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 poisonous for Propionibacterium acnes but will not affect most other micro-organisms: P.acnes is an aerotolerant anaerobe gram-positive organism micro-organism, identified as a commensal organism. This 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.
Probably the most frequently used anti-acne ingredient is benzoyl peroxide. It has anti-bacterial properties, but the disadvantage is its non-selectivity. Bacteria present on the skin and in the hair follicle are completely eliminated. This includes Propionibacterium acnes, the organism that is held responsible for the development of acne, and thus prevents acne from progressing. Commercially available products may contain up to 10% benzoyl peroxide, while a minimum concentration required to fight acne is considered to be 2,5%
The absolute amount of benzoyl peroxide is dependent on the severity of the acne outbreak and observed skin irritation induced by benzoyl peroxide. Skin irritation is more frequently observed with darker skinned people compared to Caucasian skin. Racial distinction is, however, not a very good method. Proserpio distinguishes five different skin types. That approach much better describes the actual situation:
Benzoyl peroxide, like all peroxides, is not very stable. The bond energy of the –O–O- bond is small (▲H~29 kcal/mole). Thermal bond breaking occurs easily and two benzoyl radicals are formed. A multitude of reactions may/will subsequently occur. The benzoyl radicals can directly react with the wall of bacteria, moulds & yeasts, without exhibiting any selectivity. All micro-organisms present on the skin, with who that live in symbiosis, are affected/destroyed. The reactivity is so high that it also will react with skin tissue and the accessible sub-cutaneous tissue. The damage caused by the benzoyl radicals is sincere, also leading to cytotoxicity. In the most positive case it will cause skin irritation and/or sensitisation.
Last but not least: the benzoyl radical may lose carbon dioxide and a phenyl radical may be formed. The phenyl radical may abstract a hydrogen atom from a suitable substrate, and benzene is formed. Not the most wanted product indeed in personal care & cosmetic products and medical devices. Benzene is carcinogenic and has hormone disturbing properties.
In the European union benzoyl peroxide is strictly forbidden in personal care & cosmetic products. As benzoyl peroxide also exhibits dramatic cytotoxic properties it is also forbidden in medical devices. The legal situation in the USA is quite different: benzoyl peroxide may be used in OTC anti-acne products. The FDA is currently evaluating the status of benzoyl peroxide. The forecasts for the survival of benzoyl peroxide in the USA look grim, and that would be a more than realistic scenario.
Retinoids are defined as C20-terpenoids. The most important representatives are retinoic acid (tretinoin) and retinol (vitamin A). Retinol and its esters may be used in personal care cosmetic products.
Retinoic acid plays an important role in growth and development. Retinoic acid is required in all chordate animals. Retinoic acid is important during early embryonic development. Vitamin A (retinol) plays a role in the maintenance of the immune system and is (as retinaldehyde) indispensable in the chemistry of vision.
A variety of cis-trans isomers of retinoic acid are known. Retinoic acid (tretinoin; Renova®; Johnson & Johnson) identified as all-trans) and its salts exhibit anti-acne activity. It was developed by Kligman, and is considered to be one of the most powerful anti-ageing agents. Isotretinoin (13-cis-retinoic acid; Roaccutane®/Roche) is more powerful than tretinoin, but the side effects are also more outspoken.
Alitretinoin (9-cis-retinoic acid) is used as an antineoplastic ingredient, and is also used for chronic hand eczema.
All these, first generation, retinoids exhibit sincere side effects such dry lips, skin & mucous membranes, reduced tear fluid production (resulting in eye irritation), disturbed liver function, thinning skin, sensitivity to sunlight (direct sunlight shall be avoided and an SPF>50 cream must be used), hair loss (usually reversible) or hirsutism, joint & muscle pain and an increased cholesterol level. Diabetes patients shall be very careful because of potential hyperglycaemia. These retinoids shall never be used during pregnancy or planned pregnancy: retinoids are considered severely teratogenic (a CMR property). For males gynaecomastia and disturbed potency have been frequently reported. Many retinoids exhibit sincere phototoxicity and cytotoxicity.
