¹SKiN Centre for Dermatology, Peterborough, ON, Canada
²Probity Medical Research, Waterloo, ON, Canada
³Queen’s University, Kingston, ON, Canada

Conflict of interest: A. O’Toole has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Amgen, Arcutis Biotherapeutics, ASLAN Pharmaceuticals, Bausch Health, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Janssen, LEO Pharma, Moonlake, Nimbus, Novartis, Pfizer, Regeneron, Sanofi-Aventis/Genzyme, Sun Pharma, UCB and Ventyx. M. Gooderham has been an investigator, speaker, or advisory board member for, or received a grant, or an honorarium from AbbVie, Akros Pharma, Amgen, AnaptysBio, Arcutis Biotherapeutics, Aristea, ASLAN Pharmaceuticals, Bausch Health, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Coherus, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Janssen, Kyowa Kirin, LEO Pharma, MedImmune, Moonlake, Nimbus, Novartis, Pfizer, Regeneron, Reistone, Roche, Sanofi-Aventis/Genzyme, Sun Pharma, UCB and Ventyx.
Funding: None.

Abstract:
Roflumilast is a highly selective phosphodiesterase-4 inhibitor for the treatment of plaque psoriasis. Topical roflumilast 0.3% cream, approved by the US FDA and Health Canada for use in adolescents and adults, has proven efficacy and tolerability. It is non-steroidal, administered once-daily, and highly potent, with a unique delivery formulation. It can be used on most body areas, including the sensitive intertriginous regions and face. Herein, we review the safety and efficacy of roflumilast 0.3% cream, as demonstrated in clinical trials.

Keywords: roflumilast, PDE4 inhibitor, topical therapy, plaque psoriasis, intertriginous psoriasis, inverse psoriasis

Introduction

Plaque psoriasis is a chronic inflammatory skin condition with an estimated prevalence of 3%¹ and is characterized by scaly plaques which can be red to violaceous depending on the background color of skin. Psoriasis most commonly presents on the extensor surfaces but can involve anywhere on the body, including the scalp, face, and intertriginous areas. Most cases of plaque psoriasis are mild to moderate in severity, where half of patients have a body surface area (BSA) ≤3% and three-quarters have a BSA ≤10%.¹ Psoriasis significantly impacts quality of life, with the majority of patients reporting a “large impact” on their everyday life, even in those with limited BSA involvement.² Impact on quality of life is greater with special site involvement (i.e., face, groin, palms/soles) compared to no special site involvement.³ Itch is considered the most bothersome symptom in plaque psoriasis by almost half of patients.^3,4

The mainstay of treatment is topical including steroids, vitamin D analogs, retinoids, and calcineurin inhibitors (used off label), whether used as monotherapy in mild to moderate disease or as concomitant therapy with systemic agents in moderate to severe disease. Current topical therapies have limitations, however, including messy or greasy texture, complex or time-consuming application, local side effects, or perceived inefficacy, which can all lead to lack of adherence to treatment and poor outcomes.⁵ Indeed, almost 80% of patients with a BSA of ≤10% were very dissatisfied with their treatment in one US survey.²

Pathophysiology of Psoriasis and Role of Phosphodiesterase-4

Environmental, genetic, and immunologic factors play a role in this complex, chronic, multifactorial inflammatory disease that involves hyperproliferation of the keratinocytes with an increase in epidermal cell turnover rate. Phosphodiesterase-4 (PDE4) is a key enzyme involved in immune cell homeostasis. Elevated PDE4 activity in psoriatic skin leads to an increase in pro-inflammatory pathogenic mediators underlying plaque psoriasis,⁶ making PDE4 a suitable target in disease management. PDE4 inhibitors have been approved for use in dermatology, including oral apremilast for moderate to severe plaque psoriasis (and psoriatic arthritis) and crisaborole ointment for mild to moderate atopic dermatitis. Roflumilast is a selective and highly potent inhibitor of PDE4,⁷ resulting in an increase in cyclic 3′,5′-adenosine monophosphate (cAMP) activity and subsequent decrease in the expression levels of key pro-inflammatory mediators of psoriasis including interleukin (IL)-17, IL-23, interferon‐gamma and tumor necrosis factor-alpha.⁶ Reducing pro-inflammatory mediators helps balance the immune response and normalizes keratinocyte differentiation.⁶ Roflumilast has greater affinity for PDE4 than the other currently available PDE4 inhibitors used to treat skin disease; depending on the comparator and isoform analyzed, it is approximately 25-300 times more potent than apremilast and crisaborole.^7-9

