Benzoyl Peroxide and Salicylic Acid Therapy

15 May


Nearly, everyone is affected  by acne sometime in their  lifetime.  This is most preva- lent among teenagers when,  shortly after the onset of puberty, spots and blackheads start to appear. However, acne may continue or start in adulthood and, indeed, it is reported that an increasing number of people within this age group are affected  by the condition (1).

When  discussing acne,  it is important to distinguish the  varying degrees of severity of the  disease because the  selection  of a therapeutic regime  is dependent on  this  severity grading (Table  1). Pathophysiology and  classification systems  of acne  have  been  described in  detail  in other  chapters; however, before  starting to discuss its therapy with  benzoyl peroxide (BPO) and  salicylic acid (SA), it is worth providing a brief overview of this in order to understand acne active selection.

Acne,  or acne  vulgaris, is a common disease of the  pilosebaceous unit.  The disease is localized to the skin regions such as face, back, and  chest, where numer- ous pilosebaceous units are located. The pathogenesis of acne has not yet been fully established. Several factors contribute to the development of acne: increased sebum production (mainly influenced by hormones), ductal cornification, bacterial coloni- zation  of the pilosebaceous duct,  and  inflammation (2 – 5). Propionibacterium acnes, an anaerobic bacteria, is a member of the skin and pilosebaceous follicle microflora. It is thought to play  a significant role in acne because  it can proliferate within the obstructed duct,  modifying the  components of sebum and  producing enzymes, including lipases,  that  increase fatty acids  and,  consequently, cause  inflammation. Inflammatory events,  however, occur as a consequence of the bacterial colonization and  the  subsequent reactions. Recent  research revealed that  inflammatory events could  arise before or after hyperproliferative changes. There is evidence for vascu- lar  endothelial cell activation and  involvement of inflammatory responses in the very  earliest  stages  of acne  lesion  development (6). Whether a poor  diet  of excess chips  or chocolate play  a role in acne  is rather questionable. Although this  impact has been observed in individual cases, no scientific  evidence has been provided up to now (2 – 5). Another factor that is often suspected to exacerbate acne is psychologi- cal  stress.  In  the  past,  reports of  the  influence of  emotional stress  were  mainly anecdotal. However, recently, a study revealed that changes in acne severity correlate highly  with  increasing stress,  suggesting that emotional stress  from external sources may  have  a significant influence on acne, which  might  be useful  for understanding the pathophysiology of acne and  its therapy (7).

Because of increased sebum production and ductal cornification, the so-called comedo clinically  develops first.  Depending on  whether the  comedo is open  or closed  determines whether they are called  blackheads or whiteheads, respectively. If the comedo becomes inflamed, pustules, papules, or even nodules will develop, which  are described as pimples or spots  by most  consumers.


The  most  important thing  is to  minimize or  remedy the  negative psychological effects  caused by the  disease and  to prevent scar  formation. This  is achieved by removing existing  lesions  and  preventing the formation of new ones (the existence of spots  among acne sufferers might  be due  to psychological discomfort). But how can one get rid of spots?  Based on the pathophysiology of acne, there  are only few ways  that  a successful acne therapy can follow:

1.    controlling increased sebum production/reducing excess sebum,

2.    affecting  the ductal cornification/hyperkeratinization,

3.    acting  on the bacteria  that are deemed to be involved in acne pathophysiology,

4.    reducing inflammation.

There  are  numerous substances available that  provide one  or  more  of the mentioned actions   and  are  therefore effective  in  acne  therapies. The  choice  of active,  however, depends upon the severity of acne.

Table  1 shows  that  cosmetic  acne  products are  only  dedicated for mild-to- moderate acne.  In  general, they  are  predominantly used  for  dealing with  mild acne lesions  first or as accompanying skin care regime. More severe  acne requires medical consultation  and  advice,   and,  in  most  of  the  cases,  “stronger” actives that  are available on prescription only.

This chapter focuses  on two  actives  that  are indicated for mild-to-moderate acne: BPO and  SA. BPO and  SA have  been  used  for a long  time  in the  treatment of various skin diseases. Over the last years, many  acne ranges have been launched by  many  companies, consisting of cosmetics as  well  as  over-the-counter  (OTC) drugs that have included one of these actives, making use of their good reputation. Nowadays, many  formats, including cleansing, treatment and  care  products, are available in the mass  market, drugstores, or pharmacies (Table 2).


