Enhanced long-acting simvastatin delivery via effervescent powder-carrying hollow microneedles and nanocrystal-loaded microneedles

Abstract

Hyperlipidemia and its associated cardiovascular complications are the major causes of mortality and disability worldwide. Simvastatin (SIM) is one of the most commonly prescribed lipid-lowering drugs for the treatment of hyperlipidemia by competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. However, the extensive first-pass metabolism leading to low oral bioavailability and frequent daily doses may lead to poor patient compliance and adverse effects caused by plasma fluctuations. To overcome these challenges, this work purposed two microneedle (MN) delivery strategies for the potential enhancement of SIM delivery. Firstly, nanocrystal (NC) formulations of SIM were investigated, followed by incorporation into a trilayer dissolving microneedle (DMN) design. Furthermore, a novel effervescent powder-carrying MN (EMN) design was developed to enhance intradermal delivery by incorporating the effervescent agents into the drug powder. Both MN approaches exhibited significantly improved permeation and in-skin deposition ability in the Franz cell study, with the ex vivo delivery efficiency of 64.33 ± 6.17 % and 40.11 ± 4.53 % for EMNs and DMNs, respectively. Most importantly, in vivo studies using a female Sprague-Dawley rat model confirmed the successful delivery of SIM from NCs-loaded DMNs (C_max = 287.39 ± 106.82 ng/mL) and EMNs (C_max = 203.05 ± 17.07 ng/mL) and maintain therapeutically relevant plasma concentrations for 15 days following a single application. The enhanced bioavailabilities of DMNs and EMNs were 24.28 % and 103.82 %, respectively, which were both significantly higher than that of conventional oral administration.

Introduction

Hyperlipidemia is a common medical condition affecting millions of people worldwide (Owens et al., 2014) and is characterised by elevated low-density lipoprotein (LDL), total cholesterol and triglyceride levels and reduced high-density lipoprotein (HDL) levels (Shattat, 2014). Elevated plasma lipid levels are among the prevalent risk factors associated with cardiovascular disease (CVD) (Liu et al., 2022), which is regarded as the leading cause of death and disability globally.

Simvastatin (SIM), one of the most commonly prescribed statins in commercially available pharmaceutical formulations for the treatment of hyperlipidemia, can significantly reduce the total cholesterol and LDL levels and induce a modest increase in plasma HDL levels via a competitive inhibition of HMG-CoA reductase (Belay et al., 2007, Eiland and Luttrell, 2010). SIM is a prodrug that is administered in the inactive lactone form, absorbed in the intestine and converted into the active β-hydroxy acid (SIMA) metabolite by CYP3A4 in the liver. Presently, the commercially available form of SIM is ingested orally, including via tablets and oral suspensions, with doses of 5, 10, 20, 40 and 80 mg per day. At the highest dose of 80 mg, a mean reduction in the LDL level can be achieved by 48 %. Unfortunately, SIM undergoes extensive first-pass metabolism in the intestinal gut and liver and is poorly absorbed across the gastrointestinal (GI) tract due to its extremely low water solubility (Zhang et al., 2013). Therefore, the oral bioavailability of SIM is less than 5 % (Shitara and Sugiyama, 2006). Additionally, frequent daily dosing may affect the life quality of patients and reduce compliance with medications (Parker et al., 2013, Shattat, 2014). As a result, the development of an efficient long-acting delivery system to evade first-pass metabolism and improve solubility issues is necessary.