Topical Roflumilast

Topical roflumilast 0.3% cream (Zoryve^TM) was approved by the US FDA for the treatment of plaque psoriasis including intertriginous psoriasis in adolescents (aged ≥12 years) and adults in July 2022, with Health Canada approval gained in April 2023. It is uniquely formulated as an emollient water-based cream designed to deliver the roflumilast molecule throughout the epidermis without disrupting the skin’s barrier function or extracting lipids from the epidermis. A unique and patented emulsifier blend (Crodafos^TM CES) maintains the integrity of the lipid bilayer while facilitating delivery of roflumilast. The composition of Crodafos^TM CES includes cetearyl alcohol, dicetyl phosphate, and ceteth-10 phosphate which allows roflumilast to diffuse through the epidermis by saturating the stratum corneum and subsequently entering the dermis via the intracellular space. The formulation does not contain ingredients such as propylene glycol or fragrance, resulting in improved tolerability (compared to some other topicals currently available). Topical roflumilast 0.3% cream is also found in higher concentrations in the skin compared to that expected with oral dosing, with levels 61.8- to 126-fold higher in the skin compared to plasma.¹⁰ The lipophilic, protein-affinity and water-insoluble properties of topical roflumilast leads to reservoir formation in the stratum corneum and prolonged release into the skin and systemic circulation. In fact, topical roflumilast has a long half-life of 4 days,¹⁰ affording the ability for once-daily dosing, high efficacy and improved tolerability. The tolerability and low rate of adverse effects are attributable to reduced bioavailability in the topical form compared to the oral form of roflumilast.¹⁰

Clinical Trials: Efficacy and Safety of Roflumilast

Topical roflumilast has proven efficacy and safety in multiple clinical trials. A Phase 1/2a randomized controlled trial (NCT03392168) tested roflumilast cream 0.5%, 0.15% vs. vehicle for 28 days in patients with ≤5% BSA.¹¹ The primary endpoint was met with significant improvement in the Target Plaque Severity Score (TPSS) x target plaque area (TPA) with roflumilast 0.5% (P = .0007) and 0.15% cream (P = .0011) vs. vehicle; 66%-67% improvement from baseline to week 4 was noted with roflumilast vs. 38% for vehicle.¹¹

In a Phase 2b randomized double-blinded controlled trial (NCT03638258), 331 adult patients were randomized 1:1:1 to receive roflumilast cream 0.3%, 0.15%, or vehicle once daily for 12 weeks. The primary endpoint at 6 weeks of an Investigator Global Assessment (IGA) score of clear or almost clear (0 or 1) was reached by 28% in the roflumilast 0.3% group (P < .001), 23% in the roflumilast 0.15% group (P = .004), and 8% in the vehicle group (Figure 1A). The mean change in Psoriasis Area and Severity Index (PASI) from baseline at week 6 was -50.0%, -49.0%, and -17.8%, in roflumilast 0.3%, roflumilast 0.15%, and vehicle, respectively. Important secondary endpoints included an intertriginous IGA (I-IGA) response (clear or almost clear and ≥2 grade improvement from baseline) in 73% of the roflumilast 0.3% group, 44% of the roflumilast 0.15% group, and 29% of the vehicle group in the subgroup of participants with at least mild IGA intertriginous involvement (~15% of trial population).¹² Itch and itch-related sleep loss were also improved in subjects receiving roflumilast. Subjects with a baseline worst itch numeric rating scale (WI-NRS) ≥6 treated with roflumilast 0.3% cream achieved ≥4-point improvement compared with vehicle, which was significant at all time points between week 2 and week 12 (all P < .05).¹³ The least squares mean improvement in itch-related sleep loss was statistically significant for both doses of roflumilast as early as week 6 and maintained through week 12.¹³