BPO, which  is derived from a by-product of coal tar, was first used as a nonirritating oxidizing antiseptic by Loevenhart (8) in 1905. Subsequently, there was little derma- tological  interest in this  compound and  its main  use was  as a bleaching agent  for flour.   Lyon   and   Reynolds  (9),  in  1929,  claimed  that   BPO  promoted wound healing. In  1934,  Peck  and   Chargin (10)  described the  use  of  topical   BPO  in sycosis  vulgaris; and  Leake  (11), in 1942, claimed that  BPO, when  applied locally to wounds, acted  as a long-lasting oxidizing antiseptic without any  local irritant effects.  In addition, healing was  promoted and  there  was  also  a local  anesthetic action  relieving pain  and  local irritation.

Modern interest in BPO was stimulated by Pace in 1965, when BPO, combined with  sulfur in a cream formulation, was first used  in the treatment of acne vulgaris (12). Following this development, the pharmaceutical industry found a way of pre- paring stable lotions  of BPO. Combination therapy was also developed using  sulfur and  chlorhydroxyquinoline. BPO was  registered for the  treatment of acne  in the United States in 1960 and  in Germany in 1974. Due to formulation stability issues, it did  not  become  popular until  the  late  1970s, when  much-improved products became  available. More  recent  developments have  included BPO in gels, creams, and  wash  bases.


A  synonym for  BPO  is  dibenzoyl peroxide. The  empirical formula of  BPO  is

C14H10O4 (Fig. 1) The hydrous form  of BPO is a white  or granular powder with  a

characteristic phenolic odor.  It is practically insoluble to sparingly soluble  in water, slightly  to sparingly soluble  in alcohol,  and  soluble  in  acetone,  chloroform, and ether.  It is a powerful oxidizing agent  and  is widely used  in the industry as a cata- lyst and as a bleaching agent,  for edible oils and flour (13,14). As BPO is heat-labile, stability  is  a  major   concern   when  developing  new   formulations.  This  issue, however, is discussed elsewhere.

Pharmacokinetic and Pharmacodynamic

What Happens with Benzoyl Peroxide After Application on the Skin?

BPO is well-absorbed into the stratum corneum and tends  to concentrate in the pilo- sebaceous units  (15). If an active can easily penetrate into the stratum corneum, the likelihood of  systemic action  increases. Therefore, it  is  important to  know   the absorption rate  and  metabolism of the drug in order  to assess  the safety.  Using  a bovine   udder  system, it  was   demonstrated  that   BPO,  applied  in  an  acetone vehicle,  was  absorbed by 22% after  a topical  application (16) and  was  converted within the skin layers  mainly to benzoic  acid (Fig. 2) (17,18).

The  metabolite is then  absorbed into  the  systemic circulation and  rapidly excreted in urine, thereby circumventing hepatic conjugation. In vivo investigations with rhesus monkeys revealed that at in no time did the urine  samples contain hip- puric  acid. Had  any significant amount of the benzoic  acid formed by the intracu- taneous  metabolism of  BPO  been  circulated to  the  liver,  it  would have   been conjugated with  glycine  and  excreted as hippuric acid. This indicated that  topical BPO should engender no  systemic toxic  effects  due  to  drug accumulation since there  would be no appreciable opportunity for either  the drug, or its metabolites, to accumulate in body  tissues  or organs (18). In order  to determine the penetration rate  in  human beings,  in  vivo  investigations on  patients with  ulcus  cruris  were carried out.  After  application  of  a  20%  BPO  formulation,  less  than   5 mmol/L benzoic  acid were  detected in the serum and  after three  days  no metabolite could be found (19). Transferring these  results to acne therapy, a lower  penetration rate could  even  be  expected since  the  skin  barrier in  acne  patients is  normally not broken as  in  ulcus  cruris  patients and  the  applied concentration is much  lower than  the one used  for antiseptic purpose.


