Atorvastatin-Loaded Dissolving Microarray Patches for Long-Acting Microdepot Delivery: Comparison of Nanoparticle and Microparticle Drug Formulations

Abstract

The increasing popularity of prolonged-release dosage forms, owing to their ability to provide continuous drug release after administration, has significantly improved patient compliance and overall quality of life. However, achieving prolonged release beyond 24 h frequently requires the use of invasive methods, including injections or implants, which may prove challenging for people suffering from needle phobia. This study introduces atorvastatin (ATR) microparticles (MPs) or nanocrystal (NCs) dissolving microarray patches (D-MAPs) as a noninvasive alternative for intradermal drug delivery over a two-week period for the management of hyperlipidemia. The MP-loaded D-MAPs exhibited an average drug loading of 5.15 ± 0.4 mg of ATR per patch, surpassing the 2.4 ± 0.11 mg/patch observed with NC-loaded D-MAPs. Skin deposition studies demonstrated the superior performance of MP D-MAPs, which delivered 2.0 ± 0.33 mg of ATR per 0.75 cm² patch within 24 h, representing 38.76% of the initial amount of drug loaded. In contrast, NC D-MAPs delivered approximately 0.89 ± 0.12 mg of ATR per 0.75 cm² patch at 24 h, equivalent to 38.42 ± 5.13% of the initial ATR loaded. Due to their favorable results, MP D-MAPs were chosen for an in vivo study using Sprague–Dawley rats. The findings demonstrated the capacity of D-MAPs to deliver and attain therapeutically relevant ATR concentrations (>20 ng/mL) for 14 days after a single 24-h application. This study is the first to successfully demonstrate the long-acting transdermal delivery of ATR using MP-loaded D-MAPs after a 24-h single-dose application. The innovative D-MAP system, particularly when loaded with MP, arises as a promising, minimally invasive, long-acting substitute for ATR delivery. This technology has the potential to improve patient compliance and therapeutic outcomes while also significantly advancing the field of transdermal drug delivery.

Introduction

Based on the World Health Organization statistics in 2021, cardiovascular disease (CVD) is the leading cause of death worldwide, accounting for 32% of all global deaths in 2019. (2) Hyperlipidemia is a critical risk factor that leads to the development and progression of atherosclerotic diseases and is considered a major cause of CVD. (3) Hyperlipidemia is defined as an increase in the concentration of fasting total cholesterol in the body. (4) The risk of the development of atherosclerosis and CVD increases as the levels of total serum cholesterol or low-density lipoprotein (LDL) cholesterol increase. (5) Atorvastatin (ATR), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor for controlling hyperlipidemia, is administered orally at doses ranging from 10 to 80 mg/day to control hyperlipidemia. (5,6) As a class II drug according to the BCS classification, ATR faces challenges due to its low aqueous solubility and high permeability. (7−9) The use of particle size reduction, a common method to enhance solubility, is thereby explored in this manuscript. Reducing the particle size to micron or submicron levels is considered an efficient way to increase the drug surface area, dissolution rate, solubility, and bioavailability. (10,11) Nanocrystals (NCs) were chosen for their nanometer-sized crystalline structure, which was derived from the therapeutic agent itself and surrounded by a thin layer of stabilizer, ensuring high drug content and inherent stability. (12)

Compared to traditional methods such as oral or hypodermic injections, transdermal drug delivery (TDD) is an attractive option. (13) This is primarily because the skin is the largest and most accessible surface area in the human body. (14,15) However, the outermost skin layer, the stratum corneum (SC), poses a significant barrier to passive drug delivery. (16−18) Various techniques have been explored to overcome the SC barrier, with microarray patches (MAPs) being one of the most promising approaches. MAPs are micron-sized minimally invasive devices capable of bypassing SC to deliver drug products across the skin without causing any pain or bleeding. (19−21) Therefore, they can facilitate the transdermal and intradermal delivery of various drugs and vaccines. (15,22,23)

Dissolving microarray patches (D-MAPs), particularly, is a type of MAPs that is vastly used for transdermal drug delivery of a vast range of drugs and therapeutic agents. (13,19,24−30) Composed of dissolving biocompatible polymers, D-MAPs start to dissolve upon their insertion into the skin, thus liberating their drug content and facilitating their absorption into the dermal microcirculation. (24,31−34) This is critical for reducing the possibility of needle reinsertion errors and consequently improving their safety profile. They are regarded as self-disabling since they entirely disintegrate in the skin and do not require specialist disposal. (35)

Nanoparticles have been extensively used in the delivery of many conventional drugs, proteins, vaccines and nucleotides. (12) They can be formulated from a wide variety of materials, including sugars, lipids, degradable or nondegradable polymers, metals and organic or inorganic compounds. (36) In this study, NCs were chosen due to their high drug content, which could reach approximately 100%. (37) Additionally, they are considered to be inherently stable, with the requirement of adding small amounts of stabilizers for their production. (37) In this manuscript, NCs were prepared using a laboratory-scale wet bead-milling technique, chosen for its simplicity, directness, and reproducibility. (35)

The literature highlights the use of D-MAPs as a platform for transdermal delivery, involving microparticles, (24,26) nanoparticles (28,37−39) or a mixture of both (40) aimed at targeted drug delivery (38) or prolonged effects. (24) D-MAPs are typically made from cost-effective polymers with excellent safety profiles. D-MAPs in this work were fabricated using low-molecular-weight PVA (9–10 kDa) and PVP (58 kDa). This research marks the first successful application of D-MAPs for the efficient and sustained transdermal delivery of the hydrophobic drug atorvastatin (ATR). In an in vivo study utilizing Sprague–Dawley rats, this system demonstrated its versatility by achieving extended delivery of hydrophobic ATR over a 2-week period, with only a single application lasting 24 h. This innovative approach holds promise as a minimally invasive, long-acting alternative for ATR delivery, potentially improving patient adherence to treatment plans and consequently enhancing therapeutic outcomes and overall quality of life.

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Materials

Atorvastatin hemicalcium trihydrate was obtained from Cangzhou Enke Pharma-tech Co., Limited, Hebei Province, China. Poly(vinylpyrrolidone) (PVP), with a MW of 58 kDa, sold under the product brand name Plasdone K-29/32 was acquired from Ashland, Kidderminster, UK. Poly(vinyl) alcohol (PVA), MW 9,000–10,000, methanol, and acetonitrile for high-performance liquid chromatography (HPLC), phosphate-buffered saline (PBS) pH 7.4 tablets, and sodium lauryl sulfate (SLS) were all purchased from Sigma–Aldrich, Dorset, UK. All other chemicals and compounds used were of analytical reagent grade.

Lalitkumar K. Vora, Ismaiel A. Tekko, Ke Peng, Fabiana Volpe-Zanutto, Brett Greer, Alejandro Paredes, Helen O. McCarthy, Ryan F. Donnelly, Atorvastatin-Loaded Dissolving Microarray Patches for Long-ActingMicrodepot Delivery: Comparison of Nanoparticle and MicroparticleDrug Formulations, ACS Applied Materials & Interfaces, https://pubs.acs.org/doi/full/10.1021/acsami.4c05517