Development and Evaluation of Dissolving Microarray Patches for Co-administered and Repeated Intradermal Delivery of Long-acting Rilpivirine and Cabotegravir Nanosuspensions for Paediatric HIV Antiretroviral Therapy

Purpose

Whilst significant progress has been made to defeat HIV infection, the efficacy of antiretroviral (ARV) therapy in the paediatric population is often hindered by poor adherence. Currently, two long-acting (LA) intramuscular injectable nanosuspensions of rilpivirine (RPV) and cabotegravir (CAB) are in clinical development for paediatric populations. However, administration requires access to healthcare resources, is painful, and can result in needle-stick injuries to the end user. To overcome these barriers, this proof-of-concept study was developed to evaluate the intradermal delivery of RPV LA and CAB LA via self-disabling dissolving microarray patches (MAPs).

Methods

Dissolving MAPs of two conformations, a conventional pyramidal and a bilayer design, were formulated, with various nanosuspensions of RPV and CAB incorporated within the respective MAP matrix. MAPs were mechanically robust and were capable of penetrating ex vivo skin with intradermal ARV deposition.

Results

In a single-dose in vivo study in rats, all ARV MAPs demonstrated sustained release profiles, with therapeutically relevant plasma concentrations of RPV and CAB detected to at least 63 and 28 d, respectively. In a multi-dose in vivo study, repeated MAP applications at 14-d intervals maintained therapeutically relevant plasma concentrations throughout the duration of the study.

Conclusions

These results illustrate the potential of the platform to repeatedly maintain plasma concentrations for RPV and CAB. As such, these MAPs could represent a viable option to improve adherence in the paediatric population, one that is capable of being painlessly administered in the comfort of the patient’s own home on a biweekly or less frequent basis.

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Materials

RPV free-base powder and RPV LA NS (RPV LA 300 mg/mL) were supplied by Janssen Pharmaceutica (Beerse, Belgium). CAB free acid and CAB LA NS (CAB LA 200 mg/mL) were supplied by ViiV Healthcare Ltd. (Research Triangle Park, North Carolina, United States). Poly(vinyl alcohol) (PVA) 9–10 kDa (80% hydrolysed), PVA 31–50 kDa, trifluoroacetic acid (TFA) (> 99%), and D-mannitol (> 98%) were purchased from Sigma-Aldrich (Gillingham, Dorset, United Kingdom). Poly(vinylpyrrolidone) (PVP) 58 kDa, PVP 360 kDa, were provided by Ashland (Kidderminster, United Kingdom). Dimethyl sulfoxide (DMSO) and glycerol bidistilled, AnalaR NORMAPUR® analytical reagent (99.5%) were purchased from VWR International (Leicestershire, United Kingdom). Pluronic® F-108 (PF108) was purchased from BASF SE (Ludwigshafen, Germany). Poly(lactic acid) Silver Metallic (9088) was supplied by Ultimaker (Geldemalsen, Netherlands). Acetonitrile LiChrosolv® hypergrade was purchased from Merck (Darmstadt, Germany). Ultrapure water was obtained from a water purification system, the Elga PURELAB DV-25, from Veolia Water Systems (Celbridge, Ireland). All other chemicals were of analytical reagent grade and purchased from standard industrial suppliers.

Moffatt, K., Tekko, I.A., Vora, L. et al. Development and Evaluation of Dissolving Microarray Patches for Co-administered and Repeated Intradermal Delivery of Long-acting Rilpivirine and Cabotegravir Nanosuspensions for Paediatric HIV Antiretroviral Therapy. Pharm Res (2022). https://doi.org/10.1007/s11095-022-03408-6