Two identical pivotal Phase 3 trials, DERMIS-1 (NCT04211363) and DERMIS-2 (NCT04211389), enrolled patients older than 2 years of age, with 2% to 20% BSA and an IGA of at least 2 (mild).¹⁴ A total of 439 and 442 subjects were enrolled (DERMIS-1 and DERMIS-2, respectively) and randomized 2:1 to receive roflumilast cream 0.3% or vehicle. The primary endpoint was achieving IGA success (clear or almost clear [0 or 1] with ≥2 grade improvement from baseline) at 8 weeks. IGA success was achieved by participants receiving roflumilast 0.3% cream vs. vehicle by 42.4% and 6.1% (DERMIS-1) and by 37.5% and 6.9% (DERMIS-2), respectively (P < .001 for both) as shown in Figure 1B. Important secondary endpoints included I-IGA success at week 8, 75% improvement in PASI (PASI75) at week 8, and itch improvement as measured by WI-NRS at weeks 2, 4, and 8. In participants with an I-IGA score of at least 2 at baseline (approximately 20% of trial population), I-IGA success at week 8 was achieved by 71.2% vs. 13.8% (DERMIS-1) and 68.1% vs. 18.5% (DERMIS-2) in roflumilast 0.3% cream vs. vehicle, respectively.¹⁴ The majority of patients achieving I-IGA success also achieved an I-IGA score of clear (0) with 63.5% vs. 10.3% (DERMIS-1) and 57.4% vs. 7.4% (DERMIS-2) (P < .001) clearing intertriginous areas with roflumilast 0.3% vs. vehicle, respectively. PASI75 was reached with roflumilast 0.3% vs. vehicle in 41.6% vs. 7.6% (P < .001) and 39% vs. 5.3% (P < .001) in DERMIS-1 and DERMIS-2, respectively. Itch, the most bothersome symptom of psoriasis, also improved in patients with a baseline WI-NRS score of ≥4 at baseline. WI-NRS reduction of at least 4 points from baseline was achieved as early as week 2 in 34.9% vs. 22% (DERMIS-1, P = .12) and 41.9% vs. 21.1% (DERMIS-2, P = .003) and at week 8 in 67.5% vs. 26.8% (DERMIS-1, P < .001) and 69.4% vs. 35.6% (DERMIS-2, P < .001).¹⁴

Topical roflumilast was well tolerated with rates of treatment emergent adverse effects (TEAEs) similar in both groups: DERMIS-1 (roflumilast: 25.2% and vehicle: 23.5%) and DERMIS-2 (roflumilast: 25.9% and vehicle: 18.9%).¹⁴ Less than 1% of patients in any group experienced a serious adverse event. Rates of discontinuation due to TEAEs were low and similar between groups. The most commonly reported TEAEs were headache and diarrhea consistent with the effects of oral PDE4 inhibition, but present at much lower rates than seen with oral agents. Diarrhea was mild to moderate and reported in 3.5% and 2.8% of participants receiving roflumilast in DERMIS-1 and DERMIS-2, respectively, compared to none in the vehicle group. No patients interrupted therapy or discontinued due to diarrhea.¹⁴ Headache was reported in 1% and 3.8% in the roflumilast group and 1.3% and 0.7% in the vehicle group. The cream was well tolerated with low rates of application site pain: DERMIS-1 (roflumilast: 0.7% and vehicle: 0.7%) and DERMIS-2 (roflumilast: 1.4% and vehicle: 0%). Investigator-rated tolerability was consistent with patient-rated tolerability, with 98- 99% of roflumilast patients and 98% of vehicle patients showing no signs of irritation and 99% of patients reporting ‘no or mild’ sensation with application when assessed at both weeks 4 and 8.¹⁴

Long-term Use of Topical Roflumilast

Long-term use of roflumilast was investigated in a 52-week openlabel extension (OLE) of the Phase 2b study.¹⁵ There were two cohorts in the OLE: cohort 1 (n=230) was comprised of patients who completed the initial 12-week phase of the Phase 2b study (for a total of 64 weeks of therapy), and cohort 2 (n=102) had naïve patients with a diagnosis of at least mild psoriasis for a minimum of 6 months. The completion rate after 52 weeks was 73.5%, with low rates of discontinuation due to TEAEs or inefficacy, and the majority of discontinuations were due to withdrawal or loss of follow-up. The proportion of patients achieving IGA success was consistent over time, with 34.8% of cohort 1 patients and 39.5% of cohort 2 patients achieving IGA success with 64 weeks and 52 weeks of as-needed therapy, respectively. I-IGA success was achieved by 60% at week 12 and maintained by 66.7% of cohort 2 patients by week 52 but was not recorded in cohort 1 patients. Of the patients who achieved clear or almost clear skin during the open label portion, the mean durability of maintaining their response was 10 months.¹⁶ Topical roflumilast was well tolerated in the OLE, with the majority of TEAEs rated mild or moderate, 97% considered unrelated to treatment, and ≥97% showed no signs of irritation on physician assessment.¹⁵

