SA can be regarded as an old-timer in acne therapy. Its benefits in treating skin disorders and other diseases have been known for generations. SA is a natural ingredient in numerous plants like the willow tree, sweet birch bark, wintergreen leaves, or chamomile flowers. The Romans knew of the efficacy of willow bark in treating ailments such as pain and fever, and the salicylic word in salicylic acid is derived from the Latin for willow, salix. For the first time, in 1838 the chemist Raf- faele Piria succeeded in synthesizing Salicin from willow bark components. In 1860, Kolbe synthesized pure SA and proposed its use as a preservative and drug. Due to better tolerability of stomach, (SA is highly irritating to gastric mucosa if ingested orally, and therefore is used only as a topical agent), SA was enhanced and the deri- vate acetyl salicylic acid was born 30 years later (53). This well-established active, better known under the trade name of Aspirinw (Bayer Healthcare AG, Leverkusen, Germany), has been used systemically for pain relief and fever for over 100 years. For topical use, however, the pure acid is used for several skin disorders like acne, dandruff, psoriasis, or ichthyosis.
The systematic name for SA is a 2-hydroxybenzoic acid with the empirical formula C7H6O3 (Fig. 3). It belongs to the group of hydroxyacids, which are carboxylic acids, classified into the a- and b-types according to their molecular structure (a-acids are the so-called fruit acids, whereas SA represents the only b-type).
SA is a white, odorless, crystalline powder, or occurs as white or colorless acicular crystals. It is slightly soluble in water and freely soluble in alcohol and
Pharmacokinetic and Pharmacodynamic
What Does Happen to Salicylic Acid After Application of a Salicylic
Acid-Containing Product to the Skin?
Numerous studies have demonstrated that following deposition onto the skin, SA will readily penetrate the stratum corneum and enter the systemic circulation (55). However, the nature of the vehicle influences both the rate and extent of absorption. For instance, a hydroalcoholic vehicle allows for a higher percutaneous absorption than a cream (56), and the addition of PEG 400 to aqueous solutions decreases the in vivo absorption. Ethanol has been shown to enhance penetration into guinea pig epidermis (57). It is the vehicle that influences the absorption rate. It also depends on the structure of the skin and skin hydration condition. A broken or weak skin barrier will allow higher penetration than a healthy one. For instance, SA absorption is significantly higher in psoriatic skin than in healthy skin. After application of 10% SA in vaseline, 40% SA of the applied amount was recovered in the urine of psoriatic people, whereas only 20% were recovered in people with healthy skin (58) (Table 5).
Besides the skin condition, the penetration or release rate also depends on the pH of the formulation. Using a membrane model, it could be demonstrated that penetration of SA increases with lower pH values (59).
In terms of penetration, it is also noteworthy that SA has the ability to build up a depot in the skin, specifically in the stratum corneum. It has been demonstrated that SA can be detected 13 days after the last application (60). Investigations on swine skin indicate that SA mainly penetrates through the transfollicular route (61), leading to the sebaceous follicle, the target site for delivery of SA, and other anti-acne drugs. This can be verified using the follicular biopsy technique where SA was shown to be delivered to the follicle (62). Having spoken about the pen- etration and the penetration way of SA, the next question arises about the distri- bution and metabolism. In contrast to BPO, SA is not metabolized within the skin, but absorbed unchanged. It is distributed in the extracellular spaces (150 mL/kg body weight) with maximum SA plasma levels occuring six to 12 hours after application. Patients with a contracted extracellular space due to dehy- dration or diuretics for example, have higher SA levels than those with a normal extracellular space. The extracellular space is smaller on a weight basis in infants and children, which suggests a basis for the relative increase in SA levels and intoxi- cation in this group for a given dose. In this context, it is important to know that SA plasma levels absorbed percutaneously are additive with salicylates absorbed orally or rectally (57). In contrast to BPO metabolism, the metabolism of SA takes part in
TABLE 5 Total Body Application of 10% SA in Vaselinew on Psoriatic
Skin and Healthy Skin
the liver by conjugation with glycine to salicyluric acid, with glucuronic acid to etherglucuronide, and by hydroxylation to gentisinic acid and benzoic acid. The half-life of SA is about two or three hours if a normal dosage is used. However, if overdosed, or due to limited liver metabolism capacity, half-life could be prolonged to 15 to 30 hours, which should be considered when using SA containing products while suffering with liver diseases. About 65% to 85% of a topically administered SA dose is recoverable from the urine. Almost 95% of a single dose of SA is excreted within 24 hours of its entrance into the extracellular space.
