10.5826/dpc.1304a216
Introduction: Atopic dermatitis (AD) causes dry and itchy skin and inflammation that severely impairs the quality of life of affected children and adults. While topical glucocorticosteroid application is typically the first-line treatment of choice, steroid treatment is associated with side effects and, increasingly, patient concerns about prolonged use. Novel drugs and drug delivery vehicles are required for patients with AD.
Objective: To summarize the current literature on novel topical agents for atopic dermatitis and novel delivery vehicles.
Methods: A literature search was conducted, and a narrative review was compiled to summarize recent evidence.
Results: Novel topical drugs approved or in late-phase clinical trials for the treatment of AD include the Janus kinase inhibitor ruxolitinib, the phosphodiesterase-4 inhibitors crisaborole, and roflumilast, and the aryl hydrocarbon receptor activator tapinarof. While current topical drugs for AD are delivered via creams, ointments, gels, and related vehicles, novel delivery approaches such as electrospun patches, sprays, liposomes, nanoparticles, and lasers are being developed to enhance transdermal delivery, reduce side effects, and increase treatment adherence.
Conclusion: Topical application of creams or ointments is currently the predominant vehicle for the delivery of atopic dermatitis drugs. In vitro studies on novel vehicles show promising results to overcome the issues associated with topical delivery. Still, these findings have to be corroborated by controlled studies with human patients in the future.
text/xml
2160-9381
3121
en
Matthew Farkouh
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
tapinarof
Novel Vehicles For Drug Delivery In Atopic Dermatitis: A Narrative Review 
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2023-10-31
2022-12-28
2023-10-31
2024-01-15
e2023216
Dermatol Pract Concept
Introduction: Atopic dermatitis (AD) causes dry and itchy skin and inflammation that severely impairs the quality of life of affected children and adults. While topical glucocorticosteroid application is typically the first-line treatment of choice, steroid treatment is associated with side effects and, increasingly, patient concerns about prolonged use. Novel drugs and drug delivery vehicles are required for patients with AD.
Objective: To summarize the current literature on novel topical agents for atopic dermatitis and novel delivery vehicles.
Methods: A literature search was conducted, and a narrative review was compiled to summarize recent evidence.
Results: Novel topical drugs approved or in late-phase clinical trials for the treatment of AD include the Janus kinase inhibitor ruxolitinib, the phosphodiesterase-4 inhibitors crisaborole, and roflumilast, and the aryl hydrocarbon receptor activator tapinarof. While current topical drugs for AD are delivered via creams, ointments, gels, and related vehicles, novel delivery approaches such as electrospun patches, sprays, liposomes, nanoparticles, and lasers are being developed to enhance transdermal delivery, reduce side effects, and increase treatment adherence.
Conclusion: Topical application of creams or ointments is currently the predominant vehicle for the delivery of atopic dermatitis drugs. In vitro studies on novel vehicles show promising results to overcome the issues associated with topical delivery. Still, these findings have to be corroborated by controlled studies with human patients in the future.
Matthew Farkouh
2023/10/31
10.5826/dpc.1304a216
e2023216
Guadalajara, Mexico, Ponce Health Sciences University, Ponce, Puerto Rico, USA
2160-9381
tapinarof
en
e2023216
Keam SJ. Tapinarof Cream 1%: First Approval. Drugs. Jul 2022;82(11):1221-1228. doi:10.1007/s40265-022-01748-6
Novel Vehicles For Drug Delivery In Atopic Dermatitis: A Narrative Review 
https://dpcj.org/index.php/dpc/article/download/3121/2339
             Novel Vehicles For Drug Delivery in Atopic
                  Dermatitis: A Narrative Review
              Christopher Farkouh1, Michelle Anthony2, Parsa Abdi 3, Natalia Santiago4,
                                       Matthew Farkouh5


1 Rush Medical College, Chicago, IL, USA
2 University of Arizona College of Medicine, Department of Pathology, Tucson, AZ, USA
3 Memorial University, St. Johns, Newfoundland, CAN
4 Universidad Autónoma de Guadalajara School of Medicine, Guadalajara, MEX
5 Ponce Health Sciences University, Ponce, Puerto Rico, USA



Key words: atopic dermatitis, vehicle, crisaborole, tapinarof
Citation: Farkouh C, Anthony M, Abdi P, Santiago N, Farkouh M. Novel Vehicles For Drug Delivery In Atopic Dermatitis: A Narrative
Review. Dermatol Pract Concept. 2023;13(4):e2023216. DOI: https://doi.org/10.5826/dpc.1304a216
Accepted: April 24, 2023; Published: October 2023
Copyright: ©2023 Farkouh et al. This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted
noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Christopher Farkouh, BS, 1035 West Van Buren Street, Chicago, IL 60607. Phone: (732) 882-6414
Email: christopher_s_farkouh@rush.edu




  ABSTRACT              Introduction: Atopic dermatitis (AD) causes dry and itchy skin and inflammation that severely
                        ­impairs the quality of life of affected children and adults. While topical glucocorticosteroid appli-
                         cation is typically the first-line treatment of choice, steroid treatment is associated with side effects
                         and, increasingly, patient concerns about prolonged use. Novel drugs and drug delivery vehicles are
                         required for patients with AD.
                        Objectives: To summarize the current literature on novel topical agents for atopic dermatitis and
                        novel delivery vehicles.
                        Methods: A literature search was conducted, and a narrative review was compiled to summarize
                        recent evidence.
                        Results: Novel topical drugs approved or in late-phase clinical trials for the treatment of AD include
                        the Janus kinase inhibitor ruxolitinib, the phosphodiesterase-4 inhibitors crisaborole, and roflumilast,
                        and the aryl hydrocarbon receptor activator tapinarof. While current topical drugs for AD are deliv-
                        ered via creams, ointments, gels, and related vehicles, novel delivery approaches such as electrospun
                        patches, sprays, liposomes, nanoparticles, and lasers are being developed to enhance transdermal
                        delivery, reduce side effects, and increase treatment adherence.