Discussion

PDE4 inhibition with topical roflumilast is a promising non-steroidal option for patients with plaque psoriasis of varying severities. Key data from the pivotal trials, DERMIS-1 and DERMIS-2, report IGA success in approximately 40% of study participants with psoriasis ranging from mild to severe. Results are supported by earlier phase studies measured at earlier time points. IGA success was noted as early as week 4, and responses were maintained to week 64 with as-needed use, suggesting that once a response is obtained, it can likely be sustained over time. Itch, the most bothersome symptom of plaque psoriasis, improved by 2 weeks (the first assessed time point) in all studies and itch improvement maintained over time. Itch-related sleep loss also improved compared to vehicle. Early responses such as itch and sleep improvement can encourage adherence to therapy and improve outcomes.

Given the spectrum of obstacles in the treatment of plaque psoriasis, including patient adherence and tolerance with topical therapies, as well as the management of itch and special sites (e.g., scalp and intertriginous areas), topical roflumilast appears to address these challenges. Individuals with psoriasis are often prescribed multiple topical medications to treat different skin areas, which contributes to a complicated treatment regimen and patient non-adherence. Topical roflumilast addresses this significant unmet need with its once-daily, non-steroidal and carefully designed vehicle that is appropriate for use on most body areas, avoiding the need for multiple prescriptions and simplifying the treatment regimen. A foam formulation is also being developed for use on the body and scalp.

The PASI75 responses noted with topical roflumilast were also comparable with a recent trial of oral apremilast for patients with mild to moderate psoriasis (ADVANCE trial, NCT03721172).17 With similar baseline characteristics (PASI 6-7, BSA 6-7% and the majority of patients with IGA 3 or moderate severity) in DERMIS-1/ DERMIS-2 and the ADVANCE trial, the proportion of patients achieving PASI75 were similar or better with roflumilast compared to oral apremilast. In ADVANCE, 21.6% of those receiving oral apremilast 30 mg twice daily achieved PASI75 compared to 4.1% receiving placebo at 16 weeks. In DERMIS-1 and DERMIS-2, after 8 weeks of therapy, 41.6% and 39% of roflumilast patients achieved PASI75 compared to 7.6% and 5.3% of vehicle patients, respectively. The comparability of a topical therapy demonstrating efficacy that is similar to or better than an oral PDE4 agent such as apremilast, can be explained by the properties of topical roflumilast, which include the lipophilicity and reservoir in the stratum corneum combined with the higher affinity of roflumilast for PDE4. In patients with mild to moderate psoriasis, topical roflumilast may potentially delay or even avoid the need for oral therapy by providing similar efficacy. The limitation will be patients with higher BSA where the risk of TEAEs, such as diarrhea, may be higher or those with psoriatic arthritis where a systemic therapy may be preferred.

Conclusion

Targeting PDE4 with a highly selective inhibitor such as roflumilast is a proven effective strategy for the treatment of plaque psoriasis. Topical roflumilast cream 0.3%, already approved by Health Canada and the FDA for use in adolescents and adults, has demonstrated efficacy and tolerability. It is non-steroidal, administered oncedaily, and highly potent, yet delivered in a cosmetically elegant formulation that is well tolerated by patients. It can be used on most body areas, including the sensitive intertriginous regions and face, making one product suitable for treating all areas of involvement. Topical roflumilast will offer patients and their health care providers a simple, convenient, safe, effective, and durable therapeutic option for the management of psoriasis.

