Special Delivery of Topical Interest: Understanding Vehicle Formulation for Nonsteroidal Prescription Eczema Creams

Novel steroid-sparing topical creams approved for mild-to-moderate atopic dermatitis (AD) in recent years have stimulated a generational shift in skin-directed therapy akin to the targeted biologic breakthrough in systemic therapy for patients with moderate-to-severe disease. The growing availability of many topical nonsteroidal therapies, and others under regulatory review or in development, with favorable safety profiles that minimize or avoid skin-associated adverse effects, particularly those associated with topical corticosteroids, represents major advancements in addressing longstanding unmet needs in AD:

• Renewed emphasis on proactive treatment to improve symptom control and reduce fl are unpredictability in a dynamic and chronic disease hallmarked by waxing and waning severity in response to endogenous and exogenous exacerbating factors.
• Options that are equally viable across skin types/tones; anatomic distributions, including intertriginous and sensitive sites; and pruritic or otherwise symptomatic nonlesional areas without the need for treatment adjustment.
• Minimization of polypharmacy and multistep regimens and the associated patient confusion, cost, treatment fatigue, and adverse impacts on adherence.  

Achieving these clinical benefits has required identifying appropriate therapeutic targets and refining drug-target interactions through medicinal chemistry. However, achieving optimized clinical profiles that extend beyond efficacy and safety to include improved tolerability, acceptability, convenience, and real-world patient satisfaction has also required significant innovation in topical vehicle formulation to enable successful adoption of new pharmaceutical products. In treating skin disease, all components of topical preparations must be held to a standard to do no harm but may also present an opportunity to positively contribute to skin healing and itch relief.

Although this topic is relevant across inflammatory skin diseases, it is especially relevant in AD and chronic hand eczema (CHE), where skin care practices focus on avoiding irritants, allergens, and barrier-disrupting agents, such as harsh surfactants and detergents, while utilizing products with protectants, emollients, occlusives, and/or humectants to restore moisture and reduce exposure to proinflammatory and prurito-genic triggers. For example, optimized topical formulations can combine anti-inflammatory and moisturizing properties into a single application, reducing the need for multistep routines in AD.

As dermatologists, we are accustomed to scrutinizing full ingredient lists of over-the-counter products to recommend or avoid, and we have now entered an era in which selecting among the plethora of topical prescription options demands familiarity with comprehensive ingredients lists comprised of both active and inactive (excipient) ingredients.

In this article, we dissect the vehicle constituents of 5 products in order of their US market entry for AD/CHE: pimecrolimus 1%, ruxolitinib 1.5%, rofl umilast 0.05/0.15%, tapinarof 1%, and delgocitinib 2%. The purpose of this article is not to analyze study designs or compare clinical data, but rather to explore what differentiates these agents beyond their active molecule. Not all AD creams are equivalent, and differences in delivery systems may affect skin barrier effects (perturbation vs preservation), epidermal retention, the drug release rates of the pharmaceutical active ingredient, and, ultimately, dosing schedules. Topical drug formulation is highly specialized, with general principles but no universal one-size-fits-all approach. Each product represents a deliberate combination of an active substance’s biophysical properties, tailored formulation technology, and a customized set of excipients.

DEVELOPMENT TIMELINE OVERVIEW

The evolution of topical therapies for AD has been driven by limitations of topical corticosteroids, which have been the mainstay of treatment for decades. While effective, risks include skin atrophy, telangiectasias, striae, dyspigmentation, acne, periorificial dermatitis, tachyphylaxis, and topical corticosteroid withdrawal syndrome that may be mitigated with noncontinuous and/or short-term (<4–6 weeks) usage.¹ This presents an obvious challenge and leaves therapeutic gaps for chronic inflammatory dermatoses. Topical corticosteroids span many potency classes and are available in multiple formulations, including creams, ointments, foams, solutions, oils, shampoos, tapes, and sprays, providing considerable versatility. However, the wide range of branded, generic, and compounded formulations can present challenges in consistency and reliability, as formulation can significantly influence potency and the risk of irritancy or allergenicity to excipients.²

Despite dermatologists’ familiarity with topical corticosteroids as the “Swiss Army knife” of our practice, use is limited by patient steroid phobia, the need to restrict potent agents to localized short-term use on specific body sites due to safety concerns, and reliance on complex multistep regimens in many AD cases. It is still commonplace to prescribe a low potency agent for the face, a foam or solution for the scalp or other hair-bearing areas, and a high- or ultra potent ointment for the hands in the same AD clinic visit. In summary, although topical corticosteroids remain widely used in daily practice, their risk-benefit profile becomes less favorable with prolonged use, exemplifying that they are not ideally suited for long-term management of chronic inflammatory skin diseases.

