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

Abstract

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.

Keywords: AIDS, acquired immune deficiency syndrome; CAB, cabotegravir; HIV, human immunodeficiency virus; MAP, microarray patch; RPV, rilpivirine.

Fig. 1

Diagrammatic representation of fabrication process of pyramidal 19 × 19 ARV MAPs, displaying (a) fabrication process of 19 × 19 RPV MAPs and (b) 19 × 19 CAB MAPs.

Fig. 2

Diagrammatic representation of fabrication process of bilayer 16 × 16 ARV MAPs.

Fig. 3

Schematic representations of the rat cohorts in the in vivo delivery of RPV and CAB. (a) MAP-mediated ID delivery cohort of four MAP arrays was used, with blue squares representative of RPV MAPs and red squares representative of CAB MAPs. (b) In the first control cohort, rats received an IM injection of RPV LA into the right thigh and IM injection of CAB LA into the left thigh. (c) Similarly, in the second control cohort, rats received an ID injection of RPV LA into the right-hand side and an ID injection of CAB LA into the left-hand side of their backs.

Fig. 4

(a) ATR-FTIR spectra of RPV and NS excipients. (b) DSC thermograms of RPV and NS excipients. (c) P-XRD diffractograms of RPV and NS excipients. (d) In vitro release profiles of RPV in PBS (pH 7.4) / methanol (20/80% v/v) from bulk RPV and lyophilised RPV NS; p ≤ 0.033 (*), ≤ 0.002 (**), < 0.001 (***). (e, f) Evaluation of short-term stability of lyophilised RPV NS stored at room temperature (19°C) and protected from light, showing (e) mean particle size (d.nm) and (f) concentration (mg/mL) of RPV. (Means ± SD, n = 3).

Fig. 5

Comparison of the mean particle sizes of (a) novel lyophilised RPV NS, (b) concentration-enhanced CAB LA NS, and (c) RPV LA NS, to mean particle sizes of the NS following reconstitution of the MAP in deionised water. Reconstituted ARV MAPs representative of final ARV MAP formulations in each case.

Fig. 6

Light microscope images of optimised formulations representative of RPV 1.2 19 × 19 RPV MAPs (a, b), CAB 1.6 19 × 19 CAB MAPs (c, d). SEM images of 19 × 19 RPV MAPS (e) and 19 × 19 CAB MAPs (f) representative of the same optimised 19 × 19 formulations. Light microscope images of optimised formulations representative of RPV 2.3 16 × 16 RPV MAPs (g, h), CAB 2.2 16 × 16 CAB MAPs (i, j). SEM images of 16 × 16 RPV MAPS (k) and 16 × 16 CAB MAPs (l) representative of the same optimised 16 × 16 formulations.

Fig. 7

(a, b) Comparison of percentage height reduction of ARV MAPs following compression of 32 N/array, for (a) 19 × 19 and 16 × 16 RPV MAPs and (b) 19 × 19 and 16 × 16 CAB MAPs. (Means + SD, n = 5). (c, d) Percentage of holes created in Parafilm® M layers by ARV MAPs following an insertion force of 32 N/array, for (c) 19 × 19 and 16 × 16 RPV MAPs and (d) 19 × 19 and 16 × 16 CAB MAPs. (Means + SD, n = 3).

Fig. 8

Light microscope images of excised neonatal porcine skin following insertion and removal of dissolving ARV MAPs. Displaying implantation of MAP tips in the skin for (a) 19 × 19 RPV MAP, (b) 19 × 19 CAB MAP, (c) 16 × 16 RPV MAP, and (d) 16 × 16 CAB MAP (t = 24 h).

Fig. 9

Concentration of (a) RPV and (b) CAB in full-thickness excised neonatal porcine skin following application of 19 × 19 and 16 × 16 MAPs inserted for three different durations (1, 5, and 24 h) and a needle-free patch as a control. RPV and CAB concentrations in excised neonatal porcine skin were determined at the respective time points and expressed as μg/cm³. This experiment was conducted under temperature control at 33°C (means ± SD, n = 3).

Fig. 10

(a, b) The mean plasma concentrations and pharmacokinetic profiles of (a) RPV and (b) CAB in Sprague–Dawley rats following a single-dose application (means + SD, n = 6). (c, d) The mean plasma concentrations and pharmacokinetic profiles of (c) RPV and (d) CAB in Sprague–Dawley rats following administration of LA NS as an IM loading dose, followed by two repeated dissolving 16 × 16 MAP dose applications at 14-d intervals (cohort 1), or a dissolving 16 × 16 MAP loading dose, followed by two repeated dissolving 16 × 16 MAP dose applications at 14-d intervals only (cohort 2) (means + SD, n = 3 at 1 h, 5 h; n = 6 at all other sampling time points). (a–d) The IC₉₀ (12 ng/mL) for RPV and 4xIC₉₀ (664 ng/mL) for CAB is highlighted by the dashed black line. (e) Digital image displaying the dissolving 16 × 16 RPV MAP tips still implanted within the back of the rat’s skin two weeks following MAP application and removal (representative of t = 14 d).