Microneedles (MNs) are minimally invasive devices that can bypass the stratum corneum (SC) barrier, thereby allowing drug molecules to enter the microcirculation and achieve systemic delivery via intradermal routes (Larrañeta et al., 2016). Conventional MN preparations often encounter challenges related to the water solubility of drugs. SIM is an extremely hydrophobic compound with a water solubility of 6.3 μg/mL and a Log P of 4.4 (Zhang et al., 2013). This work, therefore, developed two MN delivery strategies to improve bioavailability and simplify the preparation process. First, SIM was formulated into nanocrystals (NCs) using wet media milling techniques and then, loaded into the rapidly separable trilayer dissolving MNs (DMNs). NCs are nanoparticles made of the pure drug with crystalline properties, stabilised by a thin layer of surfactant or polymer (Müller et al., 2011). Because of their large specific surface, NCs lead to an enhanced drug dissolution rate and have been used to deliver drugs via multiple administration routes (McGuckin et al., 2022). The uniform particle size distribution of the NCs enables the drug-encapsulated formulation to be homogeneously distributed at the needle tips. Upon skin insertion, the intermediate layer rapidly dissolves in the presence of interstitial fluid and deposits the needle tips beneath the skin. The water-soluble backbone matrix dissolves over time, and the NCs are subsequently released into deeper viable tissues (Vora et al., 2018). The development included a comprehensive screening of the nanoformulations as well as characterisation of the NCs loaded DMN. The other strategy is a novel effervescent powder-carrying hollow microneedle (EMN) system, which is an innovation of previous pure powder-carrying MN (PMN) strategies (He et al., 2024). To date, PMNs investigation for directly dry powder delivery included insulin (Kim et al., 2020), Bacille Calmette–Guerin (BCG) vaccines (Chen et al., 2017) and tofacitinib citrate (Cárcamo-Martínez et al., 2021), where most of them possessed high water solubility. In this work, SIM as an extremely hydrophobic drug was applied in this system, utilising effervescent agents as excipients. After application, the polymeric shell dissolve in a short time when contact with the interstitial fluid and the powder loaded inside is then deposited for release (Kim et al., 2020). Instead of loading pure drug powder, in this work, effervescent agents were introduced for the first time into the powder formulations. This design is proposed to disperse the drug powder more uniformly in the skin by the bubble generation, leading to higher contact area of drug particles with the interstitial fluid, which can potentially enhance the permeability. Moreover, the effervescence may weaken the connection of the drug-laden tips with the 3D-printed baseplate, thereby enhancing the in-skin deposition performance for the sustained release purpose. Such a drug powder filling approach can potentially simplify the MN fabrication problems caused by hydrophobic compounds and water-soluble backbone matrices. In addition, keeping the drug in a dry state may correspondingly reduce the possibility of chemical reactions, and any stability issues and activity loss during the fabrication process, therefore, can be circumvented in this way (Cárcamo-Martínez et al., 2021).

This work proposed, for the first time, the concept of enhancing the intradermal delivery of the hydrophobic compound SIM dry powder with the assistance of an effervescent agent. These included a comprehensive screening of the polymeric hollow shell and MN characterisation. Both DMNs and EMNs were subjected to ex vivo studies to evaluate drug permeation and deposition performance by comparison with their control group (crude SIM-loaded DMNs and pure SIM-loaded PMNs), and in vivo delivery performance was assessed in subsequent animal studies.

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Materials

Simvastatin was purchased from Enke Pharma-tech (Cangzhou, China). Simvastatin hydroxy acid was purchased from Biosynth® Carbosynth (Compton, UK). Acetonitrile (for HPLC, gradient grade, ≥ 99.9 %) was purchased from Sigma-Aldrich (Poole, Dorset, UK). Poly(vinyl pyrrolidone) (PVP) (MW 58 kDa, marketed as Plasdone™ k29/32) was purchased from Ashland (Kidderminster, UK). Phosphoric acid (85 %) and formic acid were purchased from Fluorochem (Derbyshire, UK). Poloxamers 188 and 407 were purchased from BASF (Geismar, LA, USA). Hydroxyethyl cellulose (HEC) (MW 250 kDa), citric acid monohydrate, sodium bicarbonate, phosphate buffered saline (PBS) (pH 7.4), carboxymethylcellulose (CMC), poly(vinyl alcohol) (PVA) (80 % hydrolysed, MW 9–10 kDa and MW 31–50 kDa) and sodium dodecyl sulfate (SDS) were purchased from Sigma-Aldrich (St. Louis, MO, USA). The full-thickness porcine skins were collected from the stillborn piglets within 24 h postmortem and stored in a freezer (−20 °C) until further usage. Female Sprague-Dawley rats were purchased from Charles River Laboratories (Harlow, UK).

Nuoya Qin, Mingshan Li, Lalitkumar K. Vora, Ke Peng, Akmal Hidayat Bin Sabri, Yushi Tao, Alejandro J. Paredes, Helen O. McCarthy, Ryan F. Donnelly, Enhanced long-acting simvastatin delivery via effervescent powder-carrying hollow microneedles and nanocrystal-loaded microneedles, International Journal of Pharmaceutics, Volume 665, 2024,
124691,ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124691.