Abstract
The type and amount of melanin synthesized by the melanocyte, and its distribution pattern in the keratinocytes, determines the actual color of the skin. Melanin is obtained through a series of oxidative reactions involving the amino acid tyrosine in the presence of the enzyme tyrosinase. In particular, tyrosinase catalyses different reactions: the hydroxylation of tyrosine to L-DOPA and the oxidation of L-DOPA to dopaquinone that is then converted by a series of complex reactions to melanin. Among the skin-lightening and depigmenting agents storically used in skin whitening products, we find magnesium-L-ascorbyl-2-phosphate (MAP), hydroquinone (HQ), arbutin (hydroquinone-beta-D-glucopyranoside), hydroxyanisole and N-acetyl-4-S-cysteaminylphenol. However, in consideration of reports of potential mutagenicity and epidemics of ochronosis for the main part of these actives, there has been in the last years an increasing trend in finding alternative herbal and pharmaceutical depigmenting agents. According to the literature available data, several other mole– cules with a much more better toxicological profile together with good efficacy are available today as whitening/lightening agents. Azelaic acid, one of these molecules, is today well known to most dermatologists for its good tossicological profile associated with effi– cacy and multitasking actions able to assure, together a lightening action, also a more healthy skin thanks to its additional antibacte- rial and antioxidant/lenitive action. According to this, it is concluded that azelaic acid is a multi actions active that can find large application in the formulation of skin care lightening products. In addition, the preparation tips of a formulation (skin whitening cream) containing 10% of an ultra-pure, micronised, 100 % obtained from sunflower oil ingredient are discussed.
Introduction
Up to 10% of skin cells in the innermost layer of the epidermis produce a dark pigment known as melanin. Upon exposure of the skin to UV radiation, melanogenesis is initiated with the first step of tyrosine oxidation through an enzyme called tyrosinase (1). Tyrosinase is a multifunctional, glycosylated, copper containing oxidase that is found exclusively in melanocytes (2). It is therefore a good specific marker for the cells. Tyrosinase is synthesized by melanosomal ribosomes found on the rough endoplasmic reticu- lum 3. The biosynthetic pathway for melanin is mainly based on three steps. The first two steps in the pathway are hydroxylation of L-tyrosine to 3-4-dihydroxyphenylalanine, L-DOPA and the oxi- dation of L-DOPA to o-dopaquinone. This o-quinone is a highly reactive compound and can polymerize spontaneously to form melanin pigmentation. Such a reactivity can bring to some prob- lems in humans. For examples, exogenous causes, particularly ultra-violet light exposure, are a common factor in pigment ab- normalities such as melasma, solar lentigines and ephelides4. Also exposure to certain drugs and chemicals as well as the exist- ence of certain disease states can result in hyperpigmentation.
The type and amount of melanin synthesized by the melano- cyte, and its distribution pattern in the surrounding keratinocytes, determines the actual color of the skin.
Depigmentation and skin lightening products, which have been in use for ages in Asian countries where skin whiteness is a major esthetic criterion, are now also highly valued by Western popula- tions, who expose themselves excessively to the sun and develop skin spots as a consequence (5).
The allure of a pale complexion is nothing new and many doc- tors have been looking into this subject for some time, proposing diverse and varied recipes for eliminating all unsightly marks (freckles and liver spots were clearly targeted). Pliny the Elder (Naturalis Historia), Dioscoride (De Universa medicina), Castore Durante (Herbario nuove), and other authors from other time pe- riods have addressed this issue. In the 16th century, Durante pro- posed diverse plant-based preparations, for example herbal teas prepared from Erythreae centaurium, Chamaeleon root, pow- dered Gentiana verna root mixed with honey, lemon juice, to name a few (6).
