Abstract
In Ayurveda the grains of wheat, barley and rye have been used since old time for the treatment of topical hyperpigmentation. Only about 3000 years later it was found that this property was due to the inhibition of tyrosinase, the enzyme involved in the melanin formation process, by azelaic acid.
But, azelaic acid, a saturated dicarboxylic acid, is not only a whitening agent, it exhibits also bactericidal and antiflammatory properties and this has resulted in the application of it for the treatment of acne vulgaris and rosacea.
It also shows other interesting properties and synergies with other active ingredients, such as for example some ones useful in hair regrowth products.
A commercial production of azelaic acid from botanical resources (wheat, barley and rye for example) is commercially not feasible, but today a natural derived azelaic grade (from high oleic sunflower oil) is present on the market, with a chemical structure identical to one observed in nature. This grade of azelaic acid is characterized by a very high purity, the highest in the market (> 99% by weight), very important feature to have a product characterized by the absence of collateral effects together a great effectiveness.
Introduction
Azelaic acid is a naturally occurring 9-carbon straight-chained saturated dicarboxylic acid (isolated from cultures of Pityrosporum Ovale) naturally present in rye, wheat, and barley. A single mechanism of action has not been identified to explain the several beneficial effects of azelaic acid on the skin. In fact, it is well known in the art, from the results of several accurate experimental scientific works, topical azelaic acid has anti-inflammatory and antibacterial properties, in addition to comedolytic action. It also competitively inhibits tyrosinase, an enzyme involved in the conversion of tyrosine to melanin, and may than successfully used to reduce epidermal hyperkeratinization.
So this active ingredient, an efficient antibacterial and anti-proliferative agent, can find its natural application in the formulation of skin care cosmetics.
According to the high number of scientific published data, it is the ideal active to treat skin to inhibit the pigment producing enzyme tyrosinase (1), 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 (2). While treating cases of chloasma with topical 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.
This acid is then used to treat bacterial-related acne breakouts by attacking the infected pores to help in reducing inflammation and lowering the production of keratin which creates clumps of dead skin cells that trap sebum in skin pores causing more breakouts. With that said, as azelaic acid was more commonly used to treat acne related problems, doctors noticed it had side effects to it which were related to skin lightening. In 1978, the tyrosinase-inhibiting activity of certain lipid fractions, 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 ensued (3).
It is known in the art that Inhibition of 5-α-reductase type 1 is an answer to androgenic alopecia, Azelaic acid is a very potent 5-α-reductase inhibitor. The powerful combination {azelaic acid + zinc sulphate + vitamin B6} for the treatment of androgenic alopecia is cosmetically suitable contrary to the steroidal and non-steroidal pharmaceutical preparations present on the market for the treatment of this kind of disease.
Today there is unanimous agreement regarding efficacy of azelaic acid together absence of undesirable effects of note.
Azelaic acid may be, then, used in the personal care products, in medical 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.
Today several grades of azelaic acid are available. AZECO Cosmeceuticals has developed and placed on the market an ultra-pure, micronised cosmetic grade of azelaic acid with vegetable origin, COSMOS approved. 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 | Applications |
| Effective in the treatment of oily and impure skin. | Moisturizing skin creams, serum and lotions, cleansers and toners. Men’s skin care products. |
| Provides a progressive lightening / brightening effect for a more uniform complexion | Moisturizing skin creams, serum and lotions, cleansers and toners. Men’s skin care products. |
| Reduces skin pigmentation and color irregularities such as age spots , revealing smoother, brighter, more supple skin with fewer irregularities | Creams, serums, lotions, cleansers,and toners designed to reduce thesigns of aging. Whitening products, skin peeling products. Men’s skin care products (also after-shaving products). |
| Moisturizing skin creams, serum and lotions, | |
| Improving the appearance of sun damaged skin and fighting skin aging | Moisturizing skin creams, serum and lotions. Men’s skin care products. |
| Enhancing performance of certain topical over-the-counter , drugs or quasi-drugs and prescription products | Acne treatment combinations, skin lightening / whitening combinations, sunscreen combinations. Men’s skin care products. |
Azelaic acid in cosmetics products with skin disorders
Thanks to its antibacterial abilities, Azelaic acid is detrimental for particular organisms such as Propionibacterium acnes and Staphylococcus epidermidis. These bacteria, which reside in the sebaceous glands present in the dermis (4), are held responsible for acne vulgaris. Azelaic acid acts specifically on P.acnes and S.epidermidis, without affecting most other bio-organisms.
It also decreases the production of keratin, required for the growth of P.acnes; P.acnes destroys the wall of the sebaceous glands to obtain the required nutrients, more particularly proteins that are hydrolysed into the corresponding amino acids (5).
Treatment for acne include benzoyl peroxide, salicylic acid, α-hydroxy acids, retinoids, antibiotics (doxycycline, clindamycin), nicotinamide (vitamin B3) and keratolytic preparations (6). Benzoyl peroxide and salicylic acid especially are currently under scrutiny. The FDA issued the statement: “The Food and Drug Administration (FDA) is warning that the use of certain acne products containing the active ingredients benzoyl peroxide or salicylic acid can cause rare but serious and potentially life-threatening allergic reactions or severe irritation. An active ingredient is the component that makes the medicine effective against the illness or condition it is treating.”(7).
