Asthma and allergies affect millions of people globally. Avoiding triggers and allergens is a basic management technique for all asthma subtypes (>80% of asthma patients also suffer from allergies), and pharmacological treatment is the cornerstone for acute exacerbations and ongoing maintenance. Typical treatment options for asthma include inhaled, oral, or injectable dosage forms. However, transdermal drug delivery has great potential to provide an alternative route of administration of necessary asthma and allergy therapies that have traditionally been given in other dosage forms. In Part 1 of this two-part series, we discussed the work done towards incorporating short- and long-acting β2-agonists into transdermal drug delivery systems. Here in part 2, we describe the current literature for transdermal applications of leukotriene antagonists, theophylline, and other adjunct medications that do not fall into one specific drug class. A brief overview of biologics, particularly monoclonal antibodies, and the role in asthma is also included, including some context of transdermal mAb delivery for disease states beyond asthma. Because of the relatedness of asthma and allergies, transdermal applications for allergen immunotherapy is also discussed.
allergyasthmadrug deliverymicroneedletransdermalThe author(s) declared that financial support was received for this work and/or its publication. This work was supported by the National Institutes of Health awards 1R35GM149337. Funding to support Joseph Correa’s efforts was partially provided from the Iowa Biotech Training Program as funded by a T32 grant awarded by the National Institute of General Medical Sciences Predoctoral Institutional Research Training Grant (NIGMS T32 GM152268) and administered by the Center for Biocatalysis and Bioprocessing (CBB) at the University of Iowa.Introduction
Asthma is a complex pulmonary disorder with many subtypes, impacting more than 300 million patients globally [1]. Disease management is multimodal and includes many drug classes, including β2-agonists, corticosteroids, leukotriene antagonists, long-acting muscarinic antagonists, and other miscellaneous adjunct therapies [1–3]. More recently, monoclonal antibodies (mAbs) have emerged as a treatment option for patients suffering from asthma [4–6]. Disease subtype and severity both impact the selection of individual and combination therapies [1, 3, 7].
Inhalation dosage forms are common for pulmonary disorders, including asthma, but oral drugs are also used as maintenance therapies [3, 8]. However, newer therapies such as mAbs are only available as injectables/infusions [9–11]. Transdermal delivery (absorption of drug through the skin into the systemic circulation) has not been widely considered a viable dosage form for pulmonary disorders. However, transdermal dosage forms can overcome many challenges of inhaled, oral, and injectable products [12, 13]. Physical enhancements such as microneedles (MNs) allow the benefits of transdermal delivery to be further extended to drug molecules that cannot otherwise permeate through the skin [14]. MNs are micrometer-scale projections that create temporary epidermal micropores, allowing a drug to bypass the lipophilic stratum corneum and permeate directly into the dermis [15]. MNs can be used alone or in combination with other physical enhancement approaches such as iontophoresis and ultrasound [13, 16–18].
In Part 1 of this mini-review series, we summarized transdermal studies of short- and long-acting β2-agonists (SABAs and LABAs, respectively), which are typically administered as inhalations. Here we summarize transdermal studies of other asthma treatments, including studies using MNs and other physical enhancements. At the end we briefly cover transdermal allergen-specific immunotherapy, as >80% of asthma patients also suffer from allergies [2].
Leukotriene antagonists
Montelukast and zafirlukast are commonly prescribed oral leukotriene receptor antagonists [3]. Lowered bioavailability from first pass hepatic metabolism and food effects are challenges with montelukast and zafirlukast, respectively. Commercially available montelukast tablets contain 4–10 mg of drug with ∼64% bioavailability, equating to ∼2.6–6.4 mg delivered systemically [19, 20], while food reduces zafirlukast bioavailability by 40% [21]. We are unaware of transdermal zafirlukast studies, but transdermal montelukast for asthma has been investigated to achieve controlled release for reduced dosing frequency, improved bioavailability, and improved patient compliance [20, 22–24]. A film formulated with sodium alginate and lignosulphonic acid released 100% of loaded montelukast in 3 h; however, cross-linking with barium chloride or calcium chloride and plasticization with glycerine or polyethylene glycol achieved more controlled release [22]. Without plasticizers, cross-linking with barium chloride and calcium chloride resulted in 100% and 50% release, respectively, over 36 h (the cross-linking improved film stability, producing more controlled release). Over the same timeframe with the plasticizers, the films reached 60–80% drug release for barium chloride and 50–70% for calcium chloride.
In another study, montelukast doses in the milligram range were delivered through ex vivo porcine skin from a pure-drug MN [20]. A patch containing 3.36 mg of drug delivered an average of 1.5 mg through the skin while just under 1 mg remained in the patch and 0.33 mg remained on the skin. A patch loaded with 5.83 mg of montelukast delivered ∼3.23 mg, which is within the desired range for clinical use [20].
Theophylline
Theophylline is an oral bronchodilator used in the treatment of asthma and other obstructive pulmonary diseases, also aiding preterm infants needing respiratory support [25–31]. Theophylline doses for asthma management range from 300 to 600 mg/day [32], which is higher than what transdermal dosage forms are typically able to deliver. For this reason, it is possible that transdermal may not be suitable as a first line theophylline dosage form, but chemical and physical permeation enhancements could improve theophylline permeation to the point of being a useful adjunct therapy (particularly for specialized populations).
Transdermal theophylline permeation from suspensions and gels has been well studied in vitro and in vivo. In vitro permeation studies of theophylline prodrug suspensions demonstrated that higher aqueous solubility improves prodrug delivery, increasing flux across mouse skin up to 7 times that of more lipophilic prodrugs [33, 34]. Drug permeation, including theophylline, is often significantly impacted by the composition of transdermal gel formulations [35]. For example, for an ethanol/panasate 800 binary vehicle in an ethylcellulose gel, increasing ethylcellulose concentrations decrease theophylline permeation through mouse skin in vitro; however, all tested concentrations of ethylcellulose with the binary vehicle achieved higher permeation than either vehicle independently [36]. In another in vitro study, theophylline flux across excised porcine skin was 10 times higher in a water vehicle vs. propylene glycol formulations [37].