In sub-Saharan Africa where the practice is common, herbal teas are still being prepared from local plants (Tephrosia vogelii, Mirabilis jalapa, Phytolacca dodecandra). In Rwanda, about thirty plants are traditionally used to lighten the complexion of girls for certain ceremonies, such as marriage, for instance. The use of preparations to lighten skin tone is referred to as “voluntary de- pigmentation”. Depending on the African country in question, the procedure may be called “xessal” (Senegal), “tcha-tcho” (Mali), “ambi” (Gabon), “maquillage” (Congo), “kwitukuza”, which liter- ally means “making one’s skin red” (Rwanda) (7). Illegal cosmetics or preparations, in other words ones not regulated by any drug laws or cosmetics laws, may be used to achieve the desired re- sults. Steroids, hydroquinone and its derivatives, kojic acid, and mercury derivatives are the most commonly used active ingredi- ents. They are far from being harmless. Undesirable effects (hypercorticism) may be observed in subjects using dermocorticoids. Applying high-dosage preparations on large areas of skin can lead to an overall change in the state of health (skin atrophy, arte- rial hypertension, osteoporosis, diabetes, etc.) of the patient. A study sponsored by Chanel and conducted on around forty Chinese women in 2014 revealed that the “purity of the complexion” had an influence on the presumed age of a person. The Chinese women on the panel saw the lightening of skin spots with photo- graph retouching software as a means of giving the impression that one is four years younger than one’s actual age, versus just two years for wrinkle smoothing (8). Considering these results, the interest of Japanese and Chinese women in depigmentation prod- ucts becomes more understandable, as they are viewed as verita- ble anti-aging products.
The elite of Caucasian populations were preoccupied with the search for a pale complexion for centuries, until the discovery of tanning in the 1930s reversed the situation. However, overexposure to the sun still pushed the demand of Europeans for effective anti-dark spot preparations. Lastly, melasma, a type of skin hyper- pigmentation linked to pregnancy, to thyroid disorders, and to certain drug treatments (contraceptives), is yet another reason for using skin lightening cosmetics (9).
So hyperpigmentation is a common skin condition that refers to any darkening of the skin. Dark patches form usually on the face and hands or other areas that are commonly exposed to the sun. This darkening of the skin occurs when an excess of melanin forms deposits in our skin.
Azelaic acid as lightening / depigmenting agent in skin care products
In 1978, the tyrosinase-inhibiting activity of certain lipid frac- tions, mainly C9–C11 dicarboxylic acids, was demonstrated for the first time in vitro. The interest in azelaic acid, which is a C9-dicarboxylic acid, for treating pigmented lesions thus en- sued 10.
Azelaic acid is a naturally occurring C9 dicarboxylic acid de- rived from Pitysporum ovale. Its depigmenting activity appears to be mediated by inhibition of mitochondrial oxidoreductase acti- vation and DNA synthesis, although it is also a competitive and reversible inhibitor of tyrosinase. Its lightening effect appears to be selective and most apparent in highly active melanocytes, with minimal effects in normally pigmented skin11.
This acid is produced naturally by a yeast, Malassezia furfur. Its inhibitory activity against tyrosinase is reflected in the appear- ance of depigmented maculae on the skin of subjects suffering from a mycosis, Pityriasis versicolor12. This fungus produces li- poxygenases that are capable of acting on the unsaturated fatty acids present on the skin surface. In culture, this fungus is capa- ble of oxidizing oleic acid into azelaic acid (10).
About azelaic acid, there is unanimous agreement regarding its efficacy and absence of undesirable effects of note. It is a natural skin bleaching agent and a naturally effective lightener for the skin. It has the advantage of giving a paler skin, naturally. Many studies are available today to show this ingredient is able to light- en complexion.
A placebo-controlled clinical study conducted on 52 women with dark or pigmented skin (phototypes IV to VI) suffering from melasma demonstrated the superiority of a cream containing 20% azelaic acid. The women found their skin was smoother and were thus satisfied overall 12. The anti-inflammatory, anti-keratinizing
and bacteriostatic activity of azelaic acid justifies its use also in depigmenting skin with diseases such as rosacea or acne (12), (13).