SA is likely to cause some degree of local skin peeling and discomfort, such as burning or skin reddening, as it is a mild irritant (54,63). Beside this topical adverse event, one major adverse reaction is the potential intoxication caused by increased penetration of SA. Intoxication has been shown in patients with a damaged skin barrier who received a treatment on the whole body over several days (such as psoriatic or ichthyotic patients). This can be explained due to high penetration of SA through a damaged skin barrier. Clinically, the patients have thirst, tinnitus, headache, lethargy, confusion, nausea, vomiting, diaphoresis, depression, and disorientation (54,57). According to the opinion of the Scientific Committee on Cosmetic Products and Non-Food Products (SCCNFP), however, this event is rare and depends on various factors, such as the age of patient, the intensity of the skin damage, the concentration of SA in the formulation, or the surface of the application. Ointments containing 3% to 6% SA have caused nausea, dyspnoea, hearing loss, confusion, and hallucinations in three patients with extensive psoriasis. They had two soap and water baths daily combined with UV therapy and six ointment applications. Under these conditions, the symp- toms developed in four days and were associated with significant SA plasma levels (46 – 64 mg/100 mL). Fortunately, the symptoms disappeared rapidly after discon- tinuation of the ointment applications (63). The application of SA to extensive areas, particularly in children, may involve a risk of toxicity from absorption. As discussed earlier, children are particularly susceptible (63). Having a greater pro- portion of body surface and weight, they are exposed to a higher risk of systemic effects during large surface treatment. However, the number of reported cases of intoxication of children is quite lower than one would expect. This could be due to the fact that the horny layer barrier of children over one year is nearly identical to the one of adults and therefore their skin has nearly the same absorption rates, or because SA formulations were only rarely used on infants and children.
As salicylate plasma levels can be indicative of SA intoxication, plasma levels should be measured first in case of any intoxication suspicion. Symptoms occur at a plasma level of 35 mg/100 mL or higher (63,64).
Overall, the correlation between body salicylate and clinical severity of the intoxication is poor. Severe manifestations are linked with diseased skin and mul- tiple applications on large body areas of formulations containing high concen- trations of SA (63). Therefore, to prevent a toxic reaction, three factors should be kept in mind: the quantity of SA used should not be excessive (repeated, large areas of the body), the available extracellular fluid volume should not be limited (smaller children, because their extracellular fluid volume is much smaller in com- parison to the potential surface area available for treatment), and the ability to metabolize and excrete the absorbed medication should not be impaired (64).
In terms of safety, the question of sensitization potential is as important as the adverse topic reaction. In the past, there have been numerous discussions on the sensitization potential of SA. Studies and literature research reveal that only in rare cases a sensitization potential was detected (65). According to the SCCNFP, SA is also not classified as a sensitizer. The results of human repeated insult patch tests conducted with formulation up to 2% SA confirm that topical appli- cation does not cause skin sensitization. On the other hand, other scientists doubt the available data. Although there are many examples of positive patch tests, no example was found that fulfilled the operational definition of clinically relevant allergic contact dermatitis. Allergic contact dermatitis to SA in man probably remains unproven in their opinion (66). However, based on data and current think- ing, SA can be regarded as not being a sensitizer, or at most a weak sensitizer.
Overall, the safety of SA can be taken as granted when considering the given precautions and contraindications. SCCNFP considers that SA is safe for “other uses” than as a preservative, at a concentration up to 2% for the leave-on and rinse- off cosmetic products, and at a concentration up to 3% for rinse-off hair products (63).