Azelaic acid (1,7-hepanedicarboxylic acid) is a naturally occurring dicarboxylic acid. It occurs amongst others in cereals like wheat, barley and rye. Extracts of these cereals have been used since 3000 years in Ayurveda products to treat hyperpigmentation (skin lightening). Azelaic acid also exhibits bactericidal properties and was shown to be very effective for the treatment of acne vulgaris. Azelaic acid has also been shown to be effective for the treatment of baldness.
When azelaic acid is obtained from natural resources, it is not commercially available; the extraction process is very difficult and expensive. On the other hand, azelaic acid can also be produced by ozonisation of oleic acid. Ozonisation is a hazardous reaction that can easily run out of control. The alternative is oxidation of oleic acid with peracetic or performic acid. This route goes via the 9,10-epoxide, followed by subsequent oxidation of the epoxide. The oxidation of oleic acid results in the formation of azelaic acid and nonanoic acid. Oleic acid required is obtained from hybrid sunflower oil and milk thistle oil. This choice of starting material enables to produce a grade of azelaic acid of more than 99% purity where regular azelaic grades are specified at 85-90%. Azelaic acid is an odourless, white and highly crystalline solid with a melting point of 110oC. It is soluble in glycerol and glycols, but poorly soluble in water (2,1 g/l). The solubility of azelaic acid is pH dependant; the mono- and disodium salts are significantly better. Also micro-emulsions based on sorbitan esters using glycerol and lauryl alcohol as co-surfactants enable to dissolve azelaic acid.
Azelaic acid is a medicine used to skin improvements. Skin care applications of azelaic acid cover major skin care areas that represent highly significant market areas:
- Hair-growth & regrowth
How is azelaic acid used to combat acne?
Acne is caused by clogged pores due to excessive growth of the outer skin layer. Skin flakes reject themselves at an accelerated rate and therefore mix more quickly and easily with sebum and bacteria in the fine openings of your skin. This causes inflammations that lead to acne.
Azelaic acid combats acne in different ways. Firstly, it softens and loosens the horny layer (the top layer of the skin), significantly reducing the risk of clogged pores.
Secondly, the active ingredients in azelaic acid block the growth process of acne bacteria. This prevents the further development of pimples.
Finally, it also inhibits the production of dark skin cells by regulating the production of melanin. This is effective in healing spots and/or scars caused by inflamed pimples.
Products used for the treatment of acne vulgaris
Next to ordinary acne (acne vulgaris) several other forms of acne are known, such as acne conglobata (a severe form of acne, mainly with males) and acne keloidalis. Acne ectopica (hidradenitis suppurativa, caused Staphylococcus epidermidis) is a form of acne that shows up in unusual places, such as the armpits, groin and on the buttocks. It can be very serious and painful. Recurrent infections and abscesses are highly inconvenient for the patient. This form of acne usually occurs after the age of 20, especially with smokers. Acne-like anomalies may also be caused by mechanical influences such as acne under a chin strap or head band (helmet), or because of contact with comedogenic products such as tar, oil, chlorine, steroids (oral contraceptives) and particular cosmetics. Mallorca acne may occur upon (over)exposure to direct sun light. It shows up as a large ensemble of white spots on the skin, and has little to do with the opportunistic behavior of Propionibacterium acnes. Medications for acne include benzoyl peroxide, salicylic acid, α-hydroxy acids, retinoids, antibiotics (doxycycline, clindamycin), nicotinamide (vitamin B3) and keratolytic preparations. Especially benzoyl peroxide and salicylic acid are under scrutiny; the FDA recommends a careful approach using these products. The use of topically or orally applied antibiotics is frequently identified as “healing is worse than the disease”. The same can be said from the oral use of retinoids, that eventually may lead to birth defects.
These side effects are absent with when using azelaic acid. Azelaic acid is believed to function on the basis of its antimicrobial activity and normalization of keratinization (the process by which epithelial cells mature as they move towards the skin surface and then desquamated). The limitation for the use of azelaic acid is its solubility; nonetheless significant progress has been made by improving the solubility characteristics. The European Union considers azelaic acid as a cosmetic ingredient that can be applied without concentration restrictions. In the USA azelaic acid is FDA approved for the treatment of acne (and rosacea). A variety of commercial products containing 10-25% azelaic acid are available. The effect of the topical acne treatment using azelaic acid on the transmembrane pH gradient of Propionibacterium acnes and Staphylococcus epidermidis was studied in vitro at external pH values found on human skin (pH 4.0-6.0).
The results indicate that the antibacterial activity of azelaic acid is associated with the perturbation of intracellular pH of the organisms.
The use of azelaic acid as anti-acne ingredient is highly favourable compared to the traditional anti-acne ingredients, as the side effects are minimal and can easily be controlled by adjustment of the concentration azelaic acid in the cream or gel.
General ingredient characteristics
Azelaic acid is considered as the rising star for anti-acne OTC products. Azelaic acid may be used in personal care & cosmetic products, in medical devices and in pharmaceutical products without concentration limitations. It shows no significant side effects, it has no cytotoxic properties and does not exhibit CMR 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 solubility.
The mode of action of azelaic acid is not well-known, although it is considered likely that azelaic acid is detrimental for Propionibacterium acnes, but will not affect most other micro-organisms. P.acnes is an aerotolerant anaerobe gram-positive organism, identified as a commensal. The selectivity for P.acnes enables to normalise the P.acnes population while leaving the other native micro-organisms in peace.
The absence of adverse effects, compared to other products used for fighting acne, makes azelaic acid a preferred ingredient for anti-acne products.