The mechanism for the activity of retinoids for acne is unknown. On a cellular level there is evidence that it decreases the ability of epithelial cells in hair follicles to stick together, leading to fewer blackheads; it also seems to make the epithelial cells divide faster, causing the blackheads to be pushed out.
α-Hydroxycarboxylic acids, usually abbreviated as α-hydroxy acids and frequently named fruit acids, are characterised as carboxylic acids from the carbon atom in the 2-position carries a hydroxyl group. Well-known members of this group are glycolic acid, lactic acid, pyruvic acid, malic acid, tartaric acid, citric acids, and others. These are usually relatively strong acids that are also effective solvents for the cement between the cells of the epidermis. This cement is composed of ceramides, triglycerides and some sterols, mostly cholesterol. Elimination of the cement between the dead skin cells of the stratum corneum enables easy exfoliation.
α-Hydroxy carboxylic acids are not true anti-acne products. Because of their exfoliating qualities the tallow glands are opened up to enable the sebum to flow out and distributes on the skin. This is best identified as the keratolytic activity of α-hydroxyarboxylic acids, but there is no activity against Propionibacterium acnes, the organism that is considered the main culprit.
α-Hydroxy carboxylic acids, usually applied as a combination of the free acids and their conjugated bases, are suitable for both personal care & cosmetic application, for medical devices and pharmaceutical preparations. Many of these products are body-own products or occur in nature, without CMR properties, no serious side effects (except when used in extreme concentration), inducing only limited phototoxic properties and no cytotoxicity.
Adapalene is frequently identified as a third generation retinoid. However, the structure of adapalene does not at all compare to retinoids such as vitamin A (retinoic acid; vitamin A), retinaldehyde or retinol. The structure of adapalene compares more to quinine, it is also used for the treatment of malaria and similar protozoal infections. Adapalene is a pharmaceutical ingredient that shall not be used in personal care & cosmetic products and medical devices.
Adapalene, commercially available as Differin® Gel [0,1-1,0% adapalene) is used for the treatment of acne vulgaris, by means of shedding dead skin cells and promoting the formation of new skin cells. It also helps to unclog pores and reduces inflammation. When using an acne treatment with the active ingredient of adapalene, acne may worsen temporarily at first but should eventually improve. Side effects can include skin irritation, stinging and burning sensations, and sensitivity to UV light.
The functionality of adapalene is improved when using the product in conjunction with clindamycin, an antibiotic used for the treatment of bacterial infections. Clindamycin is also used for the treatment of otitis media, pneumonia and endocarditis, and is sometimes used to handle MRSA (Methicillin Resistant Staphylococcus Aureus).
Major side effects of adapalene are skin irritation (or burning or stinging sensation), dryness and peeling of the skin, itching and redness of the skin. Adapalene shall not be used if the patients suffer from eczema, in case of sunburn or pregnancy. It may take considerable time before the functionality of adapalene becomes obvious (8-10 weeks).
Another pharmaceutical anti-acne ingredient is taratozene, also defined as a third generation retinoid.
It is used for the treatment of acne, psoriasis and photo-damaged skin. The mechanism of action is still unknown. Common side effects include worsening of acne, increased sensitivity to sunlight, dry skin, itchiness, redness and in some cases extreme drying and cracking of skin. For most patients these side effects are uncomfortable but mild and decrease markedly after the first 2–4 weeks of use, except for increased sensitivity to sunlight. Taratozene is not allowed for personal care & cosmetic products and medical devices, and must be prescribed by a medical professional. Despite the undesired side effects of taratozene it is frequently preferred better than tretinoin, that has even more serious side effects.
