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.
WHAT IS THE GOAL OF ACNE THERAPY?
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).
BENZOYL PEROXIDE History
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.