Review | Dermatol Pract Concept. 2023;13(4):e2023216                                                                                 1
                      Conclusions: Topical application of creams or ointments is currently the predominant vehicle for
                      the delivery of atopic dermatitis drugs. In vitro studies on novel vehicles show promising results to
                      overcome the issues associated with topical delivery. Still, these findings have to be corroborated by
                      controlled studies with human patients in the future.




Introduction                                                      Methods
Atopic dermatitis (AD) is a chronic cutaneous disorder that       A literature search was conducted of the various articles de-
affects up to 30% of children and 20% of adults depending         tailing presently used atopic dermatitis drugs and vehicles,
on the geographical region [1,2]. This chronic type of eczema     and a narrative review was compiled to summarize recent
is characterized by dry skin, pruritus, eczematous lesions,       evidence.
and lichenification [3,4]. The multifactorial etiology of AD
entails genetic predisposition, environmental factors, and
hypersensitivity against certain environmental allergens [5].
                                                                  Results
The skin barrier is characterized by increased permeability,      Novel Drugs Against AD
with disturbances in ceramide metabolism and composition          Corticosteroids
fairly common in AD. This increased permeability of the skin
                                                                  Atopic dermatitis patients have been conventionally treated
allows for the entry of irritants, allergens, and pathogens,
                                                                  with topical corticosteroids as a first-line intervention [9].
leading to inflammation [6].
                                                                  The corticosteroids prevent antigen processing and proin-
    The clinical diagnosis follows the evaluation of essential
                                                                  flammatory cytokine release, thereby modulating the im-
AD features (pruritus, eczematous morphology, chronicity),
                                                                  mune response [4]. Despite the efficacy of steroidal agents
crucial features (early age of onset, xerosis, atopy), and sev-
                                                                  in reducing pruritus and eczematous lesions, their safety
eral associated features [4]. Treatment options are individu-
                                                                  has been questioned, mainly when administered to sensitive
ally chosen and encompass topical therapies, phototherapy,
                                                                  body areas such as the face or used for extended periods [10].
systemic agents, or a combination thereof [4,7]. Each of these
                                                                  Along with these concerns, patients’ adherence to the treat-
therapeutic approaches has risks, benefits, and limitations.
                                                                  ment regimen may be suboptimal, resulting in aggravation
    For topical preparations, the vehicle by which a drug is
                                                                  and extension of the symptoms [11]. In severe atopic cases,
administered maintains a central role in the treatment out-
                                                                  systemic corticosteroids may be prescribed, yet due to side
come because efficient and selective delivery of the pharma-
                                                                  effects and rebound flares with such a treatment, their use is
cologically active ingredient to the target site determines its
                                                                  not recommended [12,13].
efficacy. Simultaneously, the tolerability of a product and
its cosmetic acceptability play outsized roles as it is incum-    Ruxolitinib
bent upon the patient to apply the treatment for it to work       Ruxolitinib is an inhibitor of Janus kinases (JAK) 1 and 2,
regularly.                                                        which are involved in signaling pathways that mediate the
    The most common vehicles for AD topical therapies are         elevation of proinflammatory cytokines [14]. Oral JAK
creams or ointments. Nonetheless, topical and systemic side       inhibitors have been employed in treating atopic dermati-
effects are of concern with these vehicles, and their clinical    tis patients. Yet safety concerns have been raised with this
efficacy varies due to the complete application on the skin       mode of administration due to non-specific delivery of the
[4,8]. Therefore, long-term use of topical agents, particularly   active drug and the development of cytopenias [15]. Theo-
steroidal drugs, is not recommended, and novel or improved        retically, a topical agent targeted to specific affected areas
vehicles are developed to increase the transport of the active    could result in far less systemic exposure and, thus, a safer
ingredient to a specific target site and the drug efficacy [4].   profile. In a phase II trial on patients with atopic dermatitis,
                                                                  topical administration of ruxolitinib (1.5%) twice a day sig-

Objectives                                                        nificantly decreased dermatitis-associated pruritus compared
                                                                  to the empty vehicle control after three days of use [16,17].
In the present review, the current literature on novel drugs      This, in turn, resulted in significant improvements in patients
against atopic dermatitis and their vehicles is synthesized to    life quality within two weeks after the initiation of therapy.
overview available evidence and identify research gaps.           Two ruxolitinib phase III trials corroborated these findings,




