SALICYLIC ACID History

15 May

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.

Chemistry

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

ether  (54).

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.

Safety

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).

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