Salicylic acid is chemically described as 2-hydroxybenzoic acid. It is also considered to be a β-hydroxy acid. Salicylic is used as a preservative in personal care & cosmetic products with a maximum concentration of 0,5% (not to be used in products for children younger than three years of age. Salicylic acid may be used in excess of 0,5% for purposes other than inhibiting the development of micro-organisms in the product. This purpose has to be apparent from the presentation of the product.
Salicylic acid is poorly soluble in water (2,5 g/l; 25°C). The sodium salt is easily soluble in water but is subject to decarboxylation phenol being the primary reaction product.
Salicylic acid is frequently used in personal care & cosmetic products as exfoliant to shed off dead skin cells (keratolyticum) to avoid dead cells to block the pores allowing the sebum to pass through. EU Regulation allows a maximum of 2% in stay-on products.
Salicylic acid may exhibit multiple side effects: skin irritation (eventually quite serious), dry skin, itching & stinging, unusually warm skin and swelling of the face, lips and tongue (potentially leading to suffocation). Possible suffocation may also be induced by salicylic acid derivatives such as fragrance compounds (e.g. benzyl salicylate, methyl salicylate) and particular UV filters. Furthermore salicylic acid may exhibit side effects that are potentially life threatening.
The FDA is currently evaluating the status of salicylic acid as the product may eventually not safe to use in personal care & cosmetic products and medical devices.
Sulphur is probably one of the oldest anti-acne ingredients. At present rarely used, and if it is used it is always in combination with other anti-acne ingredients. Sulphur is a bright yellow crystalline solid found in free form in Nature, and is mostly from volcanic origin. It melts at 115°C and has a typical, unpleasant smell. Sulphur occurs as an eight-membered ring structure
Sulphur is able to remove dead skin cells and eliminate excess oil from the skin’s surface. This process can help in the prevention of acne, but sulphur is also known to cause adverse side effects. Redness is a common side effect when using products with sulphur. Acne may begin to subside at first but skin can become worse if it is sensitive. Soreness is also accredited to the use of acne products containing sulphur.
Sulphur has germicidal, fungicidal, parasitical, and keratolytic properties.. The germicidal activity may be the result of its conversion to pentathionic acid (H2S5O6) by particular microorganisms. Also the formation of hydrogen sulphide and polysulphides, as well as (di)methyl (poly)sulphides. Polysulphides generally have the formulae RSnR). These substances have a particular odour: hydrogen sulphide (H2S) smells after rotten eggs, methylmercaptan (CH3SH) has a distinctive putrid odour while the odour of dimethyl sulphide is commonly described as cabbage-like. Dimethyl disulphide has the characteristic odour of onions. The odour threshold value for these products is very low, usually < 1 ppm. Creams and ointments containing elementary sulphur always have the typical odour of these sulphides and are usually difficult to fragrance. Apart from the poor odour sulphides are usually toxic. The LD50-value of hydrogen sulphide is 800 ppm; H2S acts in a similar fashion as carbon monoxide and is considered to be a sincere CMR ingredient.
The application of antibiotics for the treatment of acne is exclusively reserved for medical professionals. Antibiotics are not allowed in personal care & cosmetic products and medical devices. Antibiotics can be taken orally, but also administered via the skin. Frequently the use of antibiotics is combined with the use of benzoyl peroxide to avoid antibiotic resistance. Topically applied antibiotics are clindamycin and erythromycin. Orally taken antibiotics are doxycycline & minocycline (tetracyclines) and also erythromycin.
The side effects of these antibiotics are numerous: skin rash, upset of the stomach and intestine and fungal infections. Sometimes the side effects can quite serious indeed, such as severe allergic reactions (difficult breathing, facial swelling), destruction of the intestinal flora (bloody diarrhoea), vaginal candidiasis and mouth sores. Combined with potential antibiotic resistance the use of antibiotics for the treatment of (juvenile) acne should only be considered if there are no other options left.
Virtually all antibiotics used for the very severe cases of acne also have cytotoxic properties and have distinct CMR and hormone disrupting properties. Antibiotics also should not be used during pregnancy, unless unavoidable.