Development of three-layer microneedle system for controlled and sustained release of Levonorgestrel: A pioneering approach to long-term contraceptive delivery

Andi Dian Permana; Anugerah Yaumil Ramadhani Aziz; Nur Rezky Aulia Ilyas; Aprilia Paramitha Dwi Putri; Juan Domìnguez-Robles; Rangga Meidianto Asri; Habibie; Muhammad Nur Amir; Nurul Fauziah; Lutfi Chabib; Muhammad Pandoman Febrian

doi:10.1016/j.ijpharm.2024.125085

Development of three-layer microneedle system for controlled and sustained release of Levonorgestrel: A pioneering approach to long-term contraceptive delivery

Int J Pharm. 2024 Dec 12:669:125085. doi: 10.1016/j.ijpharm.2024.125085. Online ahead of print.

Affiliations

¹ Department of Pharmaceutical Science and Technology, Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia. Electronic address: andi.dian.permana@farmasi.unhas.ac.id.
² Department of Pharmaceutical Science and Technology, Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia.
³ Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Seville, Seville 41012, Spain.
⁴ Department of Pharmacy, Islamic University of Indonesia, Yogyakarta 55584, Indonesia.
⁵ Catur Dakwah Crane Pharmaceuticals, Sentul Industrial Area, Bogor 16810, Indonesia.

PMID: 39674386
DOI: 10.1016/j.ijpharm.2024.125085

Abstract

The increasing prevalence of unintended pregnancies, a persistent issue affecting public health and hindering progress towards the Sustainable Development Goals (SDGs), highlights the critical need for innovative contraceptive approaches. While current methods, including hormonal contraceptives such as levonorgestrel (LNG), offer potential solutions, challenges like limited access and inconsistent use persist. This study introduces a new approach with the development of a three-layer microneedle (TIMN) containing LNG designed to provide extended contraceptive efficacy. The TIMN was formulated with varying concentrations of polyvinylpyrrolidone (PVP) and polycaprolactone (PCL) in the first layer, resulting in microneedles approximately 700 µm in height. In this study, TIMN demonstrated superior mechanical strength with less than 10% reduction in needle height under compression. The formulations maintained a surface pH within the skin's normal range, ensuring safety and compatibility, while water vapor transmission (WVT) values indicated good stability under high humidity. Moisture absorption ability (MAA) testing showed low water absorption, suggesting suitability for extended use. In vitro release studies revealed that TIMN released 28.34% of LNG after 24 h and up to 97.34% over 14 days, demonstrating controlled and sustained release. Ex vivo studies confirmed TIMN's longer-lasting LNG availability compared to the control, and in vivo pharmacokinetic studies showed that TIMN maintained therapeutic LNG levels for up to 14 days, outperforming oral LNG suspension. Biocompatibility tests, including HET-CAM and hemolysis assays, confirmed TIMN's safety, with no significant irritation or toxicity. Histopathological analysis further supported the absence of adverse reactions. The TIMN formulation, exhibits promising properties for long-term drug delivery, including mechanical strength, stability, controlled release, and biocompatibility, making it a viable candidate for improved contraceptive therapy.

Keywords: Levonorgestrel; Long-term contraception; Sustained release; Three-layers microneedle; Transdermal delivery.