Azelaic acid in suncare products

Azelaic Acid, a dicarboxylic acid, thanks to its antibacterial, antioxidant, keratolytic and comedolytic activity, is gaining every day more and more popularity in the skincare sector. Azelaic acid is a naturally occurring C9 dicarboxylic acid derived from Pitysporum ovale, it is also naturally produced by a yeast, Malassezia furfur. An active with these abilities can surely find its applicability in sunscreen and after-sun products.

Knowledge of skin biology and of the chemistry of UV filters and formulations has strongly improved in the last 30 years, enabling cosmetic chemists to formulate unique and effective sunscreen products and after- sun formulations. Moreover, efficacy testing methods for these products have become almost standardized worldwide. Thus in normal skin, sunscreen and after-sun formulations can be applied topically to reduce the negative effects of sun exposure. However, for various reasons, they are very often inadequate or inappropriate in the case of acne-prone skin or more generally of skin with other disorders, from the most simple such as a high sebum production, to the more serious such as melasma, rosacea, etc. One of the main problems coming from the above listed skin disorders is hyperpigmentation, in general caused by the overproduction of melanin. Common hyperpigmentary disorders, in fact, include, but are not limited to, post- inflammatory hyperpigmentation (PIH), melasma and solar lentigines or sunspots. PIH results from excess pigment that evolves after trauma such as burns, acne, allergies and others.

APPLICATION OF AZELAIC ACID IN SUNSCREEN PRODUCTS

Post-inflammatory hyperpigmentation typically results from inflammation, e.g. it is caused by acne or skin injury, and it occurs most frequently with patients of Fitzpatrick skin types IV-VI (1). Melasma is characterized by patches of discoloration—typically facial—as a result of pregnancy-related hormonal changes, oral contraceptives or sun exposure (2).

Pathak et. al., hypothesizing that sun exposure exacerbates hyperpigmentation, showed ultraviolet (UV) irradiation appeared to cause cellular injury, leading to an increased synthesis of proteins, melanosomes and tyrosinase that ultimately yielded new melanin (3).

Many of the numerous conditions that contribute to acne are actually accentuated during the summer months when exposure to sunlight is maximized. Thus, how can sunscreen products be formulated and used in a way that maximizes their acne-control benefits in the setting of acne-prone skin? A possibility is the formulation of a sunscreen product not only intended to protect skin against sunlight but also to exhibit activity on skin disorders.

Due to sunlight’s influence in hyperpigmentation, sunscreen is a common part of treatment in clinical trials. Sunscreens are used for photoprotection not only for hyperpigmentation, but also for preventing sunburn, DNA damages, photo-immunosuppression and photoaging. Two common forms of sunscreens, chemical and physical, are able protect the skin. In chemical sunscreens, chemicals such as avobenzone or ethylhexyl methoxycinnamate are able to absorb UV light of certain wavelengths (in the UVA range the first and in the UVB range the last). Zinc oxide and titanium dioxide, micronized and then in a nano size, are physical sunscreens commonly used in cosmetic products. Sunscreen Protection Factor (SPF) provides a quantitative value on the effectiveness of a sunscreen formulation. By definition, is a measure of how much solar energy (UV radiation) is required to produce sunburn on protected skin (i.e., in the presence of sunscreen) relative to the amount of solar energy required to produce sunburn on unprotected skin. As the SPF value increases, sunburn protection increases. The SPF indicates mainly UVB protection.

Then, when the target is a skin with disorders, the SPF value is not the only parameter to be taken in consideration, because the final product has also to be compatible with this kind of skin without worsen the clinical frame, rather going to improve it.

Although one important factor for the above discussed skin disorders is the increase of sebum production, three additional factors have to be considered: ductal cornification, bacterial colonization of the pilosebaceous duct and inflammation (1). Thus propionibacteria, which form part of the resident cutaneous microflora, are thought to play an important role in the pathogenesis of inflamed lesions. Sebaceous follicles in which comedogenesis is occurring along with increased amounts of sebum are characterized by marked overgrowth of Propionibacterium acnes and that proliferation can be accompanied by generation of pro- inflammatory molecules and subsequent inflammation.

In addition, lipases and other enzymes from P. acnes hydrolyze sebum triglycerides into free fatty acids that are both comedogenic and pro-inflammatory. Furthermore, rupture of the follicle, with the release of the follicular contents to the surrounding connective tissues, accelerates progression of inflammatory changes.

Kligman, Katz (2) and Kanaar (3) have shown that certain sebaceous lipids, especially squalene and free fatty acids, are comedogenic. Meanwhile, Morganti, Fabrizi and co-workers (4–8) have demonstrated that higher concentrations of linoleate and soluble azelaic acid may improve the treatment of acne.

