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.
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
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
|Delivery System||Description||Mechanism of Action||Features||Products (Disease)|
Microspheres with a coating of inert, natural, or synthetic polymeric materials around solid or liquid micronized drug particles29
Enhances the stability of the API and allows for controlled release27
Uniform, spherical, and porous polymeric delivery system37
Release API onto skin surface in a controlled manner in response to rubbing, elevated temperature or changes in pH39
|Polymeric emulsion technology / Prismatrex™||
Particles, moisturizers and hydrating ingredients are encapsulated together within the same oil droplets that are evenly distributed throughout a 3D mesh matrix52
Penetrate through stratum corneum and accumulate in hair follicles13
Abbreviations: API, Active pharmaceutical ingredient; AD, atopic dermatitis; AV, acne vulgaris; PsO, psoriasis
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 232,33 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
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.
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.
Medical writing assistance for this manuscript was provided by KTP (Knowledge Translation Partners), Montreal, Canada, funded by Bausch Health Canada.
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