Permeation enhancement
Many permeation enhancers have been studied for transdermal theophylline. Without permeation enhancement, in vivo serum theophylline concentrations often fall below the therapeutic range when delivered as a gel [36, 38]. For example, in a 12-cat study, theophylline was loaded into either Lipoderm or pluronic lecithin organogel gel vehicles and applied to cats’ ear skin, achieving serum theophylline levels of 3–4 μg/mL over 24 h on average, which is lower than the 5 μg/mL therapeutic minimum for feline asthma [38].
Ester derivatives improve transdermal theophylline delivery [32–34]. Six-amino hexanoic acid esters increased theophylline permeation across human skin in vitro up to 3.9 times vs. negative control; up to 300 μg/cm2 of theophylline was delivered over 48 h with 6-amino hexanoic acid esters, reaching flux as high as 9.9 μg/cm2 h [39]. ε-aminocaproic acid esters achieved in vitro flux across human skin up to 100 μg/cm2 h, a 45-fold increase compared to control water vehicle with a flux of 2.2 μg/cm2 h [40]. Reactions of dodecyl-6-aminohexanoate with CO2 in the air produce a two-chain ammonium carbamate that has further enhanced in vitro theophylline permeation through human skin to over 50 times the control, reaching flux up to 176.7 μg/cm2 h [41].
Terpenes (naturally occurring compounds often found in essential oils) are another group of permeation enhancers investigated with theophylline [31, 42–45]. Menthol significantly increased theophylline flux across murine skin to 29.15 μg/cm2 h vs. 16.78 μg/cm2 h without enhancers [31]. In rat skin, higher ethanol concentration slightly improved flux, but terpenes from Magnolia fargesii essential oil significantly had a much greater effect, achieving flux of ∼24 μg/cm2 h vs. <5 μg/cm2 h without terpenes [42]. Addition of oleic acid, menthone, and farnesol to theophylline suspensions significantly increased flux 3.3, 1.9, and 48.1 times over controls, respectively [43, 44]. Lauric acid reduced lag time from 2 to 3 h to <1 h but did not significantly increase theophylline permeation across excised mouse skin in vitro after 24 h [36]. However, in vivo studies across shaved rat abdomens increased bioavailability from 72% to 99% with lauric acid [36]. The authors attributed these discrepancies to differences between in vitro equilibrium-driven permeation and in vivo systemic absorption [36]. Other chemical permeation enhancers that have improved theophylline transdermal delivery include sugar-derived and amino acid-derived enhancers and calcium thioglycolate [46–50].
Physical enhancement
In addition to chemical permeation enhancers, theophylline has been loaded into polymeric MNs for improved in vitro transdermal permeation [51]. Compared to a transdermal patch, MN arrays made with 20% Gantrez® AN-139 polymer significantly increased theophylline permeation across porcine skin, delivering 83% of loaded drug vs. 5.5% delivered from the patch over 24 h [51]. The MN arrays had strong mechanical properties with less than 20% needle height reduction and high pore formation in porcine skin with minimal insertion force. In addition to theophylline delivery, MNs could be useful for monitoring theophylline plasma concentrations (a required part of long-term therapy) [52], which presents a non-invasive way to manage chronic therapy needs.
Specialized populations
Preterm infants and neonates represent a population that could particularly benefit from transdermal theophylline, taking advantage of increased permeability of neonatal skin [26–30]. Evans et al. reported that a hydroxymethyl cellulose gel loaded with 15% theophylline applied to the skin could achieve therapeutic serum theophylline levels in preterm infants [28], though other studies failed to reach therapeutic levels with the same drug loading in glycerin-based gels [29].
Additional drugs for asthma treatment
Transdermal studies of other miscellaneous asthma therapies have been limited, and these therapeutics largely do not fit into one major group. Such drugs include corticosteroids, glycopyrrolate, and cromolyn [53–59]. Some therapies have also been investigated for topical, intranasal, or ophthalmic administration for local delivery, but those studies are not covered here.
Corticosteroids
Corticosteroids for asthma include inhaled fluticasone for maintenance therapy and oral prednisone and methylprednisolone for acute episodes [3, 7]. Fluticasone has been loaded into bilosomes for transdermal delivery, which significantly increased flux across rat skin from 1.81 μg/cm2 h (aqueous control) to 5.89 μg/cm2 h [53]. Prednisone loaded into a propylene glycol gel could not permeate through intact porcine skin, but following laser-microporation, up to 197.18 μg/cm2 permeated over 24 h [59]. When loaded into a nanoliposomal sludge with a hydroxypropyl methylcellulose (HPMC) and polyvinyl pyrrolidone (PVP) base, prednisone reached a flux of 26.6 μg/cm2 h, which was significantly greater than flux from an aqueous cream, petroleum jelly, or PVP/HPMC gel [57]. Methylprednisolone has also been studied with MN pretreatment; number of MN pretreatments and duration of MN insertion significantly affected amount of methylprednisolone recovered from tissue [55]. It should be noted that prolonged use of topical corticosteroids can lead to many adverse effects including hypopigmentation and skin atrophy, limiting the practical use of topical or transdermal corticosteroids [60, 61].
Glycopyrrolate
Glycopyrrolate is a long-acting muscarinic antagonist used treat asthma, other pulmonary conditions, and some non-pulmonary indications [54, 56, 62]. Passive glycopyrrolate permeation from water transported 21.49 μg/cm2 across porcine skin over 24 h, which increased to 42.23 μg/cm2 and 202.25 μg/cm2 with MN pretreatment and iontophoresis treatment, respectively. Interestingly, combining iontophoresis with MNs did not further enhance the permeation, delivering 191.04 μg/cm2 across porcine skin [56].