In a 6-month study (14) on 132 Asian women with melasma, a mean 4 years of treatment with azelaic acid caused both a greater lightening of pigmented lesions and a reduction in lesion size. In another study (15) azelaic acid was applied at concentrations of 15% or 20% twice daily for 3 to 12 months. Clinical and histologicalresolution in facial lentigo maligna was obtained and it was suc- cessful in treating rosacea, solar keratosis and hyperpigmentation associated with burns and herpes labialis.
In conclusion, azelaic acid is generally well tolerated and can be used for extended periods. Its most frequent side effects in- clude transient erythema and cutaneous irritation characterized by scaling, itching and burning, which generally resolve after 2–4 weeks of application (15).
Considering here are different ways to combat hyperpigmenta- tion, sometimes, It may useful also to combine different whiten- ing/lightening active agents in the same cosmetic formulation. This was demonstrated by a study (16) sponsorized by Pierre Fabre Dermocosmetique, based on the use of a combination of azelaic acid with oligopeptide-68 and glycolic acid, where the efficacy of this active combination in a dermo-cosmetic serum on reducing actinic lentigo and improving photoaging was evaluated. The aim of this monocentric open-label clinical study was to assess the clinical and instrumental efficacy and tolerability in use condi- tions of a serum containing a complex based on oligopeptide-68 2%, azelaic acid 8% and glycolic acid 3% for photo-aged skin dur- ing 12 weeks. This association already demonstrated an anti-ag- ing efficacy on human cutaneous explants. 42 Caucasian volun- teers (45 – 70 years old) were included and analyzed. At inclusion (D0), subjects presented peri orbital wrinkles graded 3 to 6 (from 1 to 9 scale) and at least one target facial lentigo. This serum was applied on face and neck twice daily (morning and evening), clin- ical and instrumental photo-aging signs assessments were per- formed. The local score for the target lentigo improved signifi- cantly after 4, 8 and 12 weeks of serum application (42% of im- provement). AEVA assessment showed a significant improvement of the rough structures (deep wrinkles) after 4 weeks (p=0.008).
So azelaic acid seems very reliable for lightening the complex- ion, and we feel it’s a great alternative to other types of skin light- eners, here’s why: First and foremost, it’s much safer of the main part of the available alternative products; its ability to lighten complexion is also thanks to anti-inflammatory and successfulability in treating various forms of acne. Two advantages in one active ingredient. It’s safe for all skin complexions, especially those with a deeper and darker skin tone. It’s effective in bringing life back into dull and aged skin by brightening and evening out the tone of your skin. Unlike hydroquinone, azelaic acid does notaffect the pigments of the skin, but rather tackles abnormal mel- anocytes (small melanin cells) instead.
Azelaic acid may be used in the personal care products, in med- ical devices and in pharmaceutical products of many countries without concentration limitations. It shows no significant side effects, it has no cytotoxic properties and does not exhibit CMR (Carcinogenic, Mutagenic and Reprotoxic) properties. The major constraint for the use of azelaic acid is its solubility. However, the solubility problem of azelaic acid can be solved using particular
solvent systems or using smart formulation techniques. Because of the poor solubility the bio-availability is also limited, but that problem may simultaneously be solved while tuning the solubili- ty. Several commercial personal care preparations containing 5 – 12% azelaic acid are today available on the market.
Today several grades of azelaic acid are available, some of them are derived from animal sources some other from vegetable sources. AZECO Cosmeceuticals has developed and placed on the market an ultra-pure, micronised cosmetic-grade of azelaic acid with vegetable origin, COSMOS approved.
Table 1 shows the main characteristics of this grade of azelaic acid.
This grade of azelaic acid is the ideal active ingredient for a variety of personal care products (also COSMOS / ECOCERT approved), providing not only lightening / brightening action but all together important benefits. Here’s a brief overview:
Benefits/Claims
- Effective in the treatment of oily and impure skin.
- Provides a progressive lighte- ning/brightening effect for a more uniform complexion.
- Reduces skin pigmentation and color irregularities such as age spots , revealing smoother, brighter, more supple skin with fewer irregularities.