2                                                                             Review | Dermatol Pract Concept. 2023;13(4):e2023216
where topical ruxolitinib treatment (0.75% or 1.5%) was            Novel Vehicles for Delivery of AD Drugs
associated with a significantly more frequent success than         Topical Delivery
the vehicle control treatment, and less than 1% of patients        The traditional administration of atopic dermatitis treat-
experienced side effects [18]. In a maximum-use trial of           ments is the application of a cream or ointment directly on
ruxolitinib (1.5% cream, twice daily for 28 days and as re-        the affected skin area. Current guidelines recommend the
quired during the 28 days thereafter), almost a third of the       topical administration of glucocorticosteroid class II creams
patients experienced treatment-related adverse events [19].        for mild or transient eczema and class III creams for mod-
Long-term studies on the efficacy and safety of ruxolitinib        erate or recurrent eczema [30]. Nonetheless, such topical
for atopic dermatitis treatment are missing to date.               administration may not ensure complete absorption of the
                                                                   pharmaceutically active ingredient and diminish the pharma-
Crisaborole                                                        cokinetic capacity of the drug. Moreover, long-term admin-
Crisaborole     is    a    benzoxaborole        inhibitor    of    istration of steroidal creams is not recommended due to side
phosphodiesterase-4 (PDE-4), an enzyme responsible for de-         effects associated with chronic exposure to the compound,
grading the second messenger cAMP in immune cells [20].            including skin atrophy, telangiectasia, and striae distensae
If PDE-4 is inhibited, cAMP levels rise, and inflammatory          [30]. Some novel atopic dermatitis drugs, eg crisaborole, are
responses are modulated [21]. In two phase III trials, the         again delivered by topical application [22,31+. With cur-
condition of atopic dermatitis patients, measured as the           rently limited evidence for their efficacy in comparison with
Investigator Static Global Assessment score, improved sig-         established glucocorticoids and calcineurin inhibitors such
nificantly earlier and to a greater extent than in the vehicle     as tacrolimus, they are, at present, particularly recommended
controls at the study endpoint of 28 days [22]. The frequency      for those patients for whom steroid treatment is contraindi-
of adverse events and participant retention was low, indicat-      cated or for those who are recalcitrant and hence cannot be
ing good tolerability of crisaborole ointment [22]. Informa-       treated with calcineurin inhibitors [32]. In a recent study by
tion on the benefits of crisaborole treatment for infants and      Thom et al, the efficacy of crisaborole ointment was com-
toddlers is yet lacking, albeit atopic dermatitis frequently de-   pared to that of the calcineurin inhibitors tacrolimus and
velops soon after birth. Hence, future investigations with this    pimecrolimus based on patient data from randomized con-
patient group are relevant.                                        trolled trials that tested either crisaborole or the calcineurin
                                                                   inhibitors [33]. Based on this indirect comparison, crisab-
Roflumilast                                                        orole was superior to both calcineurin inhibitors in improv-
Roflumilast is another PDE-4 inhibitor with anti-                  ing the Investigator Static Global Assessment scores [33].
inflammatory properties [23]. While this drug has demon-           In this context, prospective trials directly comparing both
strated efficacy in treating chronic obstructive pulmonary         agents within the same study setting are required to judge the
disease (COPD) and asthma [24,25], clinical trials on its          superiority of crisaborole over established calcineurin agents
effectiveness in treating atopic dermatitis are ongoing. The       conclusively. One such trial with a comparatively small study
INTEGUMENT-I phase III trial (ClinicalTrials.gov identifier        cohort (N = 235 in four patient groups) was conducted but
NCT04773587) tested the safety and efficacy of a 0.15%             terminated early due to a business decision, yet initial results
Roflumilast cream, administered for four weeks, compared           were obtained (ClinicalTrials.gov Identifier NCT03539601).
to vehicle control. The trial has been completed, but the re-      Within the four study groups (vehicle control, crisaborole,
sults are yet to be published [26].                                hydrocortisone butyrate, pimecrolimus), the largest improve-
                                                                   ment was seen for patients treated with hydrocortisone, yet
Tapinarof (VTAMA)                                                  the organizers acknowledged that the subgroups were too
Tapinarof activates the aryl hydrocarbon receptor (AhR).           small to conduct reliable statistical analysis [34]. It is also yet
AhR is a transcription factor for pro-inflammatory cyto-           unclear to what extent crisaborole creams or ointments can
kines, which are downregulated upon AhR activation [27].           overcome the side effects raised with glucocorticoid treat-
Tapinarof, therefore, acts       as   an   immune-modulator,       ment, and their suitability for long-term treatment must be
anti-oxidative, and anti-inflammatory treatment. In a recent       validated.
phase IIb trial, topical administration of Tapinarof cream             Patches are an alternative vehicle for the topical applica-
(0.5% or 1%) for 12 weeks resulted in a greater improve-           tion of an atopic dermatitis drug [35-37]. These have been
ment of eczema and a reduced affected body area than in the        developed for the administration of urea and pioglitazone
vehicle control group [28]. In dose-finding studies and phase      [35,36]. The urea patch is produced as a combination of elec-
II trials, adverse events were rare and of low or moderate         trospinning of poly(vinyl butyral-co-vinyl alcohol-co-vinyl
intensity [28,29].                                                 acetate) fibers to generate a membrane and electrospraying