Cromolyn
As a mast cell stabilizer, cromolyn is FDA approved for asthma, nasal allergies, and conjunctivitis; it is also used off-label for food allergies and irritable bowel syndrome [63]. Cromolyn has low absorption from the gastrointestinal tract, prompting development of inhaled, nasal, and ophthalmic dosage forms. Potential transdermal applications were first investigated in 1985, comparing saline solutions of pyranoquinolinedicarboxylic acid derivatives to cromolyn, though transdermal permeation was not specifically investigated [64]. More recently, transdermal cromolyn sodium permeation from ethosomes and liposomes was evaluated. Transdermal flux from ethosomes (18.49 mg/cm2 h) was significantly higher than liposomes (1.80 mg/cm2 h) and phosphate-buffered saline control (1.18 mg/cm2 h) [58].
Biologics
Despite the many therapies available to treat asthma and allergies, treatment options and outcomes may still not be optimized for patients with severe asthma. Monoclonal antibodies (mAbs) have emerged as specialized, targeted biologic therapies, with six mAbs currently approved for add-on asthma treatments [9, 65] (Table 1). These mAbs are given as injections or infusions [9], which comes with challenges of pain, needle phobia, and the expense and inconvenience of in-clinic administration [15]. Research exploring transdermal mAbs for asthma is currently lacking, likely because passive transdermal delivery is not conducive to the transport of such large molecules. Additionally, mAb treatments for asthma require high doses (ranging from 30 mg to >300 mg), also presenting challenges for passive transdermal delivery.
Comparison of the six approved mAbs for asthma treatment.
mAbs specific considerations
Omalizumab [66–68]
Mepolizumab [69–71]
Reslizumab [72, 73]
Benralizumab [69, 74, 75]
Dupilumab [76, 77]
Tezepelumab [11, 78, 79]
Brand name
Xolair®
Nucala
Cinqair®
Fasenra®
Dupixent®
Tezspire®
Molecular target
IgE
IL-5
IL-5
IL-5 receptor α
IL-4/IL-13
TSLP
Inflammation type treated
Type 2
Type 2
Type 2
Type 2
Type 2
Type 2 and non-type 2
Eosinophil count for greatest efficacy (cells/µL)
≥260
≥150
≥400
≥300
≥150
≥150
Age indication for asthma therapy (years)
≥6
≥6
≥18
≥6
≥6
≥12
Route and dosing
Subcutaneous injection75–375 mg every 2–4 weeks
Subcutaneous injection100 mg every 4 weeks (ages ≥12 years)40 mg every 4 weeks (ages 6–11 years)
Intravenous infusion3 mg/kg every 4 weeks
Subcutaneous injection30 mg every 4 weeks for first 3 doses then every 8 weeks (ages ≥12, and ages 6–11 years, ≥35 kg)10 mg every 4 weeks for 3 doses, then every 8 weeks (ages 6–11 years, <35 kg)
Subcutaneous injection200 or 300 mg every 2 weeks (after 400 or 600 mg initial dose for ages ≥12 years; loading dose may vary for ages 6–11 years based on weight)
Subcutaneous injection210 mg every 4 weeks
Technologies such as iontophoresis, ultrasound, and MNs readily permit transdermal protein delivery [10, 12, 80, 81], and there have been recent studies of transdermal biologics for diabetes, hypoglycemia, and osteoporosis [10, 80, 82, 83]. MN delivery of mAbs such as denosumab, bevacizumab, and anti-PBP2a for conditions including cancer, osteoporosis, and corneal neovascularization have also been performed [84–87]. The doses delivered in these studies ranged from 1.1 µg to 10 mg, which leaves much room for improvement given the high mAb doses required for asthma management. A variety of innovations in MN delivery have generally focused on improving the possible range of delivered doses–these innovations include lyophilized reservoirs, powder jet injectors, and micro/nano-particle encapsulation [80, 84, 88, 89]. With further successes and developments, there could be potential for large molecule asthma therapeutics to be developed into non-invasive transdermal systems.
Microneedles and allergies
Allergens exacerbate symptoms in many patients with allergic asthma [3]. Allergy management aids asthma treatments for these patients, and advances in allergy desensitization, particularly allergen-specific immunotherapy (AIT), have emerged as important strategies [90, 91]. AIT has been used for pollen, molds, and food allergens [91–94] and is often administered subcutaneously (“allergy shots”) or sublingually, improving allergy symptoms and lessening overall medication use [7, 91]. Despite the success of AIT, there are side effects - including redness, injection pain, sneezing, and hives [91, 92, 95]. AIT is not recommended for patients with severe or uncontrolled asthma because serious adverse reactions such as anaphylaxis are more common in those patients [91, 96, 97].
MNs have been explored for providing sustained allergen exposure and targeting skin-specific immune cells (dendritic cells, Langerhans cells) [95, 98]. One focus of MN-mediated immunotherapy has been on peanuts and cow milk [99–104]. Loading allergens into MN arrays does not affect antigenicity but does reduce immune cell infiltration, Th2 cells, and IgE while increasing IgG1, IgG2, TGF-b, and IL-10 levels, all of which contribute to suppressed allergic responses [105–108]. A major benefit of MN-mediated immunotherapy is minimization of side effects that often arise from invasive subcutaneous injections with traditional AIT [100, 103, 104, 106, 109]. While the small size of a MN patch can limit the dose of allergen exposure, doses as low as 0.1–0.5 µg in MN-mediated epicutaneous immunotherapy can produce maximum therapeutic effect in mouse models [90].
Discussion
Transdermal treatments for asthma and allergies could improve patient compliance and minimize adverse effects by offering unique advantages over traditional inhaled, oral, and injectable routes. Here in Part 2 of this mini-review series, we broadly discussed formulation approaches and physical enhancement techniques to enable transdermal delivery of adjunct asthma therapies and allergy treatments.
Large molecular size and high doses have been long-standing challenges for transdermal delivery, impacting many of the drugs described in this mini-review – specifically, theophylline and mAbs. However, emerging research in physical enhancement methods for protein delivery suggests potential future feasibility for large molecule transdermal delivery. By disrupting the skin barrier, MNs, iontophoresis, and ultrasound show promise in assisting large molecule delivery through skin [10, 80]. Many innovations have also been explored to increase transdermal dosing range, but the field needs continued growth in this area. Commercially available transdermal patches are loaded with up to 40 mg [110, 111], while drug-loaded and drug-coated MNs generally contain up to 10 mg [88, 112]. However, MNs can deliver larger doses up to 33 mg [17, 113], potentially also requiring lower doses to achieve comparable efficacy as other dosage forms [85, 89, 114–116]. Hollow MNs can deliver larger doses than coated or dissolving MNs [117–119], and solid MNs as a pretreatment (followed by application of another formulation over the MN-treated skin) can significantly increase dose delivered [120–122]. Permeation enhancers, applying multiple MN patches, or combination permeation enhancement approaches are additional options to deliver higher doses.
