Seborrheic dermatitis (SD) affects approximately 1–3 % of the adult population, causing skin inflammation, pronounced flaking and pruritis [1]. Dandruff, a milder form of the condition, is more common, estimated to affect half of the global population, and primarily presents with skin flake and itch [2]. Symptoms are a source of psycho-social stress and lead to a reduced quality of life [3], [4]. SD has been linked to the lipid-dependent species of Malassezia yeast, specifically Malassezia globosa and Malassezia restricta, which colonise the scalp [5]. Topical treatments account for approximately 512 million USD of consumer expenditure annually in the Unites States [6]. These therapies are under continuous development, especially shampoo formulations, towards those that are faster acting and have multi-functional benefits.

This review provides a comprehensive overview of the range of pharmacological management options for SD. We focus on zinc pyrithione (ZnPT), a particulate material with anti-fungal properties and the market leading treatment agent. We extend our previous review [7], by critically examining the delivered ZnPT dose, comparing it alongside thresholds for toxicity and efficacy to establish a therapeutic window for performance. Lastly, we explore strategies for formulation optimisation, highlighting the importance of therapies that can balance efficacy, safety, and consumer appeal.

Barrier impairment in SD is demonstrated by electron microscopy studies showing disorganised stratum corneum packing [8] and functional studies showing an increase in trans-epidermal water loss [9]. These changes are driven by microbial dysbiosis, which is in turn influenced by an interplay of environmental and host factors. Yeast belonging to the M. restrica and M. globosa species are believed to be the primary causative micro-organism [5], [10]. It should also be recognised that bacteria, including Staphylococci and Propionibacterium species [11], may also be involved, however their role is not entirely clear (i.e. they may be a cause or consequence of yeast imbalance).

Scalp microbiome dysbiosis results in a disrupted balance of lipids and other organic compounds, including elevated oleic acid, malassezin, pityriacitrin, indolocarbazole and squalene peroxide, which can then cause scalp barrier impairment [12], [13], [14], [15]. Shifts in relative amounts of sapienic acid may also be involved, given its abundance [16] and role in atopic dermatitis [17] but requires further investigation. Lipids can either facilitate growth of certain micro-organisms or prevent it [18] (as discussed further in Section 3.5) and the balance is therefore crucial for maintaining either a state of healthy barrier function or a dysbiotic state associated with barrier compromise.

Since Malasezzia are normal skin commensal micro-organisms [19], host factors such as immunity, neuro-endocrine function and genetics are important in predisposing individuals to SD. In recent years there has been a shift in focus to these intrinsic factors that enable colonization, playing a central role in SD pathobiology [20].

The innate immune response may play a role in pathogenesis as evidenced by skin infiltration of natural killer cells and macrophages [21]. Any adaptive immune response is likely cellular in nature rather than humoral due to a lack of detectable anti-Malassezia antibodies [22], [23]. These observations on their own however are unable to distinguish whether immunity is involved as a cause or consequence of SD. A link to a causative role is provided by the increased prevalence of SD among the immunocompromised, estimated to be up to 80 % in HIV [24], organ transplant [25] and lymphoma [26] patients.

The potential role of genetics in SD is complex [27]. One human twin study has shown only a minor role for an hereditary association [28], while transgenic mice models have identified both autosomal dominant and recessive forms of SD [29], [30]. Animal data shows SD-like symptoms are associated with expression of T-cell receptor genes [30] and missense mutations involved in epidermal differentiation, such as the Mpzl3 gene [31], [32]. While not necessarily a genetic factor, the mode of delivery at birth (vaginal vs caesarean) is capable of shaping the skin microbiome [33] and therefore could potentially influence the development of skin disorders such as SD.

Prevalence data alludes to a hormonal component in SD and related flaking disorders. There is a temporal relationship with sebaceous gland activity in that prevalence of SD peaks in the first three months during an infantile form called cradle cap [34] and again during puberty [35]. Furthermore, SD is more common among males who have higher sebaceous gland activity and androgens [36]. It should be noted however that SD can occur in skin regions without high activity, so a definitive role is yet to be established.

SD prevalence is higher with emotional stress and depressive disorders [37]. This could be due to immune and neuroendocrine mechanisms [38] causing elevated glucocorticoids, which are known to inhibit epidermal lipid synthesis and secretion [39] as well as delay barrier recovery [40]. SD has also been associated with Parkinson’s disease, potentially via increased sebum levels [41]. These associations must be interpreted with caution as there is the potential for confounding lifestyle factors to be involved, such as the increased tendency to remain indoors, with low sunlight exposure found to be correlated with SD [42], [43].