Review | Dermatol Pract Concept. 2023;13(4):e2023216                                                                                3
of the fibers with urea to soak the fibers in the active sub-      ingredient efficacy and ensure its delivery to the target site.
stance [35]. The idea behind such a patch is to enable the         They typically target the entire immune system and the re-
controlled release of the active substance, in this case, urea,    lease of pro-inflammatory cytokines rather than the isolated
and enhance its transdermal delivery. At present, there is no      inflamed skin area. Importantly, due to the risk of side effects
study assessing the efficacy of such urea patches in human         of systemic drugs, the dose should be relatively low and be
subjects. Obaidat et al report the generation of polyvinylpyr-     oriented on the effective topical concentration [43]. Purohit
rolidone fiber patches by electrospinning for the transdermal      et al report on their analysis to determine the systemic tofaci-
delivery of pioglitazone [36]. The results of in vitro experi-     tinib concentration based on the concentration of tofacitinib
ments demonstrated delivery and retention of the drug in the       ointment and systemic exposure after crisaborole ointment
skin [36]. Investigations on the efficacy and safety of such       application [43,44]. Their findings indicate a proportional
patches in human patients are yet to be conducted.                 systemic exposure of both drugs according to the body sur-
    Another topical treatment was developed to apply bo-           face area treated.
tanicals in adults suffering from atopic dermatitis [37-39].
Compared to the vehicle, the botanical product yielded supe-       Nanoparticles
rior results in improving the Investigator Global Assessment       Loading an active pharmacological substance onto nanopar-
scores and the affected body area [38,39]. Unfortunately, no       ticles has proven efficient for delivering numerous drugs
details on the product particular characteristics or its perfor-   across distinct indications. For the treatment of atopic der-
mance in direct comparison with a competitor product were          matitis, such nanoparticles are being developed to enhance
provided.                                                          the efficient delivery of the active substance to the target site
    Hogue et al. tested whether applying corticosteroids in        [45,46]. These have shown efficacy in vitro for the delivery of
a spray rather than a cream could overcome the adherence           conventional atopic dermatitis drugs such as betamethasone,
issues observed with conventional corticosteroid treatments        hydrocortisone, dexamethasone, and tacrolimus [47-53]. No
[40]. Patients with a history of failed corticosteroid therapy     studies have yet investigated the use of nanoparticles for the
were recruited and asked to apply desoximetasone in spray          delivery of novel atopic dermatitis drugs. Of note, the use of
form. A subgroup of the patients was reminded by phone             nanoparticles for the delivery of atopic dermatitis drugs must
calls to use the spray daily. The results revealed an effect of    consider the potential for induction of anti-inflammatory re-
the spray vehicle and the phone call reminders on treatment        actions [54]. Choi et al demonstrated that the material and
adherence [40]. These findings point towards spray prepara-        protein corona around the nanoparticles determines their
tions as alternative vehicles for those patients who consider      inflammatory potential, which is relevant for inflammatory
the messiness of ointment or cream vehicles as an obstacle         skin conditions [54]. Colloidal silica nanoparticles were
for their regular application [41].                                found to be superior to mesoporous silica nanoparticles in
    Nanoliposomes are developed that enclose the active in-        terms of the inflammatory reactions in the skin following
gredient within a lipid layer and thereby prevent its prema-       treatment and the induction of pro-inflammatory cytokines
ture solution to improve transdermal delivery of the drug to       and dermatitis-associated immunoglobulins [54].
its target site. Naeimifar et al developed a ruxolitinib emul-
gel with nanoliposomes and tested its efficacy on patients         Iontophoresis
with mild atopic dermatitis [42]. In addition to improving         Iontophoresis entails the application of a low-voltage cur-
dermatitis-associated symptoms such as itching and the local       rent to the skin to stimulate the transdermal delivery of a
Scoring Atopic Dermatitis score, the skin condition at the         pharmacological agent [55]. This method has proven effi-
application site was evaluated. Symptoms significantly im-         cient for the administering corticosteroids for various in-
proved after a four-week use of the nanoliposomal emulgel,         dications, including skin diseases [56]. There are currently
and so did the skin’s condition regarding hydration, melanin       no controlled clinical studies with human patients that as-
content, and erythema [42].                                        sessed the suitability of this method for atopic dermatitis
                                                                   drugs. In vitro data using human skin preparations revealed
Systemic Delivery                                                  transdermal delivery of hydrocortisone, albeit similar effi-
Systemic treatment is currently only recommended for those         cacy was obtained by passive diffusion when healthy skin
with severe scored or persistent eczema [30]. Recommended          was tested [57]. However, iontophoresis resulted in signifi-
oral systemic drugs for such cases are glucocorticoids,            cantly higher absorbance of hydrocortisone than passive
dupilumab, methotrexate, azathioprine, and mycopheno-              diffusion when eczematous skin and psoriatic skin were
late mofetil [30]. The incentive for developing systemic ve-       tested [58]. The clinical use of this method has yet to be
hicles rather than topical vehicles is to enhance the active       established for atopic dermatitis patients. A summary of the




4                                                                              Review | Dermatol Pract Concept. 2023;13(4):e2023216
                Table 1. Novel drugs against atopic dermatitis and their vehicles for delivery.
        Drug                    Target/proposed effect                        Available vehicles                   References #
 Glucocorticoids    Prevention of antigen processing and               Topical/cream or spray                 4, 30, 40, 47-51, 57
                    proinflammatory cytokine release                   systemic/oral nanoparticles,
                                                                       iontophoresis
 Crisaborole        Phosphodiesterase-4 inhibitor                      Topical/cream or ointment              20, 34, 58-67
 Ruxolitinib        Janus kinases 1 and 2                              Topical/cream or nanoliposomes 42
 Tapinarof          Activation of hydrocarbon receptor and down- Topical/cream                                28, 29, 68, 69
                    regulation of pro-inflammatory cytokines
 Roflumilast        Phosphodiesterase-4 inhibitor                      Topical/cream                          23
 Botanicals         Unknown                                            Topical/cream                          38, 39
 Pioglitazone       Reduction of pro-inflammatory cytokines            Topical/patch                          36
 Urea               Emollient, keratolytic                             Topical/patch                          35



novel drugs against atopic dermatitis and their vehicles for      treatment targets with vehicles that allow a more reliable
delivery can be found below in Table 1.                           delivery of the active drug ingredient to the target site.