In summary, innovations in formulation, physical and chemical permeation enhancement, and delivery platforms may advance the field towards fully realizing the clinical potential of transdermal systems for asthma and allergy management – including therapeutics that are most often delivered as inhalations or injectables.
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
ReferencesBosi AtRCastaniereICliniEBegheBBeghèB. Acute severe asthma: management and treatment. Minerva Med (2021) 112(5):605–14. 10.23736/S0026-4806.21.07372-933634676CastilloJRPetersSPBusseWW. Asthma exacerbations: pathogenesis, prevention, and treatment. J Allergy Clin Immunol Pract (2017) 5(4):918–27. 10.1016/j.jaip.2017.05.00128689842GohalGMoniSSBakkariMAElmobarkME. A review on asthma and allergy: current understanding on molecular perspectives. J Clin Med (2024) 13(19):5775. 10.3390/jcm1319577539407835BusseWW. Biological treatments for severe asthma: a major advance in asthma care. Allergol Int (2019) 68(2):158–66. 10.1016/j.alit.2019.01.00430792118KardasGPanekMKunaPDamiańskiPKupczykM. Monoclonal antibodies in the management of asthma: dead ends, current status and future perspectives. Front Immunol (2022) 13–2022. 10.3389/fimmu.2022.98385236561741McGregorMCKringsJGNairPCastroM. Role of biologics in asthma. Am J Respir Crit Care Med (2019) 199(4):433–45. 10.1164/rccm.201810-1944CI30525902KwahJHPetersAT. Asthma in adults: principles of treatment. Allergy Asthma Proc (2019) 40(6):396–402. 10.2500/aap.2019.40.425631690379ChanADe SimoniAWilemanVHollidayLNewbyCJChisariCDigital interventions to improve adherence to maintenance medication in asthma. Cochrane Database Syst Rev (2022) 6(6):CD013030. 10.1002/14651858.CD013030.pub235691614Biologic therapies for severe asthma. Asthma and lung UK2025 (2025). Available online at: https://www.asthmaandlung.org.uk/symptoms-tests-treatments/treatments/biologic-therapies (Accessed August 18, 2025).MoralesJOFatheKRBrunaughAFerratiSLiSMontenegro-NicoliniMChallenges and future prospects for the delivery of biologics: oral mucosal, pulmonary, and transdermal routes. AAPS J (2017) 19(3):652–68. 10.1208/s12248-017-0054-z28194704TerlMDiamantZKosturiakRJesenakM. Choosing the right biologic treatment for individual patients with severe asthma – lessons learnt from picasso. Respir Med (2024) 234:107766. 10.1016/j.rmed.2024.10776639181277LarrañetaELuttonREMWoolfsonADDonnellyRF. Microneedle arrays as transdermal and intradermal drug delivery systems: materials science, manufacture and commercial development. Mater Sci Eng R: Rep (2016) 104:1–32. 10.1016/j.mser.2016.03.001PrausnitzMRLangerR. Transdermal drug delivery. Nat Biotechnol (2008) 26(11):1261–8. 10.1038/nbt.150418997767QuinnHLLarranetaEDonnellyRF. Dissolving microneedles: safety considerations and future perspectives. Ther Deliv (2016) 7(5):283–5. 10.4155/tde-2016-001527075949RamadonDMcCruddenMTCCourtenayAJDonnellyRF. Enhancement strategies for transdermal drug delivery systems: current trends and applications. Drug Deliv Translational Res (2022) 12(4):758–91. 10.1007/s13346-021-00909-633474709ChenZWuHZhaoSChenXWeiTPengH3D-Printed integrated ultrasonic microneedle array for rapid transdermal drug delivery. Mol Pharm (2022) 19(9):3314–22. 10.1021/acs.molpharmaceut.2c0046635947780McCruddenMTCAlkilaniAZMcCruddenCMMcAlisterEMcCarthyHOWoolfsonADDesign and physicochemical characterisation of novel dissolving polymeric microneedle arrays for transdermal delivery of high dose, low molecular weight drugs. J Controlled Release (2014) 180:71–80. 10.1016/j.jconrel.2014.02.00724556420MitragotriSKostJ. Transdermal delivery of heparin and low-molecular weight heparin using low-frequency ultrasound. Pharm Res (2001) 18(8):1151–6. 10.1023/a:101097901090711587487WermuthHRBadriTTakovV. Treasure Island, FL: StatPearls Publishing (2023).AzizogluEOzerOPrausnitzMR. Fabrication of pure-drug microneedles for delivery of montelukast sodium. Drug Deliv Transl Res (2022) 12(2):444–58. 10.1007/s13346-021-01047-934480297DekhuijzenPNRKoopmansPP. Pharmacokinetic profile of zafirlukast. Clin Pharmacokinet (2002) 41(2):105–14. 10.2165/00003088-200241020-0000311888331AashliRSGSivaKBPrashanthiKMurthyHCA. Fabricating transdermal film formulations of montelukast sodium with improved chemical stability and extended drug release. Heliyon (2023) 9(3):e14469. 10.1016/j.heliyon.2023.e1446936950594AzizoğluEÖzerÖ. Fabrication of montelukast sodium loaded filaments and 3D printing transdermal patches onto packaging material. Int J Pharmaceutics (2020) 587:119588. 10.1016/j.ijpharm.2020.11958832663585ImSHJungHTHoMJLeeJEKimHTKimDYMontelukast nanocrystals for transdermal delivery with improved chemical stability. Pharmaceutics (2020) 12(1):18. 10.3390/pharmaceutics1201001831877986MurphyMGPeckCCConnerDPZamaniKMerensteinGBRoddenD. Transcutaneous theophylline collection in preterm infants. Clin Pharmacol and Ther (1990) 47(4):427–34. 