As discussed in the earlier  section,  it is unlikely that  BPO causes  systemic adverse reactions or intoxications due to its rapid renal clearance. The main adverse reaction in acne therapy is the occurrence of skin irritation such  as dryness, erythema, and scaling, which  is dependent on the BPO concentration and vehicle base (20). A high BPO level and  an alcoholic  base, for example an alcoholic  gel, has a higher associ- ated  irritation than  low levels of BPO in an emulsion base. For instance. in order  to avoid  skin  irritation, one  should start  with  the  lowest  concentration and,  having

FIGURE 2    Metabolism  of benzoyl  peroxide  in keratinocytes of SENCAR-mice. Source: Adapted from Ref. 18.

accustomed the  skin  to  BPO, continue with  increased strength formulations. In general, a  lower   strength or  less  frequent  application of  the  preparation  may reduce irritation. A further possible way  of reducing irritation is through usage of BPO washes, where the contact  time with  the skin is limited to seconds. Conse- quently, the irritation potential may  also be lessened.

Another noteworthy side effect that  needs  to be considered is contact  sensit- ization  that  has been observed occasionally among acne patients during treatment with  topical  preparations of BPO (21). Under the  guinea pig  maximization test, which  is designed for  testing  the  contact  allergenic potential of chemicals, 76% contact   sensitization  was  observed.  A  high   sensitization potential  is  observed during treatment of ulcus  cruris;  however, under the treatment of acne, the sensit- ization  rate  is disproportionally less.  Numerous investigators have  assessed the likelihood of sensitization after  use  of BPO in acne  treatment and  have  found an incidence of less than  1/500 (22), which  is not significant. (14,23).

It is also important to mention the data on toxicity of the active. Investigations regarding acute,  subacute, and  chronic  toxicity  demonstrated that  toxicity  could be regarded as harmless (24). Although BPO does  not show  toxicity,  it is still con- sidered to be a carcinogen. Over  the  last  30 years,  many  studies were  conducted to evaluate the safety  of BPO (in general, the results of epidemiology studies and animal carcinogenicity tests serve as important markers for cancer risk assessment). Epidemiology studies have provided evidence that its use to treat acne is not associ- ated  with  any increased risk of skin cancer  (25 – 27).

Furthermore, it was  investigated in several  studies whether BPO has  com- plete  carcinogenic potential, differentiated among complete carcinogenic activity, initiator activity,  promotor activity,  or progressor activity.  Studies  were  conducted in mice, rats, and hamsters where BPO was administered by the oral, subcutaneous, and  dermal route  for up  to 120 weeks  duration. These  studies revealed extensive data  supporting the  conclusion that  BPO  does  not  have  complete carcinogenic activity  (28). Two  further studies revealed that  BPO is not  a tumor initiator (29). Contrary to this,  tumor promotion was  demonstrated in chemical-induced tumors in animal studies. This tumor promotion seems  to be limited to chemical-induced tumors.  There   is  no  evidence  that   BPO  promotes  or  enhances  UV  radiation- induced carcinogenesis (28,30). The human relevance of tumor promotor or progres- sor activities has not been established up to now. In contrast, the human relevance of initiating activity is more certain, because initiators are genotoxic carcinogens that are likely to pose a hazard to humans. BPO has, at most,  a weak  genotoxic potential in some  in vitro  systems, but  this  does  not appear to be manifested in vivo based  on a lack of initiating or complete carcinogenic activity.

Overall,  based  on the current data,  the safety  of BPO use in nonprescription acne  medications can  be supported (28,31). This  is also  confirmed by the  Amer- ican  Academy of  Dermatology  and   the  German  BGA-Monograph (32),  where BPO  is  evaluated as  safe  and  effective  in  acne  therapy. However, it  should be kept  in  mind that  in  order to  obtain  more  data,  further investigations are  still going  on.  Because  of  its  carcinogenic potential,  the  Food  and   Drug   Adminis- tration (FDA)  assigned BPO to  the  category III to  OTC  products, which  means that  more  information is required to  make  a final  determination on  safety  and efficacy  of BPO for  OTC  use.  Such  drugs are  on  the  market awaiting either  the development  of  new   data   or   for  that   drug’s  monograph  to  make   its  way through  to  the   final   rule   (BPO  is  included  in   tentative  monograph  at   the moment). Therefore, the  safety  of BPO needs  to  be  carefully followed up  until final  results are  available.

Random Posts

Comments are closed.