Conclusions                                                       References
Current recommendations for treating atopic dermatitis             1. Urban K, Chu S, Giesey RL, Mehrmal S, ET AL. The global, re-
                                                                      gional, and national burden of atopic dermatitis in 195 countries
currently focus on topical or systemic administration of glu-
                                                                      and territories: An ecological study from the Global Burden of
cocorticoids. In light of their known side effects, their limit
                                                                      Disease Study 2017. JAAD Int. 2020;2:12-18. DOI: 10.1016/j
to short-term application, intolerant patients, and dimin-            .jdin.2020.10.002. PMID: 34409347. PMCID: PMC8362298.
ished patient adherence, novel drugs are being developed           2. Bylund S, Kobyletzki LB, Svalstedt M, Svensson Å. Prevalence and
that may overcome the limitations of steroidal medications.           Incidence of Atopic Dermatitis: A Systematic Review. Acta Derm
In addition, novel vehicles may increase the transdermal              Venereol. 2020;100(12):adv00160. DOI:10.2340/00015555
                                                                      -3510. PMID: 32412646. PMCID: PMC9189744.
delivery of an atopic dermatitis drug and overcome side ef-
                                                                   3. Katoh N, Ohya Y, Ikeda M, et al. Clinical practice guidelines
fects associated with conventional topical administration.
                                                                      for the management of atopic dermatitis 2018. J ­Dermatol.
These novel vehicles are currently under development, and             019;46(12):1053-1101. DOI:10.1111/1346-8138.15090. PMID:
their suitability for a broad clinical application is yet to be       31599013.
tested in controlled clinical trials. Of note, modern drug de-     4. Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care
livery vehicles such as nanoparticles are being tested based          for the management of atopic dermatitis: section 1. Diagno-
                                                                      sis and assessment of atopic dermatitis. J Am Acad Dermatol.
on the delivery of conventional drugs such as glucocortico-
                                                                      014;70(2):338-351. DOI:10.1016/j.jaad.2013.10.010. PMID:
steroids, for which more pharmacokinetic data is available
                                                                      24290431. PMCID: PMC4410183.
than for novel drugs with different molecular targets and          5. Katta R, Schlichte M. Diet and dermatitis: food triggers. J Clin
biochemical approaches. Therefore, most in vitro studies on           Aesthet Dermatol. 2014;7(3):30-36. PMID: 24688624. PMCID:
such novel vehicles test the transdermal crossing and the             PMC3970830.
accumulation of steroids in the epidermis. Likewise, effi-         6. Fujii M. The Pathogenic and Therapeutic Implications of Cer-
                                                                      amide Abnormalities in Atopic Dermatitis. Cells. 2021;10(9):
cacy and safety data on novel drugs such as crisaborole and
                                                                      2386. DOI:10.3390/cells10092386. PMID: 34572035. PMCID:
ruxolitinib are just emerging from phase II and III clinical
                                                                      PMC8468445.
trials, and conventional, topical delivery is chosen for these     7. Davis DMR, Drucker AM, Alikhan A, et al. American Academy
drugs as it is known to result in improvement of atopic               of Dermatology Guidelines: Awareness of comorbidities asso-
dermatitis-associated symptoms in topical steroid applica-            ciated with atopic dermatitis in adults. J Am Acad Dermatol.
tion. Hence, the development of novel atopic dermatitis drugs         2022;86(6):1335-1336.e18. DOI: 10.1016/j.jaad.2022.01.009.
                                                                      PMID: 35085682.
and novel delivery vehicles currently happens in parallel.
                                                                   8. Müller SM, Tomaschett D, Euler S, Vogt DR, Herzog L, Itin P.
In contrast, novel drugs have not been tested to establish
                                                                      Topical Corticosteroid Concerns in Dermatological Outpa-
novel vehicles. Therefore, future studies must elucidate              tients: A Cross-Sectional and Interventional Study. Dermatol-
whether the highest efficacy and safety of atopic dermatitis          ogy. 2016;232(4):444-452. DOI:10.1159/000446068. PMID:
drugs may be achieved by combining drugs against novel                27322385.