10.1038/clpt.1990.532328550BarrettDARutterN. Transdermal delivery and the premature neonate. Crit Rev Ther Drug Carrier Syst (1994) 11(1):1–30.7704917CartwrightRCartlidgePRutterNMeliaCDavisS. Transdermal delivery of theophylline to premature infants using a hydrogel disc system. Br J Clin Pharmacol (1990) 29(5):533–9. 10.1111/j.1365-2125.1990.tb03676.x2350529EvansNJRutterNHadgraftJParrG. Percutaneous administration of theophylline in the preterm infant. The J Pediatr (1985) 107(2):307–11. 10.1016/s0022-3476(85)80157-84020561MicaliGBhattRHDistefanoGCaltabianoLCookBFischerJHEvaluation of transdermal theophylline pharmacokinetics in neonates. Pharmacotherapy. The J Hum Pharmacol Drug Ther (1993) 13(4):386–90. 10.1002/j.1875-9114.1993.tb02747.x8361866RutterN. Percutaneous drug absorption in the newborn: hazards and uses. Clin Perinatol (1987) 14(4):911–30.3322630ZhaoXLiuJPZhangXLiY. Enhancement of transdermal delivery of theophylline using microemulsion vehicle. Int J Pharmaceutics (2006) 327(1):58–64. 10.1016/j.ijpharm.2006.07.02716926077Theophylline. Ann Arbor, Michigan, USA. In: Merative (2025). Available online at: https://www-micromedexsolutions-com.proxy.lib.uiowa.edu/micromedex2/librarian/CS/905908/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/CA8F83/ND_PG/evidencexpert/ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/evidencexpert.DoIntegratedSearch?SearchTerm=Theophylline&fromInterSaltBase=true&UserMdxSearchTerm=%24userMdxSearchTerm#quickanspanelprint (Accessed December 9, 2025).RobertsWJSloanKB. Prediction of transdermal flux of prodrugs of 5‐Fluorouracil, theophylline, and 6‐Mercaptopurine with a series/parallel model. J Pharm Sci (2000) 89(11):1415–31. 10.1002/1520-6017(200011)89:11<1415::aid-jps5>3.0.co;2-t11015687MajumdarSMueller-SpaethMSloanKB. Prodrugs of theophylline incorporating ethyleneoxy groups in the promoiety: synthesis, characterization, and transdermal delivery. AAPS PharmSciTech (2012) 13(3):853–62. 10.1208/s12249-012-9803-622648150BradleyCRAlmirezRGConnerDPRhynePRPeckCC. Noninvasive transdermal chemical collection. II. in vitro and in vivo skin permeability studies. Skin Pharmacol (1990) 3(4):227–35.2083080LeeCKitagawaKUchidaTKimNGotoS. Transdermal delivery of theophylline using an ethanol/panasate 800-Ethylcellulose gel preparation. Biol and Pharm Bull (1995) 18(1):176–80. 10.1248/bpb.18.1767735237HeardCMJohnsonSMossGThomasCP. In vitro transdermal delivery of caffeine, theobromine, theophylline and catechin from extract of guarana, Paullinia cupana. Int J Pharmaceutics (2006) 317(1):26–31. 10.1016/j.ijpharm.2006.02.04216600539BarnoskiJLee-FowlerTMBootheDMBehrendEN. Serum theophylline after multiple dosing with transdermal gels in cats. J Feline Med Surg (2019) 21(4):329–34. 10.1177/1098612X1877685329807504KopečnáMKováčikAKučeraOMacháčekMSochorováMAudrlickáPFluorescent penetration enhancers reveal complex interactions among the enhancer, drug, solvent, and skin. Mol Pharmaceutics (2019) 16(2):886–97. 10.1021/acs.molpharmaceut.8b0119630629452DolezalPHrabálekASemeckýV. epsilon-Aminocaproic acid esters as transdermal penetration enhancing agents. Pharm Res (1993) 10(7):1015–9. 10.1023/a:10189148067618378243HrabálekADoležalPVávrováKZbytovskáJHolasTKlimentováJSynthesis and enhancing effect of transkarbam 12 on the transdermal delivery of theophylline, clotrimazole, flobufen, and griseofulvin. Pharm Res (2006) 23(5):912–9. 10.1007/s11095-006-9782-y16715381FangJ-YTsaiT-HHungC-FWongW-W. Development and evaluation of the essential oil from Magnolia fargesii for enhancing the transdermal absorption of theophylline and cianidanol. J Pharm Pharmacol (2004) 56(12):1493–500. 10.1211/002235704482315563755KopečnáMMacháčekMNováčkováAParaskevopoulosGRohJVávrováK. Esters of terpene alcohols as highly potent, reversible, and low toxic skin penetration enhancers. Scientific Rep (2019) 9(1):14617. 10.1038/s41598-019-51226-531601936ThakurRAMichniakBBMeidanVM. Transdermal and buccal delivery of methylxanthines through human tissue in vitro. Drug Development Ind Pharm (2007) 33(5):513–21. 10.1080/0363904060090199417520442FangJ-YTsaiT-HLinY-YWongW-WWangM-NHuangJ-F. Transdermal delivery of tea catechins and theophylline enhanced by terpenes: a mechanistic study. Biol Pharm Bull (2007) 30(2):343–9. 10.1248/bpb.30.34317268077KopečnáMMacháčekMPrchalováEŠtěpánekPDrašarPKotoraMGalactosyl pentadecene reversibly enhances transdermal and topical drug delivery. Pharm Res (2017) 34(10):2097–108. 10.1007/s11095-017-2214-328664316KopečnáMMacháčekMPrchalováEŠtěpánekPDrašarPKotoraMDodecyl amino glucoside enhances transdermal and topical drug delivery via reversible interaction with skin barrier lipids. Pharm Res (2017) 34(3):640–53. 10.1007/s11095-016-2093-z28070753PokornaABobalPOravecMRarovaLBobalovaJJampilekJ. Investigation of permeation of theophylline through skin using selected Piperazine-2,5-Diones. Molecules (2019) 24(3):566. 10.3390/molecules2403056630720734VávrováKHrabálekADoležalPHolasTZbytovskáJ. l-Serine and glycine based ceramide analogues as transdermal permeation enhancers: polar head size and hydrogen bonding. Bioorg and Med Chem Lett (2003) 13(14):2351–3. 