The early 2000s introduced topical calcineurin inhibitors (pimecrolimus 1% cream and tacrolimus 0.1%/0.03% ointment) as steroid-sparing alternatives, but their use was limited by tolerability concerns (application site discomfort)3 and a boxed warning for a theoretical malignancy risk. This risk has been largely refuted in the literature,⁴ although patient hesitancy persists despite reassuring safety data. A nearly 15-year gap in topical options ended in 2016 with the approval of the first-in-class phosphodiesterase 4 (PDE4) inhibitor crisaborole 2% ointment, indicated for mild-to-moderate AD in patients age 3 months and older, which remains the only nonsteroidal agent for patients age 3 months to 2 years at the time of writing.⁵ However, this addition did little to improve perceptions of nonsteroidal tolerability and efficacy. These products, when tolerated, were used solely on sensitive sites most vulnerable to topical corticosteroid-associated adverse effects, primarily in steroid-averse patients, in very mild AD, for off -label indications, or as adjuncts to topical corticosteroids.

As preclinical drug developers worked to advance promising new small molecule candidates, with sizable company commitments to these programs, renewed focus on formulation emerged. Successful formulation required moving beyond the once-held view of the vehicle as an inert carrier, recognizing it instead as critical to efficacy (penetration through the stratum corneum and partitioning into the epidermis), safety (limiting dermal permeation and systemic absorption), and patient acceptance and ability to differentiate products from other existing and emerging options (cosmetic elegance across skin and hair types and disease presentations).⁶

Decades of experience show that patient adherence is key to real world therapeutic success. Although ointments based on occlusive lipids and/or hydrocarbons promote skin hydration, their oily nature makes them impractical for long-term daily use. Ointments remain useful for short-term treatment of hyperkeratotic, lichenified, and rupioid inflammatory plaques,⁷ but are generally avoided on comedogenic areas like the face and on sites where messiness and visibility may interfere with function such as the hands. Creams have become increasingly favored, reflecting patient preferences in chronic inflammatory skin disease sample groups.⁷

Over the past 5 years, several novel creams supported by robust randomized controlled phase 3 programs have been approved,^8-12 including the first-in-class topical Janus kinase (JAK) 1/2 inhibitor ruxolitinib 1.5% cream, the high affinity PDE4 inhibitor rofl umilast 0.05/0.15% cream, the first-in-class aryl hydrocarbon receptor (AhR) agonist tapinarof 1% cream, and the first-in-class recently US Food and Drug Administration (FDA)-approved pan-JAK delgocitinib 2% cream.^8-11,13-17

FUNCTIONAL EXCIPIENTS OF TOPICAL NONSTEROIDAL THERAPIES

Pimecrolimus 1% Cream

Pimecrolimus 1% cream, a topical calcineurin inhibitor that suppresses T-cell cytokine production, is used twice daily as a second-line treatment for mild-to-moderate AD in patients age 2 years and older who are not adequately controlled or cannot use topical corticosteroids. An FDA-approved generic pimecrolimus 1% cream with equivalent label language is also available. Pimecrolimus is a large (810.5 g/mol), highly lipophilic molecule with limited skin penetration and minimal systemic absorption, requiring formulation strategies, such as penetration enhancers and organic solvents, due to poor aqueous solubility. Product pH is approximately 5.5. Pimecrolimus 1% cream has 11 excipients.¹⁴

Ruxolitinib 1.5% Cream

Ruxolitinib 1.5% cream is the first approved topical JAK 1/2 inhibitor, applied twice daily for short-term or intermittent chronic treatment of mild-to-moderate AD in nonimmunocompromised patients age 2 years and older who are refractory to or unable to use other topical therapies, for up to 20% body surface area. It is poorly water soluble (306.4 g/mol, 97% protein bound) and primarily metabolized by CYP3A4, necessitating a formulation that enhances skin penetration while minimizing systemic absorption. Ruxolitinib 1.5% cream has 17 excipients.^12,13