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¹Beacon Dermatology, Calgary, AB, Canada
²Division of Dermatology, University of Calgary, Calgary, AB, Canada
³Dermatologie Clinic, Drummondville, QC, Canada
⁴Bausch Health Canada Inc, Laval, QC, Canada
⁵SKiN Centre for Dermatology, Peterborough, ON, Canada
⁶Queen’s University, Kingston, ON, Canada

Conflict of interest: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article:
Isabelle Delorme has been a member of advisory boards for AbbVie, Bausch Health, Eli-Lilly, Janssen, Novartis, Sanofi-Genzyme. She has been a part of clinical trials for AbbVie, Amgen, Anaptys Bio, Arcutis, Bausch Health, BMS, Celgene, Dermira, Devonian, Eli-Lilly, Galderma, Glenmark Pharmaceutical, Innovaderm Research, Janssen, Leo Pharma, Novartis, Regeneron. She has recieved honoraria from AbbVie, Amgen, Avene, Celgene, Eli-Lilly, Janssen, Novartis, UCB Pharma. She has been part of speaker’s bureaus for AbbVie, Celgene, Bausch Health, Eli-Lilly, Janssen, Medexus Inc., Novartis, Sanofi Genzyme. Melinda Gooderham has been an investigator, speaker and/or advisor for – AbbVie, Amgen, Akros, Arcutis, Aslan, Bausch Health, BMS, Boehringer Ingelheim, Celgene, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Janssen, Kyowa Kirin, Leo Pharma, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, and UCB. Andrei Metelitsa has been a consultant for Bausch Health, Galderma, Leo Pharma and Pfizer.
Daniel O’Sullivan, Rami Zeinab and Mark Legault are employees of Bausch Health Canada.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Abstract:
Dermatological diseases such as atopic dermatitis, acne, and psoriasis result in significant morbidity and decreased quality of life. The first line of treatment for such diseases is often topical medications. While topical delivery allows active drug to be delivered directly to the target site, the skin is a virtually impermeable barrier that impedes delivery of large molecules. Thus, the formulation and delivery system are integral elements of topical medications. Patients also have preferences for the properties of topical formulations and these preferences can positively or negatively impact adherence. Therefore, the choice of topical formulation is a key consideration. Recent developments in drug delivery systems have produced enhanced topical treatments that improve efficacy, safety, and patient acceptability. Awareness of the delivery system in which drugs are formulated is critical as this can have profound implications on treatment success. This paper provides an overview and clinical commentary on advances in topical delivery systems and their impact on dermatological practice.

Keywords: acne, corticosteroid, dermatitis, dermatology, halobetasol, psoriasis, retinoid, tazarotene, topical, vehicle, Duobrii, Arazlo, Bryhali

Introduction

Topical therapies are often the first line of treatment for common skin diseases such as atopic dermatitis (AD), acne vulgaris (AV), and psoriasis (PsO).¹ Prescribing effective therapy is crucial for optimal treatment outcomes.² However, the composition of topical treatments is complex and should be taken into consideration when choosing a topical treatment in terms of both “formulation” and “drug delivery system” wherein the formulation includes the active drug and vehicle while the delivery system refers to technologies affecting the therapeutic action of the drug (including potency, stability, dispersion, and penetration). Both formulation and delivery system should be considered for each patient on the basis of the potency of the active molecule, patient preference, skin type, skin condition, and affected site.³ Several recent reviews have discussed topical vehicles, ingredients, and their effects on the skin,^4-10 however, there is a gap in reviewing advanced delivery systems currently in clinical use. This paper provides an up-to-date review of advances in topical delivery systems with a focus on those in clinical use for the treatment of AD, AV, and PsO.

Atopic Dermatitis, Acne Vulgaris and Psoriasis

Skin conditions are a common cause of disease globally,¹¹ with AD, AV, and PsO amongst those with the highest disease burden on patients¹². These conditions disrupt the normal skin function,¹³ trigger abnormal inflammatory responses, alter skin microbiome, and increase susceptibility to irritants/allergens.^5-7 AD is a chronic, relapsing disease, presenting as inflamed skin with intense itching.^14,15 AV is due to inflammation of the sebaceous follicles, resulting in increased sebum production and a favorable environment for bacterial growth.¹⁶ PsO is a chronic disease that presents with characteristic scaling, redness, and thickening of the skin. All of these skin diseases can have important detrimental effects on short and long-term psychosocial and physical health, with substantial morbidity and reduced quality of life.^15,17,18 As such, early treatment with the most efficacious therapies available is critical.