The sun also has a strong effect on patients with acne vulgaris (9) and Infrared and ultraviolet radiations (UVR) increase both comedone formation and skin surface lipids from sebaceous glands and the epidermis (10). In fact, comedone formation that results from irritation caused by specific free fatty acids and is aggravated by UV rays induces hyperkeratosis and at the same time increases these fatty acids. This is probably the consequence of increased lipase activity caused by the spread of microbial flora (11).

It is also necessary to underline that, well-known anti-acne pharmaceutical products that are often based on benzoyl peroxide or retinoic acid, cannot be used on sun-exposed skin because of their sun-sensitization properties. Their use is therefore in general suspended during the summer and resumed in the fall. During summer it is in any case important to use sunscreen formulations, active on the acne pathogenesis, but usable also under solar exposition.

From this conflict also arises the need to formulate a sunscreen product specific for skin with some of the above reported disorders.

Azelaic acid, known for its proven efficacy on acne-prone skin and already present in the market in products for the treatment of rosacea and in a large number of cosmetic products for skin with disorders, being also capable of decreasing sebum production, can be added to sunscreen products to make them, not only able to protect the skin against the damage of ultraviolet radiation, but also able to cure disorders resulting from excess sebum, hyperpigmentation, acne, rosacea, etc.

In fact, an oily skin very often rely to an imbalance in the skin’s microbiome, that is generally linked to many skin conditions such as acne, dandruff, eczema, rosacea and early signs of aging.

Azelaic acid being a very good active ingredient for all these skin deseases, can also give advantage in terms of decrease of the sebum production. About acne, for example, its physiopathologic mechanism seems to be dependent on four main factors:

a) sebum production and excretion;
b) type of keratinization of the follicular channel;
c) microbial colonization of the pilosebaceous unit and
d) inflammatory reaction of the perifollicular area.
Azelaic acid is effective in the treatment of acne because it possesses an activity against all of these factors. In fact, it is well known in the art that the action of azelaic acid in acne treatment may relate to

1) its inhibitory effects on mitochondrial oxidoreductase and DNA synthesis;

2) a predominant antibacterial activity on cutibacterium acnes by inhibiting protein synthesis;

3) a comedolytic effect by inhibiting the proliferation and differentiation of human keratinocytes;

4) anti-inflammatory action by inhibiting the generation of pro-inflammatory oxygen derivatives in neutrophils.

In addition, as it is widely accepted that increased sebum excretion is induced by androgens, azelaic acid, having an excellent inhibitory effect on the conversion from testosterone to 5-dehydrotestosterone, can also reduce sebum production on the forehead, chin, and cheek (12).

Other properties of this cosmetic active that can be useful for a suncare product are:

1. 1)  Contains skin-soothing properties that can reduce redness and signs of sensitivity;
2. 2)  Improves the skin tone making it more even with more clarity;
3. 3)  Targets blemishes reducing inflammation and redness;
4. 4)  Improves the complexion by reducing dark spots and uneven skin tone and areas of

hyperpigmentation

AZELAIC ACID IN AFTER-SUN PRODUCTS OR MORE IN GENERAL IN SPOT-LIGHTENING COSMETICS

Hyperpigmented and post-inflammatory spots, melasma and freckles are visible, undesired skin imperfections that affect the perception of a young, healthy complexion. The main reasons for the formation of hyperpigmented spots are the sun, or better, an over-exposure to the sun and the progressive aging of the skin. The most important skin damage is not the one visible at the superficial epidermis level, but at a deeper level in the structure of the dermis. UV radiation damages the cell reproduction mechanism, modifying the distribution of melanin in the cutaneous tissue into localized, irregular, agglomerated clusters. This damage accumulates slowly but progressively and becomes visible on the skin after years of photo-exposure. In addition, aging increases the accumulation of lipofuscin granules. These yellow-brown pigments are composed mainly of lipid content, as well as sugars, proteins and metals. Their accumulation can be symptomatic of both membrane mitochondria and lysosome damage (13).

To address hyperpigmentation, skin lightening has become popular, especially in many Asian countries. Different skin types contain varying levels of the two types of melanin, pheomelanin and eumelanin. Caucasian skin mainly is characterized by pheomelanin, the yellow-red melanin, whereas Asian and African skin contains more eumelanin, the brown-black melanin. The shape and dimension of melanin granules in melanosomes also provide important contributions to the perceived color. To treat skin spots, skin lighteners should be used and they have to be able to deeply penetrate the skin layers to reach where cell proliferation takes place.

There is unanimous agreement today regarding the efficacy of azelaic acid as skin lightener together the absence of undesirable effects of note when used for this scope. 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 lighten complexion.

