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

Inken K. Ramöller; Fabiana Volpe-Zanutto; Lalitkumar K. Vora; Marco Abbate; Aaron Hutton; Peter E. McKenna; Ke Peng; Ismaiel A. Tekko; Akmal Sabri; Emma McAlister; Helen McCarthy; Alejandro J. Paredes; Ryan F. Donnelly

doi:10.1016/j.jconrel.2024.01.010

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

Inken K. Ramöller
, Fabiana Volpe-Zanutto
, Lalitkumar K. Vora
, Marco Abbate
, Aaron Hutton
, Peter E. McKenna
, Ke Peng
, Ismaiel A. Tekko
, Akmal Sabri
, Emma McAlister
, Helen McCarthy
, Alejandro J. Paredes
, Ryan F. Donnelly

Research output: Contribution to journal › Article › peer-review

21 Citations (Scopus)

121 Downloads (Pure)

Abstract

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) (C_max 2466 ng/g – T_max 3 days) when compared with RPV IM injection (18 ng/g - T_max 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 (T_max 7 days) to the external lumbar lymph nodes, which was statistically equivalent to IM delivery (C_max 8282 ng/g - T_max 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.

Original language	English
Pages (from-to)	548-566
Number of pages	19
Journal	Journal of Controlled Release
Volume	366
Early online date	13 Jan 2024
DOIs	https://doi.org/10.1016/j.jconrel.2024.01.010 https://doi.org/10.1016/j.jconrel.2024.01.010
Publication status	Published (in print/issue) - 29 Feb 2024

Bibliographical note

Publisher Copyright:
© 2023

Funding

The authors would like to thank ViiV Healthcare Ltd. and Janssen Pharmaceutica for providing the nanosuspension formulations and bulk powder drugs of CAB and RPV, respectively. This project was also supported in part by EPSRC grant EP/S028919/1 and MAPs for Peds: Development of a Microarray Patch for Delivery of Long-Acting Antiretrovirals for Treatment of Pediatric HIV Infection was 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 number 1R61AI149642-01. The authors would like to thank ViiV Healthcare Ltd. and Janssen Pharmaceutica for providing the nanosuspension formulations and bulk powder drugs of CAB and RPV, respectively. This project was also supported in part by EPSRC grant EP/S028919/1 and MAPs for Peds: Development of a Microarray Patch for Delivery of Long-Acting Antiretrovirals for Treatment of Pediatric HIV Infection was 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 number 1R61AI149642-01.

Funders	Funder number
1R61AI149642-01
Engineering and Physical Sciences Research Council	EP/S028919/1

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Antiretroviral
Cabotegravir
HIV
Intradermal delivery
Lymph-targeted
Lymphatic distribution
Nanocrystals
PrEP
Rilpivirine

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1-s2.0-S0168365924000142-mainFinal published version, 7.32 MBLicence: CC BY

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Ramöller, I. K., Volpe-Zanutto, F., Vora, L. K., Abbate, M., Hutton, A., McKenna, P. E., Peng, K., Tekko, I. A., Sabri, A., McAlister, E., McCarthy, H., Paredes, A. J., & Donnelly, R. F. (2024). Intradermal delivery of the antiretroviral drugs cabotegravir and rilpivirine by dissolving microarray patches: investigation of lymphatic uptake. Journal of Controlled Release, 366, 548-566. https://doi.org/10.1016/j.jconrel.2024.01.010, https://doi.org/10.1016/j.jconrel.2024.01.010

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title = "Intradermal delivery of the antiretroviral drugs cabotegravir and rilpivirine by dissolving microarray patches: investigation of lymphatic uptake",

abstract = "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. ",

keywords = "Antiretroviral, Cabotegravir, HIV, Intradermal delivery, Lymph-targeted, Lymphatic distribution, Nanocrystals, PrEP, Rilpivirine",

author = "Ram{\"o}ller, \{Inken K.\} and Fabiana Volpe-Zanutto and Vora, \{Lalitkumar K.\} and Marco Abbate and Aaron Hutton and McKenna, \{Peter E.\} and Ke Peng and Tekko, \{Ismaiel A.\} and Akmal Sabri and Emma McAlister and Helen McCarthy and Paredes, \{Alejandro J.\} and Donnelly, \{Ryan F.\}",

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2024",

month = feb,

day = "29",

doi = "10.1016/j.jconrel.2024.01.010",

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Ramöller, IK, Volpe-Zanutto, F, Vora, LK, Abbate, M, Hutton, A, McKenna, PE, Peng, K, Tekko, IA, Sabri, A, McAlister, E, McCarthy, H, Paredes, AJ & Donnelly, RF 2024, 'Intradermal delivery of the antiretroviral drugs cabotegravir and rilpivirine by dissolving microarray patches: investigation of lymphatic uptake', Journal of Controlled Release, vol. 366, pp. 548-566. https://doi.org/10.1016/j.jconrel.2024.01.010, https://doi.org/10.1016/j.jconrel.2024.01.010

TY - JOUR

T1 - Intradermal delivery of the antiretroviral drugs cabotegravir and rilpivirine by dissolving microarray patches: investigation of lymphatic uptake

AU - Ramöller, Inken K.

AU - Volpe-Zanutto, Fabiana

AU - Vora, Lalitkumar K.

AU - Abbate, Marco

AU - Hutton, Aaron

AU - McKenna, Peter E.

AU - Peng, Ke

AU - Tekko, Ismaiel A.

AU - Sabri, Akmal

AU - McAlister, Emma

AU - McCarthy, Helen

AU - Paredes, Alejandro J.

AU - Donnelly, Ryan F.

PY - 2024/2/29

Y1 - 2024/2/29

N2 - 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.

AB - 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.

KW - Antiretroviral

KW - Cabotegravir

KW - HIV

KW - Intradermal delivery

KW - Lymph-targeted

KW - Lymphatic distribution

KW - Nanocrystals

KW - PrEP

KW - Rilpivirine

UR - https://pure.qub.ac.uk/en/publications/91806b72-497a-4d8e-b0d2-43e2bb7c95eb

UR - https://www.scopus.com/pages/publications/85182506494

U2 - 10.1016/j.jconrel.2024.01.010

DO - 10.1016/j.jconrel.2024.01.010

M3 - Article

C2 - 38211640

SN - 0168-3659

VL - 366

SP - 548

EP - 566

JO - Journal of Controlled Release

JF - Journal of Controlled Release

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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