10.1016/S0960-894X(03)00409-812824032KushidaKMasakiKMatsumuraMOhshimaTYoshikawaHTakadaKApplication of calcium thioglycolate to improve transdermal delivery of theophylline in rats. Chem Pharm Bull (Tokyo) (1984) 32(1):268–74. 10.1248/cpb.32.2686722953DonnellyRFMajithiyaRSinghTRRMorrowDIJGarlandMJDemirYKDesign, optimization and characterisation of polymeric microneedle arrays prepared by a novel laser-based micromoulding technique. Pharm Res (2011) 28(1):41–57. 10.1007/s11095-010-0169-820490627NurrahmanAMJiwantiPKTomisakiMAmalinaIAnjaniQKKondoTMicroneedle-integrated screen-printed electrode modified with gold nanoparticle-boron-doped diamond nanoparticle nanocomposites for electrochemical theophylline detection. ACS Omega (2025) 10(43):51738–47. 10.1021/acsomega.5c0743441210775AbuBakrA-HHassanHAFMAbdallaAKhowessahOMAbdelbaryGA. Therapeutic potential of cationic bilosomes in the treatment of carrageenan-induced rat arthritis via fluticasone propionate gel. Int J Pharmaceutics (2023) 635:122776. 10.1016/j.ijpharm.2023.12277636841370BaumanWASabievAShallwaniSSpungenAMCirnigliaroCMKorstenMA. The addition of transdermal delivery of neostigmine and glycopyrrolate by iontophoresis to thrice weekly bowel care in persons with spinal cord injury: a pilot study. J Clin Med (2021) 10(5):1135. 10.3390/jcm1005113533800503DuanDMoecklyCGysbersJNovakCProchnowGSiebenalerKEnhanced delivery of topically-applied formulations following skin pre-treatment with a hand-applied, plastic microneedle array. Curr Drug Deliv (2011) 8(5):557–65. 10.2174/15672011179664231821696356GujjarMBangaAK. Iontophoretic and microneedle mediated transdermal delivery of glycopyrrolate. Pharmaceutics (2014) 6(4):663–71. 10.3390/pharmaceutics604066325533309MavusoSMarimuthuTKumarPKondiahPPDdu ToitLCChoonaraYEIn vitro,, Ex Vivo, and in vivo evaluation of a dual pH/Redox responsive nanoliposomal sludge for transdermal drug delivery. J Pharm Sci (2018) 107(4):1028–36. 10.1016/j.xphs.2017.11.01129175410RakeshRAnoopKR. Formulation and optimization of nano-sized ethosomes for enhanced transdermal delivery of cromolyn sodium. J Pharm Bioallied Sci (2012) 4(4):333–40. 10.4103/0975-7406.10327423248569YuJBachhavYGSummerSHeinrichABragagnaTBöhlerCUsing controlled laser-microporation to increase transdermal delivery of prednisone. J Controlled Release (2010) 148(1):e71–e3. 10.1016/j.jconrel.2010.07.03221529638HashimotoNNakamichiNYamazakiEOikawaMMasuoYSchinkelAHP-Glycoprotein in skin contributes to transdermal absorption of topical corticosteroids. Int J Pharmaceutics (2017) 521(1):365–73. 10.1016/j.ijpharm.2017.02.06428242377HenggeURRuzickaTSchwartzRACorkMJ. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol (2006) 54(1):1–15. 10.1016/j.jaad.2005.01.01016384751KorstenMALyonsBLRadulovicMCummingsTMSikkaGSinghKDelivery of neostigmine and glycopyrrolate by iontophoresis: a nonrandomized study in individuals with spinal cord injury. Spinal Cord (2018) 56(3):212–7. 10.1038/s41393-017-0018-229116244MinutelloKGuptaV. Cromolyn sodium. StatPearls. Treasure Island, FL: StatPearls Publishing (2025).CairnsHCoxDGouldKJIngallAHSuschitzkyJL. New antiallergic pyrano [3,2-g]quinoline-2,8-dicarboxylic acids with potential for the topical treatment of asthma. J Med Chem (1985) 28(12):1832–42. 10.1021/jm00150a0142999403Biologics (biologic medicine) cleveland clinic. (2024). Available online at: https://my.clevelandclinic.org/health/treatments/biologics-biologic-medicine (Accessed: September 8, 2024).LuuMBardouMBonniaudPGoirandF. Pharmacokinetics, pharmacodynamics and clinical efficacy of omalizumab for the treatment of asthma. Expert Opin Drug Metab Toxicol (2016) 12(12):1503–11. 10.1080/17425255.2016.124840327748630OdajimaHEbisawaMNagakuraTFujisawaTAkasawaAItoKLong-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma. Allergol Int (2017) 66(1):106–15. 10.1016/j.alit.2016.06.00427507228XOLAIR® (omalizumab) [package insert]. (2023). Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/103976Orig1s5243lbl.pdf (Accessed September 18, 2025).GhassemianAParkJJTsoulisMWKimH. Targeting the IL-5 pathway in eosinophilic asthma: a comparison of mepolizumab to benralizumab in the reduction of peripheral eosinophil counts. Allergy Asthma Clin Immunol (2021) 17(1):3. 10.1186/s13223-020-00507-033407869PavordIChanRBrownNHowarthPGilsonMPriceRGLong-term safety of mepolizumab for up to approximately 10 years in patients with severe asthma: open-label extension study. Ann Med (2024) 56(1):2417184. 10.1080/07853890.2024.241718439465531NUCALA (mepolizumab). (2023). Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/125526Orig1s021,761122Orig1s011Corrected_lbl.pdf (Accessed September 18, 2025).CINQAIR® (reslizumab) [package insert]. (2019). Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/0761033s010lbl.pdf (Accessed September 18, 2025).WechslerMEHickeyLGarinMChauhanA. Efficacy of reslizumab treatment in exacerbation-prone patients with severe eosinophilic asthma. J Allergy Clin Immunol Pract (2020) 8(10):3434–42 e4. 