(M1130-07-40) Bilayer Microneedle Array Patch for Transdermal Delivery of Novel Capsid Inhibitor Lenacapavir to Mitigate the Risk of Pediatric HIV Infection

Purpose: HIV continues being a significant health threat with about 4% of children under the age of 15 living with HIV, globally. These children also account for 10% of new infections and almost 13% of AIDS related mortality (1). With children under the age of 1 year being the most vulnerable, critical therapeutic intervention is essential. Improved accessibility to treatment for achieving long term compliance is desired and minimally invasive microneedle array patches (MAPs) are a promising approach in this direction (2). HIV-1 capsid inhibitor lenacapavir (LEN) is currently approved for treatment of multidrug-resistant HIV in combination with other ARVs as a long-acting subcutaneous injection every 6 months with oral maintenance dose. This project aimed to develop two innovative formulations for transdermal delivery of LEN for addressing unique needs of pediatric patients. Coarse drug incorporation into a polymer matrix to localize LEN into the needle tips was our first strategy. Further, to evaluate the impact of particle size and engineering, nanosuspension (NS) of LEN was formulated and incorporated into MAPs. The dual formulation strategies were designed to explore the delivery efficiency of LEN with an aim to achieve an age-appropriate long-acting HIV therapy for pediatrics.

Methods: For coarse drug loaded MAPs, LEN was first subjected to bead milling process using a TissueLyser in a polymer matrix containing poly(vinyl alcohol) (PVA) (M.W. 10,000) and poly(vinylpyrrolidone) (PVP) (K29-32). This facilitated homogenization of the highly hydrophobic LEN prior to loading into MAPs. LEN NS was prepared using wet media milling technique with temperature-controlled milling chamber for 24 hr. A polymeric blend of PVA-PVP was used as a stabilizer with an aqueous dispersion medium. Formed NS were evaluated for particle size and zeta potential and further subjected to lyophilization. LEN coarse drug mixture and LEN NS were formulated into dissolving MAP systems using aqueous blend of PVA (M.W. 10,000) - PVP (K29-32). Laser engineered MAP silicone moulds (needle array - 16 X 16; 850 µm length, 600 µm pyramidal lower tips and 250 µm cuboidal upper tips) were used. Both formulations were loaded into the pyramidal tips using a positive pressure of 5 bar for 3 min followed by removal of excess mixture from surface, and a subsequent 5 bar pressure cycle for 30 min. After drying for 24 hr, a drug-free polymeric blend of PVA (M.W. 50,000) - PVP (K29-32) was cast as the baseplate using centrifugation and allowed to dry for 48 hr. Resultant bilayer MAPs were characterized for drug content and mechanical strength. The insertion properties of LEN MAPs were evaluated using the Parafilm M^® layer model (3). Intradermal deposition of LEN was measured in full thickness neonatal porcine skin using Franz cell apparatus and analysed via a validated HPLC method. Pharmacokinetic profile of LEN coarse drug formulation was monitored in Sprague Dawley rats over a period of 35 days with a dose of 1.8 mg LEN administered per rat.

Results: The results for LEN coarse drug loaded MAPs revealed a high and consistent loading of 1884 ± 172 μg/patch of 0.5 cm². The MAPs were mechanically strong and able to withstand an insertion force of 32 N against a metal block and penetrate up to fourth layer of Parafilm M^®, equivalent to 504 μm of insertion depth. In the ex vivo skin deposition study using Franz cells, 558 μg LEN was deposited into the full thickness neonatal porcine skin, measuring a delivery efficiency of 29.65%. The optimized NS showed an average particle size of 389.36 ± 80.98 nm with a polydispersity index of 0.23 ± 0.05 and the zeta potential as -7.70 ± 2.72 mV. Impact of milling on LEN properties assessed via x-ray diffraction did not show any significant change pre- and post-milling. The drug content of the MAPs formulated using this nanosuspension was 1430.18 ± 40.63 μg/patch of 0.5 cm², and in ex vivo studies, skin deposition was found to be 268.93 μg, equivalent to a delivery efficiency of 18.80%. The data obtained indicated that drug loading and skin deposition potential of LEN coarse drug loaded MAPs was superior to the NS loaded MAPs. Acknowledging these findings, the LEN coarse drug loaded MAPs were subjected to in vivo pharmacokinetic evaluations and a sustained release of LEN was observed with approximately 16.9% delivery efficiency following single application.

Conclusion: The present work highlights two particle engineering techniques and their impact on delivery of a hydrophobic molecule. LEN coarse drug loading into MAPs facilitated better delivery efficiency ex vivo and further achieved a sustained release profile in vivo. Considering the vital nature of pediatric HIV, long-acting MAPs would aid in in the treatment of HIV infection in all relevant age groups. The formulation approaches in this research showcase innumerable possibilities for exploration in minimally invasive pediatric HIV therapy.

References: 1. UNAIDS - Global Report 2023. Available from: https://thepath.unaids.org
2. 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.
3. Larrañeta, Eneko, et al. "A proposed model membrane and test method for microneedle insertion studies." International journal of pharmaceutics 472.1-2 (2014): 65-73.

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: (A) LEN MAP manufacturing process showcasing different formulation steps and representative microscopic images of LEN MAP from side and top views, (B) Particle size and zeta potential measurements for developed LEN NS (mean ± SD, n=3), (C) LEN skin deposition in neonatal porcine skin over a period of 24 hr in Franz cell apparatus comparing the performance of LEN NS loaded MAPs versus LEN coarse drug loaded MAPs (mean ± SD, n=6), (D) Pharmacokinetic profile of LEN coarse drug loaded MAPs 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).