Roflumilast 0.05%/0.15% Cream

Roflumilast 0.05%/0.15% cream is a topical PDE4 inhibitor applied once daily for mild-to-moderate AD in patients age 6 years and older, with a 0.05% formulation available for ages 2 to 5 years. Roflumilast (403.2 g/mol) is poorly water-soluble, sparingly soluble in ethanol, freely soluble in acetone, and highly protein bound (99%). Its formulation includes emollients, occlusives, solvents, and penetration enhancers to improve hydration and barrier penetration while limiting systemic absorption. Crodafos CES, the emulsifi er utilized in roflumilast (a blend of ceteareth-10 phosphate, cetearyl phosphate, and cetostearyl alcohol), is a commercially available surfactant with a high Krafft temperature, preventing disruption of stratum corneum lipids.^47,48 Crodafos CES creams require pH adjustment during formulation. Roflumilast 0.05%/0.15% cream has 11 excipients.¹⁵

Tapinarof 1% Cream

Tapinarof 1% cream is a topical AhR agonist that modulates gene transcription via AhR activation, leading to down regulation of inflammatory cytokines and up regulation of epidermal barrier related genes. It is applied once daily for AD in patients age 2 years and older. Tapinarof (254.32g/mol) is highly protein bound (~99%) and hepatically metabolized with limited aqueous solubility, necessitating solvents and penetration enhancers. Tapinarof was originally isolated from metabolites of Photorhabdus luminescens, a bioluminescent bacterium living symbiotically within the gut of insect-specific pathogenic nematodes.⁵⁶ Product pH is approximately 5.2. Tapinarof 1% cream has 13 excipients.^17,57

Delgocitinib 2% Cream

Delgocitinib 2% cream, the first FDA-approved topical JAK inhibitor for moderate-to-severe CHE, is a pan-JAK inhibitor applied twice daily in adults unresponsive to or unsuitable for topical corticosteroids, targeting the hands and wrists. Delgocitinib (310.35 g/mol) has low plasma protein binding (22%–29%), slight water solubility, minimal metabolism, and poor permeability, necessitating penetration enhancers, stabilizers, and texture enhancers. Delgocitinib 2% cream has 9 excipients.¹⁶

RISK OF SKIN-ASSOCIATED ADVERSE EVENTS AND TOLERABILITY

With skin-directed therapies, excipient ingredients may share some of the blame for any observed skin-associated side effects. These can affect patient tolerability, experience, confidence in the product and provider, and adherence and satisfaction with treatment regimens. Common adverse reactions include contact dermatitis, skin irritation, skin infections, and application site reactions.^13-17

The acidic pH of the skin surface is essential for maintaining barrier function and antimicrobial defense. Although topical agents may alter the measured surface of the skin pH, this may not accurately reflect the true skin pH, and healthy skin can rapidly restore its baseline through an intrinsic buffering capacity.⁶⁹

In eczematous skin, buffering capacity is reduced and pH shifts toward neutral or slightly basic levels, impairing antimicrobial and barrier functions.⁷⁰ This environment promotes proliferation of Staphylococcus aureus, which thrives at a more neutral pH and can more readily proliferate in patients with AD,⁷⁰ effects that may be exacerbated by the use of more basic topical formulations. Concurrently, surfactant-induced disruption of stratum corneum lipids is particularly relevant in AD, which is characterized by reduced barrier proteins, ceramides, and lipid repair enzymes (elongases), increasing susceptibility to irritation and transepidermal water loss.⁷⁰

This underscores the need for a complete formulation to respect physiologic pH and minimize additives that compromise barrier integrity, as well as the potential for direct irritancy and allergenicity. It is challenging to discern to what extent treatment emergent cutaneous adverse events are attributable, at least in part, to excipient-related adverse effects in clinical practice.

CONCLUSION

Recent advancements in nonsteroidal topical therapies for AD and CHE highlight that both the active ingredient and excipients are critical for optimizing efficacy, safety, and patient adherence. Thoughtful selection of excipients can aim to protect against worsening disease elements and, in some instances, may be shown to enhance skin healing independent from efficacy of the active molecule. Ultimately, given the dynamic nature and phenotypic heterogeneity of AD and the wide range of lifestyle and personal preference factors that characterize our diverse patients, individual real-world experience will prove to be the most telling.