Intradermal delivery of the antiretroviral drugs cabotegravir and rilpivirine by dissolving microarray patches: Investigation of lymphatic uptake

The lymphatic system possesses the main viral replication sites in the body following viral infection. Unfortunately, current antiretroviral agents penetrate the lymph nodes insufficiently when administered orally and, therefore, cannot access the lymphatic system sufficiently to interrupt this viral replication. For this reason, novel drug delivery systems aimed at enhancing the lymphatic uptake of antiretroviral drugs are highly desirable. Dissolving polymeric microarray patches (MAPs) may help to target the lymph intradermally. MAPs are intradermal drug delivery systems used to deliver many types of compounds.

The present work describes a novel work investigating the lymphatic uptake of two anti-HIV drugs: cabotegravir (CAB) and rilpivirine (RPV) when delivered intradermally using dissolving MAPs containing nanocrystals of both drugs. Maps were formulated using NCs obtained by solvent-free milling technique. The polymers used to prepare the NCs of both drugs were PVA 10 Kda and PVP 58 Kda. Both NCs were submitted to the lyophilization process and reconstituted with deionized water to form the first layer of drug casting. Backing layers were developed for short application times and effective skin deposition. In vivo biodistribution profiles of RPV and CAB after MAP skin application were investigated and compared with the commercial intramuscular injection using rats.

After a single application of RPV MAPs, a higher concentration of RPV was delivered to the axillary lymph nodes (AL) (Cmax 2466 ng/g – Tmax 3 days) when compared with RPV IM injection (18 ng/g – Tmax 1 day), while CAB MAPs delivered slightly lower amounts of drug to the AL (5808 ng/g in 3 days) when compared with CAB IM injection (9225 ng/g in 10 days). However, CAB MAPs delivered 7726 ng/g (Tmax 7 days) to the external lumbar lymph nodes, which was statistically equivalent to IM delivery (Cmax 8282 ng/g – Tmax 7 days). This work provides strong evidence that MAPs were able to enhance the delivery of CAB and RPV to the lymphatic system compared to the IM delivery route.

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Materials

PV free-base powder and RPV long-acting nanosuspensions (LA NS) (300 mg/mL) were supplied by Janssen Pharmaceutica, Beerse, Belgium. CAB free acid CAB LA NS (200 mg/mL) were kindly supplied by ViiV Healthcare Ltd., Brentford, UK. Parafilm M™ laboratory film was provided by Bemis Company Inc., Soignies, Belgium. Poly (lactic acid) (PLA) (Ultimaker, Geldermalsen, Netherlands). Poly(vinyl pyrrolidone) (PVP) (MW 58 kDa) was sold under the product brand name Plasdone TM K-29/32 (Ashland, Kidderminster, UK). HPLC grade acetonitrile, phosphate buffered saline (PBS) tablets, poly (vinyl alcohol) (PVA) (MW 31–50 kDa, 80% hydrolyzed), and PVA (MW) 9–10 kDa were purchased from Sigma–Aldrich, St. Louis, MO, USA. Tegaderm™ and Microfoam™ surgical tape (3 M, Bracknell, UK). Trifluoroacetic acid (TFA), reagent grade, > 99% (Honeywell, Seelze, Germany). Veet® sensitive skin hair removal cream (Reckitt Benckiser Group, Slough, England). Water for injections was 100% (w/v) in 10 mL ampoules (Hameln Pharmaceuticals Ltd., Gloucester, UK). Heparin sodium flushing solution 100 I.U./mL (200 units in 2 mL) (Wochhardt UK Ltd., Wrexham, UK). Isoflurane (Abbott Laboratories, Illinois, US). Kinesiology Sports tape (95% cotton, 5% spandex, 5 × 500 cm) (Proworks Corporation, Corvallis, USA). Liquid silicone rubber (DDR-4320) was obtained from Nusil Technology (Buckinghamshire, UK). Ultrapure water was obtained using a water purification system from Elga PURELAB DV 25, Veolia Water Systems, Dublin, Ireland.

Inken K. Ramöller, Fabiana Volpe-Zanutto, Lalitkumar K. Vora, Marco T.A. Abbate, Aaron R.J. Hutton, Peter E. McKenna, Ke Peng, Ismaiel A. Tekko, Akmal Sabri, Emma McAlister, Helen O. McCarthy, Alejandro J. Paredes, Ryan F. Donnelly, Intradermal delivery of the antiretroviral drugs cabotegravir and rilpivirine by dissolving microarray patches: Investigation of lymphatic uptake, Journal of Controlled Release, Volume 366, 2024, Pages 548-566, ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2024.01.010.

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