- Improving the appearance of sun damaged skin and fighting skin aging.
- Enhancing performance of certain topical over-the-counter, drugs or quasi-drugs and prescription products.
Applications
- Moisturizing skin creams, serum and lotions, cleansers and to- ners. Men’s skin care products.
- Creams, serums, lotions, clean- sers, and toners designed to reduce the signs of aging. Whitening products, skin peeling products. Men’s skin care pro- ducts (also after-shaving pro- ducts).
- Moisturizing skin creams, serum and lotions, Moisturizing skin creams, serum and lotions. Men’s skin care products.
- Acne treatment combinations, skin lightening/whitening com- binations, sunscreen combinations. Men’s skin care products.
An example of finished whitening cream for skin care
To complete the proposal for the skin care application, Azeco Cosmeceuticals has developed some finished formulas based on 10% of its azelaic acid (micronised, then easy to be formulated) to be used daily (once or twice a day) to brighten dark spots, even skin tone. As an example we report here the data relative to a non- comedogenic and hypoallergenic lightening/whitening cream to act against hyperpigmentation caused for example by breakouts or by solar exposition. It’s targeted towards all skin types. Consistently applied will help also to keep breakouts at bay and decongest clogged pores.
The table below contain the formulation, while just after the tips on how prepare an homogeneous and stable cream are reported.
Suppliers :
[1] Evonik
[2] Croda
[3] Jan Dekker / IMCD
Specifications:
Appearance Soft light cream
Colour White
Odour Characteristic
pH Not applicable
Typical: Not applicable
Brookfield Viscosity (R4, 50 rpm, 25°C) 2150 ± 25 % mPas Typical: 2150 mPas
Manufacturing instructions:
- Prepare the Oil Phase (Phase B), being sure all the Butters and Waxes are completely dissolved (at about 70°C);
- Add the ingredients of Phase C to this phase gradually while stirring at temperature and keep stirring for at least 1-3 hours (mainly depending on the batch size and on the efficiency of the used equipment) to be sure of the complete dissolution of the powder. A white/beige, creamy and without powder residues mixture has to be obtained. This is the most critical step of the preparation. It is very important, for the storage stability of the obtained product, to stop the mixing only when a all the azelaic acid is completely solubilised;
- Prepare the water phase (Phase A), warming up to 40 – 50 °C;
- Mix together the two phases (Water Phase into Oil Phase) very gradually, from the beginning to the end of the process, mixing only with blades at middle-low speed, without the use of the turbine. The turbine has to be used only after the union at low speed for 5 minutes at most. Then slowly cool the cream.
- Add the fragrance
INCI list:
Ingredients: Aqua, Azelaic Acid, Octyldodecanol, Ethylhexyl Palmitate, Isopropyl Isostearate, Propanediol, C12-15 Alkyl Benzoate, PEG-30 Dipolyhydroxystearate, Tocopheryl Acetate, Butyrospermum Parkii Butter, Magnesium Sulfate, Caprylyl Glycol, Glyceryl Caprylate, Ethylhexylglycerin, Parfum
Shelf life: 3 years after production, 12 months after opening. Store at ambient temperature, out of direct sun light. Preferred packaging: tube, 30 ml.
Conclusions
Azelaic acid, mainly if 100% bio-based and palm oil free, ob- tained by a sustainable process from a definite vegetable source (sunflower oil) is the perfect choice for high-performing (multi- action way to act) and sustainable cosmetic solutions for skin care.
According to the high number of scientific published data, it is the ideal active to treat skin to inhibit the pigment producing enzyme tyrosinase, it has comedolytic properties and may reduce epidermal hyperkeratinization. It has been shown to be effective in the treatment of hyperpigmentary disorders such as chloasma and lentigo maligna, and to have a cytotoxic effect on the human malignant melanocyte. While treating cases of chloasma with top- ical application of an azelaic acid cream, it was observed, and confirmed by patients, that lesions of acne within the areas being treated showed significant improvement.
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