Azelaic acid depigmenting activity appears to be mediated by inhibition of mitochondrial oxidoreductase activation 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 skin (14).

The addition in the prepared cosmetic products of penetration enhancers can strongly improve the final efficacy in terms of skin lightening, while facilitating the solubilization of the added active and the final stability of the prepared products (against recrystallization of azelaic acid), as the main part of these ingredients are good solubilizers of azelaic acid. These ingredients can really dictate the efficacy of a dark spot lightener as azelaic acid. As noted, since hyperpigmentation takes place in the deeper layers of the epidermis, active ingredients should diffuse into skin to some depth. To achieve this, one could apply the “Formulating for Efficacy” strategy described by Wiechers et al., (15) which outlines how the right calibration of the oil phase polarity achieves partition and diffusion of the active molecules into the skin. In general, penetration enhancers are amphiphilic molecules, e.g., long-chain glycols or glycol ethers but with a high safety margin. Good examples include isopentyldiol or 3-methoxy-3-methyl-1-butanol. To obtain a good skin lightener action, a quantity from 5 to 10 % of azelaic acid is recommended (depending on the claimed uses of the final product) together a quantity of 3-10 % of penetration enhancers.

AZEPUR® 99 IN SUNSCREENS AND AFTER-SUN PRODUCTS

Azelaic acid is then a multifunctional skin care active that can give improvement regarding to a long list of skin concerns. In fact, its popularity is every they increasing at dermatologists and it is growing in demand from consumers for its effectiveness and gentleness for all skin types.

Azelaic acid can be used in sunscreens as, unlike other acids it does not increase the skin’s sensitivity to UV exposure. In fact, it does not absorb UV and visible light, meaning that it is highly unlikely to cause sun sensitivity (in other words, a photoirritative or photosensitive reaction). Having said that, it is strongly advised you add this active with a SPF of 30 and above. This is because azelaic acid provides a gentle exfoliation to the skin which leads to new skin cells sitting on the surface and being more susceptible to UV rays and sun exposure. It is important to underline that daily sunscreen will be able to create a physical barrier over the skin ensuring azelaic acid can work undisturbed and protected.

Today several grades of azelaic acid are available on the market. AZECO Cosmeceuticals has developed and placed on the market an ultra-pure, micronised cosmetic-grade of azelaic acid with vegetable origin, COSMOS approved.

The table below shows the main characteristics of this grade of azelaic acid.

INCI NAME and Chemical Identification	AZELAIC ACID NONANEDIOIC ACID, CAS: 123-99-9
APPEARANCE	White to off-white micronised powder
ORIGIN	100% biobased product obtained from Sunflower Oil
MANUFACTURING PROCESS	Azelaic acid is obtained by oxidative cleavage of the double bond of oleic chain of the triglyceride of the Sunflower oil, according to the following reaction:

	R = H, alkyl group pelargonic acid OH O + OO HO R=H, azelaic aci O H3C H3C OR
PURITY	99% minimum
SOLUBILITY	Soluble in glycols and polyglycols, glycerin and alcohols, easily dispersible in polar esters thanks to its unic particle size distribution
COSMETIC PROPERTIES	It normalises the microflora on the skin. It has anticomedonal effect by decreasing the amount of hyperkeratinization of the skin. It decreases tyrosinase activity and melanin synthesis to reduce overall skin pigmentation. It induces skin lightening / brightening effect. It reduces the appearance of pigmented spots. It is self-preserving It has an excellent safety profile
APPLICATIONS	It can be used in gel-emulsions and both low and high viscosity w/o and o/w emulsions and microemulsions
RECOMMENDED DOSAGE	3 – 15 % by weight

OR d

This grade of azelaic acid is the ideal active ingredient for a variety of personal care products (also COSMOS / ECOCERT approved), providing not only anti-bacterial and 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 lightening / brightening effect for a more uniform complexion

Applications

Moisturizing skin creams, serum and lotions, cleansers and toners. Men’s skin care products. Sunscreens

Moisturizing skin creams, serum and lotions, cleansers and toners. After sun products. Men’s skin care products.

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

Creams, serums, lotions, cleansers,
and toners designed to reduce the
signs of aging. Whitening products, skin peeling products. After sun products. Men’s skin care products (also after-shaving products).

Moisturizing skin creams, serum and lotions, Moisturizing skin creams, serum and lotions. After sun producs. Men’s skin care products.

Acne treatment combinations, skin lightening / whitening combinations, sunscreen combinations. Men’s skin care products.

