Development of a melt-cast microneedle patch for sustained drug release of islatravir

Abstract

Low adherence to daily oral drug regimens is a significant obstacle in effectively managing chronic therapies like HIV treatment, pre-exposure prophylaxis (PrEP), and contraception. While long-acting injectables eliminate the need for daily compliance, they often require administration by healthcare professionals. To facilitate self-administration of long-acting treatments, we developed a microneedle patch (MNP) for the sustained release of islatravir or levonorgestrel, used for HIV treatment/PrEP or contraception, respectively. The MNPs were produced using a melt-casting technique to quickly create biodegradable polycaprolactone microneedles for continuous drug delivery. The low melting point of polycaprolactone and the high thermal stability of islatravir and levonorgestrel allowed melt casting at 65 °C. Incorporating centrifugation during fabrication improved the attachment of microneedles to the patch backing, making it easier to remove MNPs from the mold and ensuring effective microneedle insertion into skin. The MNPs demonstrated a sustained release of islatravir with roughly first-order release kinetics for ∼40 days in vitro. We conclude that MNPs made with a simple melt-casting process can enable prolonged drug release for HIV treatment/PrEP, contraception, and other therapeutic applications.

Introduction

Adherence to daily drug therapy regimens remains a significant challenge in managing chronic conditions, such as HIV treatment as well as prevention approaches, e.g. pre-exposure prophylaxis (PrEP) for HIV and once-daily oral contraceptives. Research shows that adherence to daily oral medications is often poor1,2, leading to lower treatment effectiveness and a higher risk of, for example, HIV transmission3–5 and unintended pregnancies.6 While oral PrEP can reduce HIV risk by up to 99% when taken as prescribed, adherence rates are usually much lower, leading to significantly decreased protection.7 Likewise, daily oral contraceptives are the most popular method of contraception, but 50% of women report missing at least one pill a month, and 22% miss two or more doses per month.6 Oral contraceptives can be 99.7% effective when taken correctly, but effectiveness drops to 91% or less in real-world use; poor adherence is believed to be the main reason for unintended pregnancies among women using oral contraceptives.6

To address low adherence, long-acting drug delivery approaches have been explored for HIV PrEP, contraceptives, and for other chronic conditions. For example, long-acting injectable forms of cabotegravir and lenacapavir received FDA approval for HIV PrEP and have demonstrated superior adherence and efficacy compared to daily oral regimens.8–10 Islatravir (ISL, also known as EFdA and MK-8591) is a nucleoside reverse transcriptase translocation inhibitor that has been investigated for PrEP using both oral and subcutaneous formulations.11–13 In the field of contraception, long-acting reversible contraceptives such as intrauterine devices and contraceptive implants are among the most effective methods, with failure rates below 1% and no need for daily compliance.14 The progestin levonorgestrel (LNG) is the most commonly used contraceptive hormone found in long-acting delivery systems.15 These examples highlight the promise of sustained-release formulations in improving patient outcomes by minimizing reliance on user adherence. However, these long-acting approaches require administration by trained personnel, thus limiting patient access.

To improve access to long-acting medicines, this study introduces a self-administerable microneedle patch (MNP) for sustained drug release. Microneedles (MNs) are micron-scale, needle-like projections that penetrate the skin’s surface to deliver drugs in a minimally invasive way.16,17 MNPs have been demonstrated to deliver a variety of drugs,17,18 including LNG,19,20 as well as vaccines.21,22 Biodegradable MNs are particularly interesting because they can provide controlled, sustained drug release. These MNs are usually made from biodegradable polymers such as polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA) that degrade inside the body through hydrolysis while releasing their payload, eliminating the need for removal.23 Their capacity to encapsulate diverse drugs makes them especially suitable for HIV PrEP, contraceptives, and other therapeutics24 which are hydrophobic and have low daily dosing requirements.

Current fabrication of biodegradable polymer MNs typically involves casting an organic solvent solution containing the polymer and drug of interest into a MN mold followed by slow drying.19,25,26 Although this method has been effective in producing MNs, its use of organic solvents results in prolonged drying times for solvent evaporation, which increase manufacturing costs.27 Moreover, because the MNs are generally designed to separate from the MNP backing upon skin insertion, it is crucial that the biodegradable polymer formulation remain confined to the MNs and does not extend into the backing, ensuring proper needle detachment in the skin and avoiding additional manufacturing complexity.28,29

To overcome these limitations, we present a new melt-based fabrication approach that avoids the need for organic solvents during MNP molding and decreases fabrication processing time. We produced a moderate-temperature melt of polycaprolactone (PCL) containing ISL or levonorgestrel as model drugs, which solidified in the cavities of MNP molds upon cooling to form biodegradable MNPs. After applying a water-soluble backing to complete the MNP, we then assessed their mechanical strength by insertion into pig skin ex vivo and determined their kinetics of drug release through in vitro release testing. By removing organic solvents from the MNP fabrication process, our melting approach could enhance the clinical and commercial viability of MN-based systems for long-acting HIV treatment/PrEP, contraception and other sustained-release applications.

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Materials

SYLGARD 184 Silicone Elastomer Kit was obtained from Dow (Midland, MI). PCL-2 (Purasorb PC-02, inherent viscosity of 0.20–0.26 dL/g) and PCL-4 (Purasorb PC-04, inherent viscosity of 0.35–0.43 dL/g) were obtained from Corbion (Amsterdam, Netherlands). Polyvinyl alcohol (PVA, 4-88), polyvinylpyrrolidone (PVP), sucrose, chloroform, tetrahydrofuran (THF) and Nile Red were obtained from Sigma-Aldrich (St. Louis, MO). Levonorgestrel (LNG) was obtained from (Chemo Industriale Chimica S.R.L, Saronno, Italy). ISL was purchased from YUNBIO Tech (Beijing, China) with purity > 98%. Isotope-labeled ISL ([13C,15N3]-ISL) was purchased from Alsachim (Illkirch Graffenstaden, France).

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