Review | Dermatol Pract Concept. 2023;13(4):e2023216                                                                                 5
 9. Buys LM. Treatment options for atopic dermatitis. Am Fam Phy-              Acad Dermatol. 2016;75(3):494-503.e6. DOI:10.1016/j.
    sician. 2007;75(4):523-8. PMID: 17323714.                                  jaad.2016.05.046. PMID: 27417017.
10. Axon E, Chalmers JR, Santer M, et al. Safety of topical corti-       23.   Heo JY, Cho YS, Cheon HG. Topical effects of roflumilast on
    costeroids in atopic eczema: an umbrella review. BMJ Open.                 1-chloro-2,4-dinitrobenzene-induced atopic dermatitis-like skin
    2021;11(7):e046476.        DOI:10.1136/bmjopen-2020-046476.                lesions in NC/Nga mice. Pharmazie. 2010;65(12):906-912.
    PMID: 34233978; PMCID: PMC8264889.                                         PMID: 21284261.
11. Li AW, Yin ES, Antaya RJ. Topical Corticosteroid ­     Phobia        24.   Shen LF, Lv XD, Chen WY, Yang Q, Fang ZX, Lu WF. Effect of ro-
    in Atopic Dermatitis: A Systematic Review. JAMA Derma-                     flumilast on chronic obstructive pulmonary disease: a systematic
    tol. 2017;153(10):1036-1042. DOI: 10.1001/jamadermatol                     review and meta-analysis. Ir J Med Sci. 2018;187(3):731-738.
    .2017.2437. PMID: 28724128.                                                DOI:10.1007/s11845-018-1738-9 PMID: 29397527.
12. Arkwright PD, Motala C, Subramanian H, Spergel J, Schnei-            25.   Bateman ED, Izquierdo JL, Harnest U, et al. Efficacy and
    der LC, Wollenberg A. Management of difficult-to-treat atopic              safety of roflumilast in the treatment of asthma. Ann Allergy
    dermatitis. J Allergy Clin Immunol Pract. 2013;1(2):142-151.               Asthma Immunol. 2006;96(5):679-686. DOI:10.1016/s1081
    DOI:10.1016/j.jaip.2012.09.002. PMID: 24565453.                            -1206(10)61065-4. PMID: 16729780.
13. Drucker AM, Eyerich K, de Bruin-Weller MS, et al. Use of             26.   Arcutis Biotherapeutics, Inc.A. Phase 3, 4-Week, Parallel Group,
    systemic corticosteroids for atopic dermatitis: International              Double Blind, Vehicle-Controlled Study of the Safety and Efficacy
    ­Eczema Council consensus statement. . Br J Dermatol. 2018;                of ARQ-151 Cream 0.15% Administered QD in Subjects With
     178(3):768-775. DOI: 10.1111/bjd.15928. PMID: 28865094.                   Atopic Dermatitis. ClinicalTrials.gov identifier: NCT04773587.
     PMCID: PMC5901393.                                                        Updated Septemberl 14, 2022. Available from: https://clinicaltrials
14. Quintás-Cardama A, Vaddi K, Liu P, et al. Preclinical char-                .gov/ct2/show/NCT04773587,Accessed December 27, 2022.
     acterization of the selective JAK1/2 inhibitor INCB018424:          27.   Smith SH, Jayawickreme C, Rickard DJ, et al. Tapinarof Is
     therapeutic implications for the treatment of myeloprolifer-
     ­                                                                         a Natural AhR Agonist that Resolves Skin Inflammation in
     ative neoplasms. Blood. 2010;115(15):3109-3117. DOI:10                    Mice and Humans. J Invest Dermatol. 2017;137(10):2110-2119.
      .1182/blood-2009-04-214957 PMID: 20130243. PMCID:                        DOI:10.1016/j.jid.2017.05.004. PMID: 28595996.
      PMC3953826.                                                        28.   Paller AS, Stein Gold L, Soung J, Tallman AM, Rubenstein DS,
15.   He H, Guttman-Yassky E. JAK Inhibitors for Atopic Derma-                 Gooderham M. Efficacy and patient-reported outcomes from
      titis: An Update. Am J Clin Dermatol. 2019;20(2):181-192.                a phase 2b, randomized clinical trial of tapinarof cream for
      DOI:10.1007/s40257-018-0413-2. PMID: 30536048.                           the treatment of adolescents and adults with atopic dermati-
16.   Kim BS, Sun K, Papp K, Venturanza M, Nasir A, Kuligowski                 tis. J Am Acad Dermatol. 2021;84(3):632-638. DOI:10.1016/j
      ME. Effects of ruxolitinib cream on pruritus and quality of              .jaad.2020.05.135. PMID: 32502588.
      life in atopic dermatitis: Results from a phase 2, random-         29.   Peppers J, Paller AS, Maeda-Chubachi T, et al. A phase 2, ran-
      ized, dose-ranging, vehicle- and active-controlled study. J              domized dose-finding study of tapinarof (GSK2894512 cream)
      Am Acad Dermatol. 2020;82(6):1305-1313. DOI:10.1016/j                    for the treatment of atopic dermatitis. J Am Acad Dermatol.
      .jaad.2020.02.009. PMID: 32057960.                                       2019;80(1):89-98.e3. DOI:10.1016/j.jaad.2018.06.047. PMID:
17.   Kim BS, Howell MD, Sun K, Papp K, Nasir A, Kuligowski ME.                30554600.
      Treatment of atopic dermatitis with ruxolitinib cream (JAK1/       30.   Wollenberg A, Barbarot S, Bieber T, et al. Consensus-based Eu-
      JAK2 inhibitor) or triamcinolone cream. J Allergy Clin Immunol.          ropean guidelines for treatment of atopic eczema (atopic der-
      2020;145(2):572-582. DOI:10.1016/j.jaci.2019.08.042. PMID:               matitis) in adults and children: part I. J Eur Acad Dermatol
      31629805.                                                                Venereol. 2018;32(5):657-682. DOI:10.1111/jdv.14891. PMID:
18.   Papp K, Szepietowski JC, Kircik L, et al. Efficacy and safety of         29676534.
      ruxolitinib cream for the treatment of atopic dermatitis: Re-      31.   Stein Gold LF, Spelman L, Spellman MC, Hughes MH, Zane
      sults from 2 phase 3, randomized, double-blind studies. J Am             LT. A Phase 2, Randomized, Controlled, Dose-Ranging Study
      Acad Dermatol. 2021;85(4):863-872. DOI:10.1016/j.jaad                    Evaluating Crisaborole Topical Ointment, 0.5% and 2% in Ad-
      .2021.04.085. PMID: 33957195.                                            olescents With Mild to Moderate Atopic Dermatitis. J Drugs
19.   Bissonnette R, Call RS, Raoof T, et al. A Maximum-Use Trial of           ­Dermatol. 2015;14(12):1394-1399. PMID: 26659931.
      Ruxolitinib Cream in Adolescents and Adults with Atopic Der-       32.    McDowell L, Olin B. Crisaborole: A Novel Nonsteroidal
      matitis. Am J Clin Dermatol. 2022;23(3):355-364. DOI:10.1007              Topical Treatment for Atopic Dermatitis. J Pharm Technol.
      /s40257-022-00690-3. PMID: 35368221. PMCID: PMC9142470.                   2019;35(4):172-178. DOI:10.1177/8755122519844507. PMID:
20.   Murrell DF, Gebauer K, Spelman L, Zane LT. Crisaborole Topical            34861031. PMCID: PMC6600556.
      Ointment, 2% in Adults With Atopic Dermatitis: A Phase 2a,         33.    Thom H, Cheng V, Keeney E, et al. Matching-Adjusted In-
      Vehicle-Controlled, Proof-of-Concept Study. J Drugs Dermatol.             direct Comparison of Crisaborole Ointment 2% vs. ­    Topical
      2015;14(10):1108-1112. PMID: 26461821.                                    Calcineurin Inhibitors in the Treatment of Patients with
21.   Maurice DH, Ke H, Ahmad F, Wang Y, Chung J, Manganiello                   Mild-to-Moderate Atopic Dermatitis. Dermatol Ther ­(Heidelb).
      VC. Advances in targeting cyclic nucleotide phosphodiester-               2022;12(1):185-194. DOI:10.1007/s13555-021-00646-1. PMID:
      ases. Nat Rev Drug Discov. 2014;13(4):290-314. DOI:10.1038                34877623. PMCID: PMC8776944.
      /nrd4228. PMID: 24687066. PMCID: PMC4155750.                       34.    ClinicalTrials.gov. A Study of Crisaborole Ointment 2%; Cris-
22.   Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety                 aborole Vehicle; TCS and TCI in Subjects Aged ≥ 2 Years,
      of crisaborole ointment, a novel, nonsteroidal phospho-                   With Mild-moderate AD., Available from: https://clinicaltrials
      diesterase 4 (PDE4) inhibitor for the topical treatment                   .gov/ct2/show/results/NCT03539601?term
      of atopic dermatitis (AD) in children and adults. J Am                    =c3291037&draw=2&rank=1, Accessed 01.11.2022




