Therapeutic Opportunities SARIKA NAMJOSHI, RIMA CACCETTAHEATHER A.E. BENSON School of Pharmacy, Curtin University of Technology, Perth, Western AustraliaAustralia8. Riccarda Serri, MD, Matilde Iorizzo, MD , Cosmeceuticals: focus on topical retinoids in photoaging .

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