Factors to Consider with Topical Drug Delivery Systems

Applying treatment topically provides several advantages for managing skin diseases. It enables delivery of drug directly to the target site, minimizing systemic exposure.¹⁹ The skin provides for a regulated, constant delivery rate and circumvents first-pass metabolism.²⁰ However, delivering drugs to targets beneath the epidermis can be challenging.²¹ The skin is a multi-layered defense barrier constructed to withstand the penetration of external compounds.²² The stratum corneum is very effective in performing this role and minimizes the ingress and egress of molecules/ chemicals.²³ As a result, the skin is impermeable to almost all compounds with a molecular weight greater than 500 Daltons.^22,23 As diffusion is the principal mechanism by which a drug penetrates the skin,²² formulations must be optimized to maintain solubility, stability, dispersion, and penetration of the active ingredient(s) while ensuring they are sustained at the target site for sufficient time, as well as limit systemic exposure³.

The effectiveness of a topical medication depends not only on pharmacodynamic factors but also on patient preferences, adherence, and the location of disease.^2,24 Patient preferences are related to the formulation and drug delivery system whose attributes include moisturization, absorption, greasiness, stickiness, as well as ease and frequency of use.²⁵ These attributes influence adherence to the therapeutic regimen which is a major determinant of treatment success.²⁵ Teixeira et al.²⁶ reported that adherence was impacted not only by patient preferences, but also the body area affected. For example, adherence was higher for patients using gel/cream vs. ointment formulations when the body area affected was large. However, this was reversed with smaller areas. As such, delivery systems are no longer only considered ‘carriers’ of active ingredients, but also integral to the formulation. Hence, drug delivery system research and development have been the main drivers of recent advancements in topical formulations.

Advanced Topical Drug Delivery Systems

Over the years, advanced drug delivery systems have been developed to enhance effectiveness, tolerability, safety, and patient acceptability of topical formulations. Some of these advanced delivery systems are integrated into approved products utilized in clinical practice in Canada (Figures 1 & 2). As such, it is important for healthcare providers to be aware of these systems and their profound implications on treatment outcomes. The following summary provides an overview of some recent advances in drug delivery systems and their clinical application (Table 1).

Table 1. Advanced topical drug delivery systems in clinical use

Microencapsulation

Description of Delivery System

Microencapsulation is a technique that involves entrapping active ingredient(s) in a microcapsule, creating a barrier between the ingredients and the skin.²⁷ Once applied, microcapsules allow controlled release of active ingredients over time.²⁸ This offers advantages for topical delivery of agents (Table 1) where active ingredients are protected against degradation and maintained at the target site for an extended time while limiting local adverse reactions.^28,29

Clinical Application Highlights

Encapsulation is the technology behind two topical treatments approved for treatment of moderate to severe AV in the US. The first formulation is a foam-based delivery system that optimizes the topical delivery of minocycline (minocycline topical foam 4%, Amzeeq®).³⁰ Minocycline was previously not available topically due to its instability and systemic side effects.³¹ Such limitations were mitigated with microencapsulation. In phase 2^32,33 and 3³⁴ clinical trials, microencapsulated minocycline significantly reduced AV lesions and severity compared to placebo; with minimal adverse effects. The second is a cream-based formulation combining tretinoin 0.1% and benzoyl peroxide (BPO) 3% (Twyneo®).³⁵ Tretinoin and BPO are individually entrapped within silica-based microcapsules preventing the degradation of tretinoin by BPO.²⁸ The active ingredients are released over time, providing a consistent drug concentration at the affected site.³⁶ Results from clinical trials show that patients who received this encapsulated combination therapy had improved treatment outcomes compared with patients who received vehicle only. The treatment was well tolerated.³⁶

Microsponges

Description of Delivery System

Microsponges are microscopic, uniform, spherical, porous delivery systems.³⁷ Some features of micropsonges are summarized in Table 1. Their large surface area allows a range of substances to be incorporated into gels, creams, liquids, or powders.³⁸ They can absorb skin secretions, therefore reducing the oiliness of the skin.^38,39 When applied, the release of drug is controlled through diffusion, rubbing, moisture, pH, friction, or ambient skin temperature, producing a controlled release and reducing side effects.⁴⁰ Microsponge polymers possess the ability to load a spectrum of active ingredients and provide the benefits of enhanced effectiveness, mildness, and tolerability to a wide range of skin therapies.⁴¹ The microsponge system is stable over a range of pH and temperatures, compatible with most vehicles and ingredients, self-sterilizing as average pore size prevents bacterial penetration, and has a higher payload⁴² (50-60%) vs. conventional topical drugs and microencapsulation. However, due to their size (5-300 μm), passage through the stratum corneum is limited.³⁹