6                                                                                      Review | Dermatol Pract Concept. 2023;13(4):e2023216
35. Krysiak ZJ, Stachewicz U. Urea-Based Patches with Controlled              48. Md S, Kuldeep Singh JKA, Waqas M, et al. Nanoencapsulation
    Release for Potential Atopic Dermatitis Treatment. Pharmaceu-                  of betamethasone valerate using high pressure homogenization-
    tics. 2022;14(7):1494. DOI: 10.3390/pharmaceutics14071494.                    solvent evaporation technique: optimization of formulation and
    PMID: 35890388. PMCID: PMC9320356.                                            process parameters for efficient dermal targeting. Drug Dev Ind
36. Obaidat R, Shameh AA, Aljarrah M, Hamed R. Preparation                        Pharm. 2019;45(2):323-332. DOI:10.1080/03639045.2018.154
    and Evaluation of Polyvinylpyrrolidone Electrospun Nanofiber                  2704. PMID: 30404554.
    Patches of Pioglitazone for the Treatment of Atopic Dermatitis.           49. Siddique MI, Katas H, Jamil A, et al. Potential treatment of
    AAPS PharmSciTech. 2022;23(1):51. DOI:10.1208/s12249-021                      atopic dermatitis: tolerability and safety of cream containing
    -02204-6. PMID: 35013801.                                                     nanoparticles loaded with hydrocortisone and hydroxytyrosol
37. Yang Y, Chen BZ, Zhang XP, et al. Conductive Micronee-                        in human subjects. Drug Deliv Transl Res. 2019;9(2):469-481.
    dle Patch with Electricity-Triggered Drug Release Perfor-                     DOI:10.1007/s13346-017-0439-7. PMID: 29159691.
    mance for Atopic Dermatitis Treatment. ACS Appl Mater                     50. Siddique MI, Tufail S, Ker ZH, et al. Towards fast and cost-effective
    Interfaces. 2022;14(28):31645-31654. DOI:10.1021/acsami                       up-scaling of Nano-encapsulations by Ionic-­       gelation method
    .2c05952. PMID: 35790212.                                                     using model drug for the treatment of atopic dermatitis. Pak
38. Draelos ZD, Traub M, Gold MH, et al. Efficacy of Topical Bo-                  J Pharm Sci. 2019;32(5(Supplementary)):2299-2304. PMID:
    tanical Treatment of Children With Mild to Moderate Atopic                    31894058.
    Dermatitis. J Drugs Dermatol. 2019;18(10):1038-1045. PMID:                51. Sahle FF, Gerecke C, Kleuser B, Bodmeier R. Formulation and
    31584783.                                                                     comparative in vitro evaluation of various dexamethasone-loaded
39. Draelos ZD, Traub M, Gold MH, et al. Validation of Botani-                    pH-sensitive polymeric nanoparticles intended for dermal ap-
    cal Treatment Efficiency for Adults and Children Suffering                    plications. Int J Pharm. 2017;516(1-2):21-31. DOI:10.1016/j
    from Mild to Moderate Atopic Dermatitis. J Drugs Dermatol.                    .ijpharm.2016.11.029. PMID: 27845215.
    2019;18(6):557. PMID: 31251548.                                           52. Zhuo F, Abourehab MAS, Hussain Z. Hyaluronic acid dec-
40. Hogue L, Cardwell LA, Roach C, et al. Psoriasis and Atopic                    orated tacrolimus-loaded nanoparticles: Efficient approach
    Dermatitis “Resistant” to Topical Treatment Responds Rap-                     to ­ maximize dermal targeting and anti-dermatitis efficacy.
      idly to Topical Desoximetasone Spray. J Cutan Med Surg.                     ­Carbohydr Polym. 2018;197:478-489. DOI:10.1016/j.carbpol
      2019;23(2):157-163. DOI:10.1177/1203475418818082. PMID:                     .2018.06.023. PMID: 30007638.
      30556414.                                                               53. Yu K, Wang Y, Wan T, et al. Tacrolimus nanoparticles based on
41.   Zivkovich AH, Feldman SR. Are ointments better than other ve-               chitosan combined with nicotinamide: enhancing percutaneous
      hicles for corticosteroid treatment of psoriasis? J Drugs Derma-            delivery and treatment efficacy for atopic dermatitis and reduc-
      tol. 2009;8(6):570-572. PMID: 19537382.                                     ing dose. Int J Nanomedicine. 2018;13:129-142. DOI:10.2147/
42.   Naeimifar A, Ahmad Nasrollahi S, Samadi A, et al. Evaluation                ijn.S150319. PMID: 29317821. PMCID: PMC5743175.
      of tolerability and efficacy of a topical emulgel containing nano-      54. Choi JK, Park JY, Lee S, et al. Greater Plasma Protein Adsorption
      liposomal ruxolitinib phosphate in the treatment of mild atopic             on Mesoporous Silica Nanoparticles Aggravates Atopic Derma-
      dermatitis: A before-after single group pilot study. J Dermato-             titis. Int J Nanomedicine. 2022;17:4599-4617. DOI:10.2147/ijn
      log Treat. 2022:1-7. DOI:10.1080/09546634.2022.2112138.                     .S383324. PMID: 36199478. PMCID: PMC9528962.
      PMID: 35943737.                                                         55. Kalia YN, Naik A, Garrison J, Guy RH. Iontophoretic drug de-
43.   Purohit VS, Ports WC, Wang C, Riley S. Systemic Tofacitinib                 livery. Adv Drug Deliv Rev. 2004;56(5):619-658. DOI:10.1016/j
      Concentrations in Adult Patients With Atopic Dermatitis Treated             .addr.2003.10.026. PMID: 15019750.
      With 2% Tofacitinib Ointment and Application to Pediatric Study         56. Le QV, Howard A. Dexamethasone iontophoresis for the treat-
      Planning. J Clin Pharmacol. 2019;59(6):811-820. DOI:10.1002                 ment of nail psoriasis. Australas J Dermatol. 2013;54(2):115-119.
      /jcph.1360. PMID: 30556911. PMCID: PMC6590358.                              DOI:10.1111/ajd.12029. PMID: 23425157.
44.   Purohit V, Riley S, Tan H, Ports WC. Predictors of Systemic Ex-         57. Dasht Bozorg B, Bhattaccharjee SA, Somayaji MR, Banga AK.
      posure to Topical Crisaborole: A Nonlinear Regression Analy-                Topical and transdermal delivery with diseased human skin: pas-
      sis. J Clin Pharmacol. 2020;60(10):1344-1354. DOI:10.1002                   sive and iontophoretic delivery of hydrocortisone into psoriatic
      /jcph.1624. PMID: 32433779. PMCID: PMC7540423.                              and eczematous skin. Drug Deliv Transl Res. 2022;12(1):197-212.
45.   Damiani G, Eggenhöffner R, Pigatto PDM, Bragazzi NL. Nano-                  DOI:10.1007/s13346-021-00897-7. PMID: 33432519. PMCID:
      technology meets atopic dermatitis: Current solutions, challenges           PMC9351627.
      and future prospects. Insights and implications from a systematic       58. Bissonnette R, Pavel AB, Diaz A, et al. Crisaborole and atopic
      review of the literature. Bioact Mater. 2019;4:380-386. DOI:                dermatitis skin biomarkers: An intrapatient randomized trial. J
      10.1016/j.bioactmat.2019.11.003. PMID: 31872162. PMCID:                     Allergy Clin Immunol. 2019;144(5):1274-1289. DOI:10.1016/j
      PMC6909150.                                                                 .jaci.2019.06.047. PMID: 31419544.
46.   Parekh K, Mehta TA, Dhas N, Kumar P, Popat A. Emerg-                    59. Callender VD, Alexis AF, Stein Gold LF, et al. Efficacy and
      ing Nanomedicines for the Treatment of Atopic Dermatitis.                   Safety of Crisaborole Ointment, 2%, for the Treatment of
      AAPS PharmSciTech. 2021;22(2):55. DOI:10.1208/s12249-021                    Mild-to-Moderate Atopic Dermatitis Across Racial and Ethnic
      -01920-3. PMID: 33486609. PMCID: PMC7828097.                                Groups. Am J Clin Dermatol. 2019;20(5):711-723. DOI:10.1007
47.   Pandey M, Choudhury H, Gunasegaran TAP, et al. Hyaluronic                   /s40257-019-00450-w. PMID: 31419544.
      acid-modified betamethasone encapsulated polymeric nanopar-             60. Cheape AC, Murrell DF. 2% Crisaborole topical ointment for
      ticles: fabrication, characterisation, in vitro release kinetics, and       the treatment of mild-to-moderate atopic dermatitis. Expert
      dermal targeting. Drug Deliv Transl Res. 2019;9(2):520-533.                 Rev Clin Immunol. 2017;13(5):415-423. DOI:10.1080/17446
      DOI:10.1007/s13346-018-0480-1. PMID: 29488170.                              66x.2017.1304820. PMID: 28290219.




