(T1130-06-39) Transdermal Bilayer Microneedle Array Patches (MAP) for Pediatric HIV Therapy: Investigating Wear Time and Islatravir Delivery Efficiency

Purpose: Minimally invasive MAPs for transdermal delivery of small molecules and vaccines using self-administration approach are well explored. However, their evaluation with respect to end user acceptability needs much more consideration. Translation of MAPs from bench to bedside requires insight into time-based drug delivery aspects, especially for managing chronic diseases like HIV. Criticality of therapeutic intervention gains more significance when designing paediatric HIV therapy citing the fact that about 4% of the global population of people living with HIV are children under 15. This population includes 10% of new infections and almost 13% of AIDS related mortality (1). Alongside improving access to the treatment, it is imperative to understand the modalities of MAP wear time on the patient to assure desired drug delivery. HIV-1 nucleoside reverse transcriptase translocation inhibitor islatravir (ISL) (2) has been extensively studied for the treatment of multidrug-resistant HIV. However, citing the long half-life and active metabolite islatravir triphosphate (immediate chain terminator), ISL is being explored for its long-acting potential for HIV treatment to relieve the burden of daily pill-taking. MAPs serve as an ideal platform that can transform ARV (anti-retroviral) regimen by improving patient adherence. This project aimed to develop MAPs for transdermal delivery of ISL. To address unique needs of pediatric patients, research to evaluate MAP wear time was conducted. Coarse drug was incorporated into a polymer matrix to localize ISL into the needle tips (3) and MAPs were characterized for their physico-chemical properties. The impact of MAP wear time was studied using a series of Franz cell experiments, where, drug deposition and permeation were evaluated to understand the delivery efficiency profile at different wear times and further confirmed in vivo. Time-based strategies were devised to investigate the delivery efficiency profile at different MAP wear times to tailor an effective long-acting HIV therapy for children.

Methods: The bilayer dissolving MAPs were developed using a two-step manufacturing approach where ISL was blended with polymer matrix using a speed mixer. Poly(vinyl alcohol) (PVA) (M.W. 10,000) and poly(vinylpyrrolidone) (PVP) (K29-32) were used in this and formed the first drug containing layer. Drug blend was incorporated into laser engineered MAP silicone moulds (needle array - 16 X 16; 850 µm length, 600 µm pyramidal tips and 250 µm cuboidal base). The formulation was concentrated into the tips using a 5 bar positive pressure, initially for 3 min after which excess mix was scraped off followed by a 30 min pressure cycle and allowed to dry over 24 hr. Next, PVA (M.W. 50,000) - PVP (K29-32) drug-free baseplate layer was cast using centrifugal force for 15 min. MAPs were characterized for morphology, mechanical strength, insertion profile and drug content. Neonatal porcine full thickness skin was used to study the intradermal skin deposition and permeation over 0.5, 2 and 24 hr MAP wear times using Franz diffusion cells. This comparison can help correlate MAP performance in vivo and in clinics to design pediatric therapeutic regimen. Pharmacokinetic studies were performed in a murine model over 35 days. ISL MAPs were also evaluated for their stability for 6 months at room temperature (RT) and at 40 °C / 75% relative humidity and tested for parameters of drug content and mechanical strength.

Results: Developed ISL MAPs contained 2.6 ± 0.14 mg per patch of 0.5 cm². MAPs could withstand a force of 32N against a metal block revealing good mechanical strength and further also indicated a penetration depth of up to 504 μm in the Parafilm M^® model (3). Ex vivo studies were conducted, where MAPs were applied using thumb pressure for 30 s onto the full thickness neonatal porcine skin and then remained on the skin for 0.5, 2 and 24 hr, separately. The skin deposition following Franz diffusion cell assay was found to be 270 ± 68.05, 204 ± 55.78 and 237 ± 138 μg for 0.5, 2 and 24 hr, respectively. The delivery efficiency was observed to be 10.39 ± 2.88, 12.68 ± 2.14 and 37.21 ± 2.86 %, respectively, at these wear times. Citing that both skin deposition and permeation contribute towards delivery efficiency, the results indicated 24 hr to be the desirable wear time of MAPs with a 3-fold difference. Hence, 24 hr wear time was tested further in pharmacokinetics studies. In the pharmacokinetic studies, intramuscular administration of ISL was used as control. MAP and IM (control) groups showed a Tmax at 1 hr and Cmax of 23.6 and 390 ng/mL, respectively. Simultaneously, the stability study of MAPs indicated structural integrity of MAPs with drug content uniformity at RT conditions over 6 months.

Conclusion: This work emphasizes transdermal delivery of ARV’s using MAPs with an additional focus on identifying acceptable human pediatric MAP wear time citing their special needs. Combining the concept of long-acting MAPs with potent ARV’s can efficiently tailor treatment and advance HIV eradication efforts.

References: 1. UNAIDS - Global Report 2023. Available from: https://thepath.unaids.org
2. Anjani, Qonita Kurnia, et al. "Delivery of Islatravir via High Drug‐Load, Long‐acting Microarray Patches for the Prevention or Treatment of Human Immunodeficiency Virus." Advanced Healthcare Materials (2025): 2403615.
3. Vora, Lalitkumar K., et al. "A bilayer microarray patch (MAP) for HIV pre-exposure prophylaxis: the role of MAP designs and formulation composition in enhancing long-acting drug delivery." Pharmaceutics 16.1 (2024): 142.

Acknowledgements: MAPs for Peds: Development of a Microarray Patch for Delivery of Long-Acting Antiretrovirals for Treatment of Pediatric HIV Infection has been funded by the Eunice Kennedy Shriver National Institute of Child Health & Human Development and the National Institute of Allergy and Infectious Diseases (NIAID) under NIAID grant numbers R61AI149642 and R33AI149642.


Figure 1: ISL MAPs (A) skin deposition and (B) permeation using Franz cell apparatus with MAP wear times of 0.5, 2 and 24 hr. Skin deposition parameter represents the ISL that was quantified from the skin whereas the ISL in the receptor compartment is the permeated value, a sum of these two values is used to determine the delivery efficiency of the MAPs. (Statistics: ANOVA with Tukey’s multiple comparison test, *p < 0.1; **** p<0.0001) (C) Representative optical microscopy images of neonatal porcine skin and MAP appearance following different MAP wear times ex vivo, (D) Stability profile for structural integrity of MAPs over a period of 6 months at RT and 40 °C. (E) Pharmacokinetic profiles of MAPs in comparison with control (IM) in Sprague Dawley rats over a period of 35 days (mean ± SD with n=3 for the first day and n≥5 on subsequent days).