10.1016/j.jaip.2020.06.00932562877GauvreauGMSehmiRFitzGeraldJMLeighRCockcroftDWDavisBEBenralizumab for allergic asthma: a randomised, double-blind, placebo-controlled trial. Eur Respir J (2024) 64(3):2400512. 10.1183/13993003.00512-202439060015FASENRA (benralizumab). (2019). Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761070s005lbl.pdf (Accessed September 18, 2025).MasperoJFAntilaMADeschildreABacharierLBAltincatalALawsEDupilumab efficacy in children with type 2 asthma receiving High-to medium-dose inhaled corticosteroids (VOYAGE). J Allergy Clin Immunol Pract (2024) 12(12):3303–12. 10.1016/j.jaip.2024.08.03839209068DUPIXENT®(dupilumab) [package insert]. (2025). Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761055s072lbl.pdf (Accessed September 18, 2025).WechslerMEBrusselleGVirchowJCBourdinAKostikasKLlanosJ-PClinical response and on-treatment clinical remission with tezepelumab in a broad population of patients with severe, uncontrolled asthma: results over 2 years from the NAVIGATOR and DESTINATION studies. Eur Respir J (2024) 64(6):2400316. 10.1183/13993003.00316-202439326921TEZSPIRE® (tezepelumab-ekko) [package insert]. (2023). Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761224s003lbl.pdf (Accessed September 18, 2025).AnselmoACGokarnYMitragotriS. Non-invasive delivery strategies for biologics. Nat Rev Drug Discov (2019) 18(1):19–40. 10.1038/nrd.2018.18330498202KochharCImanidisG. In vitro transdermal iontophoretic delivery of leuprolide under constant current application. J Controlled Release (2004) 98(1):25–35. 10.1016/j.jconrel.2004.04.00815245886MishraRMaitiTKBhattacharyyaTK. Feasibility studies on nafion membrane actuated micropump integrated with hollow microneedles for insulin delivery device. J Microelectromechanical Syst (2019) 28(6):987–96. 10.1109/jmems.2019.2939189YeYYuJWenDKahkoskaARGuZ. Polymeric microneedles for transdermal protein delivery. Adv Drug Deliv Rev (2018) 127:106–18. 10.1016/j.addr.2018.01.01529408182CourtenayAJMcCruddenMTCMcAvoyKJMcCarthyHODonnellyRF. Microneedle-mediated transdermal delivery of bevacizumab. Mol Pharm (2018) 15(8):3545–56. 10.1021/acs.molpharmaceut.8b0054429996645KimYCGrossniklausHEEdelhauserHFPrausnitzMR. Intrastromal delivery of bevacizumab using microneedles to treat corneal neovascularization. Invest Ophthalmol Vis Sci (2014) 55(11):7376–86. 10.1167/iovs.14-1525725212779SuYShahriarSSMAndrabiSMWangCSharmaNSXiaoYIt takes two to tangle: microneedle patches Co-delivering monoclonal antibodies and engineered antimicrobial peptides effectively eradicate wound biofilms. Macromolecular Biosci (2024) 24(5):2300519. 10.1002/mabi.20230051938217528UddinMJEconomidouSNGuiraudLKaziMAlanaziFKDouroumisD. Monoclonal antibody delivery using 3D printed biobased hollow μNe3dle arrays for the treatment of osteoporosis. Mol Pharmaceutics. (2024) 21(9):4465–75. 10.1021/acs.molpharmaceut.4c0037939110837Bauleth-RamosTEl-SayedNFontanaFLobitaMShahbaziM-ASantosHA. Recent approaches for enhancing the performance of dissolving microneedles in drug delivery applications. Mater Today (2023) 63:239–87. 10.1016/j.mattod.2022.12.007Faraji RadZPrewettPDDaviesGJ. An overview of microneedle applications, materials, and fabrication methods. Beilstein J Nanotechnol (2021) 12:1034–46. 10.3762/bjnano.12.7734621614ChoiYJKimKAJungJHChoiYSBaekSKKimSTEpicutaneous allergen administration with microneedles as a novel method of immunotherapy for house dust mite (HDM) allergic rhinitis. Pharm Res (2021) 38(7):1199–207. 10.1007/s11095-021-03070-434145532LeiDKSaltounC. Allergen immunotherapy: definition, indications, and reactions. Allergy Asthma Proc (2019) 40(6):369–71. 10.2500/aap.2019.40.424931690372BousquetJAntoJMBachertCBaiardiniIBosnic-AnticevichSWalterCGAllergic rhinitis. Nat Rev Dis Primers (2020) 6(1):95. 10.1038/s41572-020-00227-033273461SatoSKodachiTYanagidaNEbisawaM. Recent insights into the epidemiology and management of anaphylaxis. Balkan Med J (2025). 10.4274/balkanmedj.galenos.2025.2025-5-8640719286SimonD. Recent advances in clinical allergy and immunology. Int Arch Allergy Immunol (2018) 177(4):324–33. 10.1159/00049493130399611ParkCOKimHLParkJW. Microneedle transdermal drug delivery systems for allergen-specific immunotherapy, skin disease treatment, and vaccine development. Yonsei Med J (2022) 63(10):881–91. 10.3349/ymj.2022.009236168240MooteWKimHEllisAK. Allergen-specific immunotherapy. Allergy Asthma and Clin Immunol (2018) 14(2):53. 10.1186/s13223-018-0282-530275845YangJLeiS. Efficacy and safety of sublingual versus subcutaneous immunotherapy in children with allergic rhinitis: a systematic review and meta-analysis. Front Immunol (2023) 14:1274241. 10.3389/fimmu.2023.127424138162647ParisJLVoraLKTorresMJMayorgaCDonnellyRF. Microneedle array patches for allergen-specific immunotherapy. Drug Discov Today (2023) 28(5):103556. 