Review | Dermatol Pract Concept. 2023;13(4):e2023216                                                                                                7
61. Draelos ZD, Stein Gold LF, Murrell DF, Hughes MH, Zane LT.                   3 to <24 Months with Mild-to-Moderate Atopic Dermatitis:
    Post Hoc Analyses of the Effect of Crisaborole Topical Oint-                 A Phase IV Open-Label Study (CrisADe CARE 1). Am J Clin
    ment, 2% on Atopic Dermatitis: Associated Pruritus from Phase                Dermatol. 2020;21(2):275-284. DOI:10.1007/s40257-020
    1 and 2 Clinical Studies. J Drugs Dermatol. 2016;15(2):172-176.              -00510-6. PMID: 32212104. PMCID: PMC7125059.
    PMID: 26885784.                                                        66.   Silverberg JI, Tallman AM, Ports WC, Gerber RA, Tan H, Zie-
62. Eichenfield LF, Call RS, Forsha DW, et al. Long-term safety of cris-         linski MA. Evaluating the Efficacy of Crisaborole Using the
    aborole ointment 2% in children and adults with mild to moder-               Atopic Dermatitis Severity Index and Percentage of Affected Body
    ate atopic dermatitis. J Am Acad Dermatol. 2017;77(4):641-649.               Surface Area. Acta Derm Venereol. 2020;100(13):adv00170.
    e5. DOI:10.1016/j.jaad.2017.06.010. PMID: 28823881.                          DOI:10.2340/00015555-3489. PMID: 32318744. PMCID:
63. Eichenfield LF, Yosipovitch G, Stein Gold LF, et al. Improve-                PMC9175045.
    ment in disease severity and pruritus outcomes with crisaborole        67.   Spergel JM, Blaiss MS, Lio P, et al. Efficacy and safety of cris-
    ointment, 2%, by baseline atopic dermatitis severity in children             aborole in patients with mild-to-moderate atopic derma-
    and adolescents with mild-to-moderate atopic dermatitis. Pedi-               titis and other atopic comorbidities. Allergy Asthma Proc.
    atr Dermatol. 2020;37(6):1030-1037. DOI:10.1111/pde.14328.                   2021;42(5):425-431. DOI:10.2500/aap.2021.42.210064. PMID:
    PMID: 28823881.                                                              34474712.
64. Fujita K, Yagi M, Moriwaki S, Yoshida M, Graham D. A phase 2b,         68.   Bissonnette R, Vasist LS, Bullman JN, Collingwood T, Chen G,
    randomized, double-blind, multicenter, vehicle-controlled study              Maeda-Chubachi T. Systemic Pharmacokinetics, Safety, and Pre-
    to assess the efficacy and safety of two crisaborole regimens in             liminary Efficacy of Topical AhR Agonist Tapinarof: Results of
    Japanese patients aged 2 years and older with mild-to-moderate               a Phase 1 Study. Clin Pharmacol Drug Dev. 2018;7(5):524-531.
    atopic dermatitis. J Dermatol. 2021;48(11):1640-1651.                        DOI:10.1002/cpdd.439. PMID: 29389078.
    DOI:10.1111/1346-8138.16120. PMID: 34435694. PMCID:                    69.   Keam SJ. Tapinarof Cream 1%: First Approval. Drugs.
    PMC9292399.                                                                  2022;82(11):1221-1228. DOI:10.1007/s40265-022-01748-6.
65. Schlessinger J, Shepard JS, Gower R, et al. Safety, Effective-               PMID: 35939180. PMCID: PMC9427914.
    ness, and Pharmacokinetics of Crisaborole in Infants Aged




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