AN EXAMPLE OF FINISHED WHITENING CREAM TO BE USED AS BASE FOR SUNSCREENS

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 treat skin with disorders and 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 and able in the mean time to treat a skin with disorders. It’s targeted towards all skin types. Consistently applied will help also to keep breakouts at bay and decongest clogged pores.

The proposed formulation can be also used as a starting point (decreasing eventually the quantity of AZEPUR® 99 and adding the necessary combination of sunscreens, both organic and physical, to achieve the target SPF and UV-A protection) for the preparation of sunscreens for all type of skin, also the ones with disorders. Being a w/o emulsion, it could have also enough resistance to water, as it is in general requested for a sunscreen products.

The table below contain the formulation, while just after the tips on how prepare an homogeneous and stable cream are reported.

SC005	Whitening Cream (w/o) Multiple action: whitening, anti-imperfections, anti-residual marks, anti-aging.
INCI Name % by weight Function
A.	Aqua 66.35 Solvent
	Propanediol 3.00 Humectant
	Magnesium sulfate 0.80 Viscosity controlling
B	Octyldodecanol 5.00 Emollient, Masking Agent.
	Ethylhexyl palmitate 5.00 Emollient
	Isopropyl isostearate 4.00 Emollient
	C12-15 Alkyl benzoate 3.00 Emollient
	PEG-30 Dipolyhydroxystearate 1.50 Emulsifier
	Butyrospermum parkii butter 0.20 Emollient
	Caprylyl glycol, Ethylhexylglycerin Glyceryl caprylate,	1.00	Antimicrobial agent

C	Tocopheryl Acetate 0.05 Antiaging agent
	AZEPUR® 99	10.00	Whitening agent, active ingredient

Manufacturing instructions:

1. 1)  Prepare the Oil Phase (Phase B), being sure all the Butters and Waxes are completely dissolved (at about 70°C);
2. 2)  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;
3. 3)  Prepare the water phase (Phase A), warming up to 40 – 50 °C;
4. 4)  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.

CONCLUSIONS

AZEPUR® 99, 100% bio-based and palm oil free, obtained 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 sun care products.

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 all hyperpigmentary disorders. Products based on this active are in general non-irritating, safe over long-term use, and dermally and systemically effective in comparison with other actives used on the market for the same function.

REFERENCES

1. ChC Zouboulis, Sebaceous glands, acne and related disorders, Dermatology 196(1) 1–188 (1998);

2. A Kligman and AG Katz, Pathogenesis of acne vulgaris comedogenic properties of human sebum in external ear canal of the rabbit, Arch Dermatol 98 53–55 (1968);

3. P Kanaar, Follicular-keratogenic properties of fatty acids in the external ear canal of the rabbit, Arch Dermatol 98 53–55 (1971);

4. P. Morganti et al., A Sunscreen Formulation for Acne-prone Skin, Cosmetics & Toiletries, Aug 2nd, 2013;

5. P Morganti et al, Effect of phosphatidylcholine linoleic acid-rich and glycolic acid in acne vulgaris, J Appl Cosmetol 15 21–32 (1997);

6. P Morganti, A Agostini, C Bruno and G Fabrizi, Role of topical glycolic acid and phosphatidylcholine linoleic acid-rich in the pathogenesis of acne, J Appl Cosmetol 15 33–41 (1997);

7. G Fabrizi, SD Randazzo, A Cardillo, L Tiberi and P Morganti, Safety and efficacy of a lamellar phosphatidylcholine emulsion to treat mild-to-moderate inflammatory acne, SÖFW Journal 125 12–15 (1998);

8. P Morganti, G Fabrizi and Xin Zhong Feng, A new delivery system to improve acne therapy, Eurocosmetics 10(5) 33–37 (2002);

9. M Allem and P Lopresti, Acne vulgaris aggravated by sunlight, Cutis 26 254–328 (1980);

10. T Fitzpatrick, Sunlight and Man: Normal and Abnormal Photobiologic Responses, Tokyo: University of Tokyo Press (1980) pp 353–374;

11. M Gloor and A Klarenfeld, Effect of ultraviolet light therapy given over a period of several weeks on the composition of the skin surface lipids, Dermatologica 154 5–13 (1997);

12. S. Passi et al., Azelaic acid–biochemistry and metabolism, Acta Derm Venereol Suppl (Stockh) 143:8-13 (1989);

13. L. Rigano, Spot-lightening Treatments, Cosmetics & Toiletries, Mar 30th, 2015

14. Breathnach AS. 1996. Melanin hyperpigmentation of skin: melasma, topical treatment with azelaic acid, and other therapies. Cutis 57(Suppl 1): 36–45;

15. JW Wiechers, CL Kelly, TG Blease and JC Dederen, Formulating for efficacy, Int J Cos Sci 26 173–82 (8) (2004);