Clinical Application Highlights

Early topical formulations of tretinoin had high concentrations of active ingredients in alcohol-based solutions leading to skin dryness and irritation.^43,44 The innovation of microsponges led to the first alcohol-free, topical retinoid delivery system (tretinoin gel, Retin-A Micro^®).⁴⁵ This microsponge gel contains tretinoin in concentrations of 0.04%, 0.06%, 0.08%, and 0.1%. Tretinoin is entrapped in patented methyl methacrylate/glycol dimethacrylate copolymer porous microspheres (Microsponges^® system), within a carbomer-based gel. In the vehicle-controlled clinical trials, tretinoin gel was significantly more effective than vehicle in reducing the severity of acne lesions; and significantly superior to vehicle in the investigator’s global evaluation of the clinical response.^46-48 Microsponge delivery of tretinoin has also been associated with decreased irritation compared to earlier alcoholbased cream (Retin-A® cream, 0.1%).⁴⁹

Polymeric Emulsion Technology

Description of Delivery System

In polymeric emulsion technology (PET), active ingredients are encapsulated within oil droplets, together with moisturizing/ hydrating ingredients (light mineral oil, diethyl sebacate).⁵⁰ The oil droplets are uniformly dispersed within an oil-in-water emulsion and separated by a three-dimensional mesh matrix.⁵¹ Recently, PET has been combined with optimized selection of excipients and emollients to produce a patented delivery system called Prismatrex™. This novel technology allows simultaneous and uniform dispersion of active ingredients onto the skin at lower doses than conventional formulations to achieve comparable therapeutic effect, while providing enhanced hydration and moisturization.⁵² Also, the technology allows many attributes of patient preferences to be met. By combining water-soluble moisturizing components within the matrix, a lotion can have a pleasant feel; the use of moisturizers over alcohol-based components creates a lowirritancy/ low-drying formulation; and the mesh network breaking down upon contact with the salts on the skin surface results in quick release and absorption, leaving behind minimal greasy or sticky residue.^50,51

Clinical Application Highlights

Prismatrex™ is used in recent formulations containing retinoids, corticosteroids, or combination of both. Topical corticosteroids are a mainstay in the treatment of AD and PsO. Due to the defective skin barrier in AD and PsO, formulations with moisturizing effects in a patient-preferred format offer additional therapeutic advantages over previous formulations.⁵³ Halobetasol propionate (HP) 0.01% lotion (Bryhali^®), formulated with Prismatrex™, provides several improvements compared to the older 0.05% cream formulation. For example, a reduced concentration of drug while maintaining comparable efficacy to the cream formulation, and a safety profile that allows extended use up to 8 weeks.⁵⁴ Furthermore, the formulation is non-greasy and aesthetically pleasing, providing a patient preferred treatment option.⁵⁵

Topical retinoids are a cornerstone in the treatment of AV. However, dryness, erythema, and peeling are important side effects that can impact treatment adherence.⁵⁶ Prismatrex™ has been used to formulate the third-generation retinoid, tazarotene (TAZ) 0.045% lotion (Arazlo®). The small particle size with this formulation allows better access to the pilosebaceous unit.⁵⁷ Also, this novel technology allows for uniform distribution of TAZ on the skin along with moisturizing ingredients and emollients, therefore, TAZ may be delivered at a lower and potentially less irritating concentration than the previous 0.1% cream formulation.⁵⁸ Two identical phase 3, vehicle-controlled studies demonstrated statistically superior efficacy for TAZ 0.045% lotion vs. placebo in once-daily treatment of moderate to severe AV.⁵⁹