Environmental conditions influence skin water activity and lipid levels important for maintaining skin barrier integrity. Seasonal variation in skin lipids [44] is correlated with dandruff severity, which doubles in the Thai dry season and during winter in the United Kingdom [45]. This coincides with a 20 % decrease in cermamide-1 linoleate, an intercellular lipid important for maintaining membrane fluidity and flexibility [46]. Prolonged exposure to a dry environment leads to a normal homeostatic response whereby stratum corneum thickness is increased to preserve water activity [47]. In mouse studies, low relative humidity (<10 %) combined with a defective barrier can result in a pathophysiological response characterized by hyperplasia and mast cell degranulation [48]. By interfering with generation of natural moisturizing factors [49], changes in humidity may lead to an intrinsically weaker barrier. Other exacerbating environmental conditions include over exposure to ultraviolet radiation [50] and pollution [51]. Differences in prevalence of dandruff and SD have been reported for urban and rural communities in India, reflecting the influence of different environments and hygiene practices [52].

The use of shampoos and cleansers that contain harsh surfactants can also contribute to barrier perturbations in SD. Detergents like sodium lauryl ether sulphate and sodium dodecyl sulphate induce conformational changes that denature hydrolytic enzymes [53] which drives hyperproliferation and amplifies the inflammatory cytokine response [54] in a cycle maintaining a defective barrier [55], [56]. Daily skin damage caused by hard brushing, hair friction and exposure to irritants in skin and hair products are also likely involved in predisposing individuals to SD, although the relative contributions and importance of each is not entirely known [57]. In regards to ‘over washing’, interesting new work has demonstrated that a daily washing protocol in a Chinese population results in the greatest reduction in flaking and improvement in scalp health [58], however further studies should be conducted to extend this finding to other populations, such as those living in drier climates where daily washing may lead to xerosis.

The pharmacotherapies available for targeting different aspects of SD are shown in Fig. 1. The most common agents used are the anti-fungals, which includes ZnPT, azoles, piroctone olamine, and lithium salts (Fig. 1A). Treatment can also address the symptoms such as inflammation (e.g., corticosteroids and calcineurin inhibitors), scaling (e.g., keratolytic agents and coal tar) or excess sebum production (e.g., sulphur and retinoids). Barrier repair agents are valuable as adjuvants in treatment and there are also a wide range of naturally occurring agents (e.g., tea tree oil, emu oil and honey) that may be used. Ingredients like coal tar and selenium sulphide have mixed modes of action involving anti-fungal, anti-inflammatory, and anti-keratolytic effects.

These agents can be incorporated into a wide range of topical products, predominantly wash-off formulations such as shampoos (Fig. 1B) with ZnPT being the current market leader (Fig. 1C).

Table 1 provides a comprehensive overview of SD pharmacotherapies, including their mechanisms of action, dosage forms and strengths, as well as advantages and disadvantages. Factors that are important for deciding the most appropriate treatment approach include 1) the case severity and distribution on presentation (e.g., scalp, trunk, face), and 2) patient medical history, including any co-morbidities (e.g., liver disease, immune compromise), and 3) use of other medications and individual sensitivities or intolerances. Generally, if the disease is mild, over-the counter-therapies such as ZnPT or coal tar shampoos can be successful as monotherapies. In moderate to severe cases, anti-fungals may be required in addition to corticosteroids to improve symptom resolution time, however it is important to recognise that the latter are not suited for long term use (i.e., beyond 2–4 weeks) due to the risk of adverse effects such as irritation, skin atrophy, striae, and telangiectasia. In severe cases, oral agents such as itraconazole or fluconazole may be considered alongside topical treatments. If symptoms are recalcitrant, other treatment options may be explored, such as calcineurin inhibitors, phosphodiesterase inhibitors, calcipotriol, or retinoids (e.g., isotretinoin) [59], [60].

A range of topical delivery vehicles are available including includes creams, lotions, and ointments, which can be designed either as leave-on or wash-off preparations. Cleansers, including shampoos, are a special class of wash-off vehicle that combines both drug delivery and detersive action to remove proteinaceous and lipid debris from the skin and hair. Dosage vehicle is an important consideration as it may influence potency, as is the case with corticosteroids (i.e., ointments provide occlusive barrier that enhance penetration over longer periods compared to creams and lotions)[61], and also because it may influence treatment compliance. Some vehicles will be more appropriate than others depending on the patient skin type (e.g., dry or oily) and area of application (e.g., face, body or scalp). In general, ointments provide the greatest level of moisturisation, however are difficult to spread and can leave a shiny coat where applied. Creams, while easier to spread, may have a greasy feel. Gels, sprays and foams are the easiest to spread but may cause irritation and dryness due to the high alcohol content [62].

Treatment of SD affecting the scalp is particularly challenging because hair presents a problem for targeted delivery and there are limited appropriate vehicles. Creams, ointments, and gels are typically not ideal as leave-on agents and may be difficult to properly remove if designed as wash-off formulations. Sprays and solutions are more appropriate but can be messy and time consuming to achieve complete coverage, which typically limits them to short-term use. These formulation vehicles only make up a small proportion of commercially available over the counter topicals (Fig. 1B). Shampoos are the ideal vehicle for scalp delivery as they allow complete coverage and can be incorporated into existing grooming routines, which is useful even in the most severe cases as part of a long-term preventative solution.