10.1016/j.drudis.2023.10355636931387ItoSHirobeSKuwabaraYNagaoMSaitoMQuanY-SImmunogenicity of milk protein-containing hydrophilic gel patch for epicutaneous immunotherapy for milk allergy. Pharm Res (2020) 37(3):35. 10.1007/s11095-019-2728-y31950282LandersJJJanczakKWShakyaAKZarnitsynVPatelSRBakerJJRTargeted allergen-specific immunotherapy within the skin improves allergen delivery to induce desensitization to peanut. Immunotherapy (2022) 14(7):539–52. 10.2217/imt-2021-020635196877MurtyRSankaranarayananABowlandIIMena-LapaixJPrausnitzMR. Angled insertion of microneedles for targeted antigen delivery to the Epidermis. Pharmaceutics (2022) 14(2):347. 10.3390/pharmaceutics1402034735214079ShakyaAKIngroleRSJJoshiGUddinMJAnvariSDavisCMMicroneedles coated with peanut allergen enable desensitization of peanut sensitized mice. J Controlled Release (2019) 314:38–47. 10.1016/j.jconrel.2019.09.02231626861Venkatesa PrabhuGKShakyaAKGillHS. Microneedles coated with cow’s milk proteins: immunogenicity, stability, and safety assessment. Mol Pharmaceutics. (2025) 22(6):2858–67. 10.1021/acs.molpharmaceut.4c0113640366634YunHJOhEYKimHKimDJKimSHShinYTransdermal allergen-specific immunotherapy using a biodegradable microneedle array patch in a murine model of peanut anaphylaxis. Allergy Asthma Immunol Res (2025) 17(5):640–57. 10.4168/aair.2025.17.5.64041044837FengYChangSJingZJiangHLiuYQinG. Transdermal delivery of sinapine thiocyanate by gelatin microspheres and hyaluronic acid microneedles for allergic asthma in Guinea pigs. Int J Pharm (2022) 623:121899. 10.1016/j.ijpharm.2022.12189935710072LiangLHwangA-RGuonTEParkKHParkCOLeeJ-HMicroarray patch based transdermal allergen immunotherapy prevents gliadin-induced anaphylaxis in a murine model. Allergy Asthma Immunol Res (2025) 17(3):330–48. 10.4168/aair.2025.17.3.33040414810WangZLuXWuLJiangXWangWWangY. Co-delivery of targeted hypoallergens and resiquimod powders using silk fibroin microneedles for effective allergen-specific immunotherapy. Theranostics (2025) 15(16):8096–116. 10.7150/thno.11415240860158ZhaoJHePJiangMHeCZhaoYZhangZTransdermally delivered tolerogenic nanoparticles induced effective immune tolerance for asthma treatment. J Controlled Release (2024) 366:637–49. 10.1016/j.jconrel.2024.01.01838215983KimJHShinJUKimSHNohJYKimHRLeeJSuccessful transdermal allergen delivery and allergen-specific immunotherapy using biodegradable microneedle patches. Biomaterials (2018) 150:38–48. 10.1016/j.biomaterials.2017.10.01329032329EMSAM® (selegiline transdermal system). (2006). Available online at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021336s005s010,021708s000lbl.pdf (Accessed December 9, 2025).Orange book: approved drug products with therapeutic equivalence evaluations. (2025).KaminskyBMBostwickJRGuthrieSK. Alternate routes of administration of antidepressant and antipsychotic medications. Ann Pharmacother (2015) 49(7):808–17. 10.1177/106002801558389325907529KochharJSLimWXSZouSFooWYPanJKangL. Microneedle integrated transdermal patch for fast onset and sustained delivery of lidocaine. Mol Pharmaceutics (2013) 10(11):4272–80. 10.1021/mp400359w24044683CheungKDasDB. Microneedles for drug delivery: trends and progress. Drug Deliv (2016) 23(7):2338–54. 10.3109/10717544.2014.98630925533874TrölsAHintermüllerMASaeedipourMPirkerSJakobyB. Drug dosage for microneedle-based transdermal drug delivery systems utilizing evaporation-induced droplet transport. Microfluidics and Nanofluidics (2019) 23(7):91. 10.1007/s10404-019-2257-3WaghuleTSinghviGDubeySKPandeyMMGuptaGSinghMMicroneedles: a smart approach and increasing potential for transdermal drug delivery system. Biomed and Pharmacother (2019) 109:1249–58. 10.1016/j.biopha.2018.10.07830551375BariyaSHGohelMCMehtaTASharmaOP. Microneedles: an emerging transdermal drug delivery system. J Pharm Pharmacol (2012) 64(1):11–29. 10.1111/j.2042-7158.2011.01369.x22150668ZhangYXuYKongHZhangJChanHFWangJMicroneedle system for tissue engineering and regenerative medicine. Exploration (2023) 3(1):20210170. 10.1002/EXP.2021017037323624VoraLKMoffattKTekkoIAParedesAJVolpe-ZanuttoFMishraDMicroneedle array systems for long-acting drug delivery. Eur J Pharmaceutics Biopharmaceutics (2021) 159:44–76. 10.1016/j.ejpb.2020.12.00633359666OgunjimiATFiegelJBrogdenNK. Design and characterization of spray-dried chitosan-naltrexone microspheres for microneedle-assisted transdermal delivery. Pharmaceutics (2020) 12(6). 10.3390/pharmaceutics1206049632485999PatelKKBrogdenNK. Impact of formulation and microneedle length on transdermal metronidazole permeation through microneedle-treated skin. Pharm Res (2024) 41(2):355–63. 10.1007/s11095-023-03640-838133717TobinKVBrogdenNK. Thermosensitive biomaterial gels with chemical permeation enhancers for enhanced microneedle delivery of naltrexone for managing opioid and alcohol dependency. Biomater Sci (2023) 11(17):5846–58. 10.1039/d3bm00972f37455601
Edited by:Adina Eichner, Martin Luther University of Halle-Wittenberg, Germany