A fixed-combination lotion containing both HP 0.01% and TAZ 0.045% (Duobrii®, HP/TAZ) is formulated using Prismatrex™ technology and indicated for PsO treatment. Higher tissue permeation efficiency of both HP (vs. HP 0.05% cream) and TAZ (vs. TAZ 0.1% cream, Tazorac®) has been achieved with the combination using Prismatrex™ technology.⁵⁰ The delivery of both active ingredients with anti-inflammatory and anti-proliferative properties into a lotion confers a synergistic effect.^50,52 Also, it has demonstrated improved efficacy, tolerability, and maintenance of therapeutic effect compared with monotherapy with either of the active ingredients.^50,52,60-62 HP/TAZ’s acute and long-term efficacy (including maintenance of efficacy after cessation of treatment), tolerability, and safety have been demonstrated in phase 2 and 3 vehicle-controlled trials and an open-label extension study.⁶³ Importantly, HP/TAZ is associated with low incidences of adverse events that may be of concern with corticosteroid and retinoid monotherapy.⁶⁴ Skin atrophy occurs in up to 5% of patients treated with topical corticosteroids.⁶⁴ In HP/TAZ clinical trials, incidences of skin atrophy were rare and generally resolved by the end of the study despite 8 weeks of daily application.^63-64 This may be because TAZ increases the number and activity of dermal fibroblasts and stimulates collagen and elastin production.⁶⁵ Irritation, pain, and retinoid dermatitis may be a challenge with retinoid monotherapy. Incidences of these AEs were lower with HP/TAZ, than with TAZ monotherapy, potentially due to the anti-inflammatory properties of HP.⁶⁴ Clinical trials have also shown that the majority of participants who achieve clear skin with HP/TAZ, experience prolonged maintenance of therapeutic effect after treatment cessation.⁶⁰ Taken together, HP/TAZ provides a treatment option for PsO that is efficacious, safe, combines the beneficial effects of corticosteroids and retinoids, delivers moisturizing and hydrating ingredients, yields longer remission, and is acceptable to patients.

Real World Clinical Commentary

A challenge frequently encountered by dermatologists when managing AD, AV, and PsO is balancing sustained disease suppression with the avoidance of local/systemic side effects. To address this concern, advanced drug delivery systems, such as Primsmatrex™, allow for more efficient delivery of lower doses of active ingredients without compromising efficacy. However, this must also be balanced with overall patient acceptance. Patients consistently cite the following preferences for treatment options: non-greasy applications, reduced skin irritation, spreadable and easily absorbed,³⁶ easily applied in certain body sites (e.g., scalp); easy to wash off with minimal residue, and fast skin responses.⁶⁶ Novel delivery systems often enhance utilization of existing ingredients making them more acceptable to patients, resulting in therapeutic advances. For example, in acne, the innovative drug delivery systems used in Retin-A Micro®, Arazlo® and Twyneo® have significantly improved tolerability of existing topical retinoid ingredients without sacrificing the overall efficacy of these molecules. While patients are advised to maintain a dosing schedule of every second day during the initial phases of treatment to avoid potential irritation, these agents are well tolerated given the nature of the formulations.

The microencapsulation of minocycline foam allows delivery in a topical formulation as opposed to an oral format, which significantly enhances the safety profile. In psoriasis, where availability of topical agents is quite limited, the Prismatrex™ technology in HP/TAZ provides an excellent new treatment option which combines two effective drugs and is a welcome addition to our therapeutic algorithm. In clinical practice, this formulation is effective, can be less irritating to the skin than TAZ alone and is less likely to induce steroid-induced atrophy as compared to HP alone. Another advantage to these advanced topicals is that they result in improved adherence and therefore better treatment outcomes in the long run. Overall, when choosing the optimal therapeutic agent for treatment of AD, AV, or PsO the dermatologist now has the option to select a formulation that uses an advanced drug delivery system to maximize the chances of achieving successful treatment outcomes. Research in advanced delivery systems is vast, with a wide range of technologies showing promise for future clinical use, such as nanoparticles⁶⁷, ethosomes⁶⁸, niosomes⁶⁹, and liposomes⁷⁰.

Conclusion

Topical treatment is a cornerstone in managing AD, AV, and PsO;¹⁹ however, the delivery of active drugs through the dermal barrier remains a challenge. Furthermore, patient acceptability is a major contributing factor to the effectiveness and adherence to topical treatments. Advances in topical drug formulations and delivery systems address many limitations seen with older formulations. These advances allow for efficient and uniform delivery of active ingredients to target sites, greater patient acceptability, and enhanced treatment outcomes.

Acknowledgements

Medical writing assistance for this manuscript was provided by KTP (Knowledge Translation Partners), Montreal, Canada, funded by Bausch Health Canada.

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