Side effects are instead virtually absent with azelaic acid. Azelaic acid is believed to function on the basis of its antimicrobial activity and/or normalisation of keratinisation (the process by which epithelial cells mature as they move towards the skin surface and are then desquamated). The European Union considers azelaic acid as a cosmetic ingredient that can be applied without concentration restrictions. In the US, azelaic acid is FDA approved for the treatment of acne and rosacea. A variety of products containing 10-25% azelaic acid are commercially available.
The effect of a topical acne treatment made with azelaic acid on the transmembrane pH gradient (ΔpH) of P.acnes and S.epidermidis was studied in vitro at external pH values found on human skin (pH 4-6). The results indicate that the antibacterial activity of azelaic acid is associated with the perturbation of intracellular pH of the organisms. The effects of topically applied azelaic acid were studied with 47 individuals (12 with normal skin, 15 with seborrheic skin and 20 suffering from acne) (8). Topical application of a 20% azelaic acid cream significantly reduced the number of lesions with the acne patients, but failed to induce clinically detectable changes in normal or seborrheic epidermis.
In vitro, azelaic acid exerted marked time- and dose-dependent anti-proliferative cytostatic effects on cultured keratinocytes, with a 50% inhibitory dose of 20 mMol. This is indicative of the anti-keratinising properties of azelaic acid, displaying anti-proliferative cytostatic effects on keratinocytes and modulating the early and terminal phases of epidermal differentiation (9).
Rosacea, also named “the curse of the Celts”, mostly affects people from northwestern descent. It is a chronic condition characterised by facial redness (erythema). Without treatment, rosacea worsens in time; treatment with antibiotics is counter-effective and their use is being discouraged. The cause(s) of rosacea are not yet clear, although it has been concluded that allergies may play a significant role. Also weather conditions (high sun intensity, cold/warm weather, wind, frost) may contribute to episodes of flushing. Also a disturbed balance of the intestinal flora is considered as a cause for rosacea.
Azelaic acid has been demonstrated to be effective for the treatment of rosacea. It is available as a 20% cream or a 15% hydrogel. It reduces inflammatory lesions and erythema in rosacea patients and also inhibits neutrophilic reactive oxygen species (ROS). In the neutrophil system, azelaic acid inhibits the ROS formation in a dose-dependent manner, markedly decreasing the number of free radicals. In the xanthine-xanthine oxidase system, none of the ROS generated was decreased by any dose of azelaic acid, indicating that azelaic acid does not scavenge generated ROS, but rather inhibits cell metabolism, possibly by decreasing enzymatic activity within the cell membrane. In a study by Akamatsu (10) it was found that NADPH oxidase activity on the neutrophil surface membrane, which mediates the neutrophilic production of most ROS, is effectively inhibited by lower concentrations of azelaic acid.
Azelaic acid as skin lightening/whitening agent
In 1978, the tyrosinase-inhibiting activity of certain lipid fractions, 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 ensued (11).
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 (12).
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 lighten 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 (13). 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 (13, 14).
In a 6-month study (15) 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 (16) azelaic acid was applied at concentrations of 15% or 20% twice daily for 3 to 12 months. Clinical and histological resolution in facial lentigo maligna was obtained and it was successful 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.
Considering here are different ways to combat hyperpigmentation, sometimes, It may useful also to combine different whitening / lightening active agents in the same cosmetic formulation. This was demonstrated by a study (17) 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 conditions of a serum containing a complex based on oligopeptide-68 at 2% , azelaic acid at 8% and glycolic acid at 3% for photo-aged skin during 12 weeks. This association already demonstrated an anti-aging efficacy on human cutaneous explants. 42 Caucasian volunteers (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), clinical and instrumental photo-aging signs assessments were performed. The local score for the target lentigo improved significantly after 4, 8 and 12 weeks of serum application (42% of improvement). 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 complexion, and we feel it’s a great alternative to other types of skin lighteners, 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 successful ability 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 not affect the pigments of the skin, but rather tackles abnormal melanocytes (small melanin cells) instead.
Azelaic acid in hair growth products
Azelaic acid is a well-known inhibitor for 5α-reductase: the enzyme that converts testosterone into 5α-dihydrotestosterone, a major cause for alopecia areata and hair loss. Due to the relative absence of dihydrotestosterone, regression of the hair follicle will take place (the catagen stage) and subsequently hair generation will take place (the anagen stage). This enables the use of azelaic acid for hair regrowth (18)
Unfortunately the number of clinical studies is limited; the pilot study dates back to 2005 (19). This study was performed to evaluate the effectiveness and safety of azelaic acid on patients suffering from alopecia and/or alopecia areata. The results using azelaic acid were compared with the effectiveness of anthralin (1,8-dihydroxy-9- oxoanthracene), a drug prescribed to treat psoriasis and frequently used for the treatment of alopecia areata. It was concluded that the performance of azelaic acid is comparable with the results obtained with anthralin for hair (re)growth.
Also Zn2+ based salts are inhibitors for 5α- reductase; the efficacy of zinc sulphate, for example, was significantly increased with the simultaneous use of pyridoxine hydrochloride (vitamin B6). Pyridoxine hydrochloride did not result in increased efficacy of azelaic acid. However, the powerful combination {azelaic acid + zinc sulphate + vitamin B6} for the treatment of androgenic alopecia is cosmetically suitable contrary to the steroidal and non-steroidal pharmaceutical preparations present on the market for the treatment of this kind of disease (20).
Conclusions
Azelaic acid can be better defined as a cosmeceutical ingredient, in fact, it shows both cosmetic and pharmaceutical properties. The performance of azelaic acid exhibits superior performance for the treatment of acne vulgaris, rosacea and melasma as for hair (re)growth and skin lightening by means of enzyme inhibitions.
The toxicological properties of azelaic acid are superior compared with the current pharmaceutical active ingredients used for the treatment of acne vulgaris or rosacea; the side effects of azelaic acid are minimal and can be mastered rather straightforwardly, using commercially available Azepur99®, the highest pure product in the market.
Azepur99®, a real sustainable ingredient, 100% bio-based and palm oil free, obtained by a sustainable process from a definite vegetable source (high oleic sunflower oil) is the perfect choice for high-performing (multi-action way to act) and sustainable cosmetic solutions for skin and hair care.
References
- Nazzaro-Porro, M., Passi, S., Morpurgo, G . & Breathnach, A. (1979a) Identification of tyrosinase inhibitors in cultures ai Pityrosporum and their melanocytotoxic effect. In: Pigment cell 4: Biologic basis of pigmemation (Ed. By S.N.Klaus), p. 234. S. Karger, Basel;
- Nazzaro-Porro, M., Passi, S., Balus, S., Breathnach, A., Martin, B. & Morpurgo, G. {1979b) Effect of dicarboxylic acids on lentigo maligna. Journal of Investigative Dermatology, 72, 296;
- Shin, J.W.; Park, K.C. Current clinical use of depigmenting agents. Dermatol Sin. 2014, 32, 205–210.
- D.Thiboutot, J.Drugs Derm., 7,13,(2008);
- C.C.Zouboulis, Acne and sebaceous gland function, Clinics in Dermatology, 22,360,(2004).
- M.Ramos da Silva, S.C.Carneiro, Acne vulgaris: Review and guidelines. Dermatology nursing / Dermatology Nurses’ Association 21,63,(2009).;
- FDA (US Food & Drug Association), Topical Acne Products Can Cause Dangerous Side Effects (http://www.fda.gov/ForConsumers/Consumer Updates/ ucm402441. htm);
- http://toxnet.nlm.nih.gov/cgibin/ sis/search2/r?dbs+hsdb:@term+@rn+@re l+123-99-9;
- A.Mayer da Silva et al, Acta Derm.Venereol.Suppl., 143,20,(1989). 10. U.Wollina, S.B.Verma, J.Cosm.derm.8,234,(2009);
- H.Akamatsu, J.Komura, Y.Asada, Inhibitory effect of azelaic acid on neutrophil functions: a possible cause for its efficacy in treating pathogenetically unrelated diseases. Arch.Dermatol.Res., 283,162,(1991);
- Shin, J.W.; Park, K.C. Current clinical use of depigmenting agents. Dermatol Sin. 2014, 32, 205–210;
- Breathnach AS. 1996. Melanin hyperpigmentation of skin: melasma, topical treatment with azelaic acid, and other therapies. Cutis 57(Suppl 1): 36–45;
- Lowe, N.J.; Rizk, D.; Grimes, P.; Billips, M.; Pincus, S. Azelaic acid 20% cream in the treatment of facial hyperpigmentation in darker-skinned patients. Clin. Ther. 1998, 20, 945–959;
- Webster, G. Combination azelaic acid therapy for acne vulgaris. J. Am. Acad. Dermatol. 2000, 43, S47–S50;
- Sarkar R, Bhalla M, Kanwar AJ. 2002. A comparative study of 20% azelaic acid cream monotherapy versus sequential therapy in the treatment of melasma in dark skinned patients. Dermatology 205: 249–254;
- Fitton A, Goa KL. 1991. Azelaic acid. A review of its pharmacological properties and therapeutic efficacy in acne and hyperpigmentary skin disorders. Drugs 5: 780–798;
- Rossi A.B., Nocera T., Lapalud P., Study sponsored by Pierre Fabre Dermo-Cosmétique, Poster presented at AAD Meeting –Washington DC., March 4-8, 2016;
- Hair growth & Azelaic acid., Elzbieta E.Brand-Garnys M.Sc., Dr.Hans M.Brand, https://azelaicacid.com/azelaic-acid-hair-growth/;
- A.J.J.Wood, V.H.Price, N.Engl.J.Med., 341,964,(1999);
- D.Stamatiadis, M.C.Bulteau-Portois, I.Mowszowicz, Inhibition of 5 alpha-reductase activity in human skin by zinc and azelaic acid, Br.J.Dermatol., 119,627,(1988).