Novel nano-in-micro fabrication technique of diclofenac nanoparticles loaded microneedle patches for localised and systemic drug delivery

Abstract

Diclofenac, a nonsteroidal anti-inflammatory drug, is commonly prescribed for managing osteoarthritis, rheumatoid arthritis, and post-surgical pain. However, oral administration of diclofenac often leads to adverse effects. This study introduces an innovative nano-in-micro approach to create diclofenac nanoparticle-loaded microneedle patches aimed at localised, sustained pain relief, circumventing the drawbacks of oral delivery. The nanoparticles were produced via wet-milling, achieving an average size of 200 nm, and then incorporated into microneedle patches. These patches showed improved skin penetration in ex vivo tests using Franz-cell setups compared to traditional diclofenac formulations. In vivo tests on rats revealed that the nanoparticle-loaded microneedle patches allowed for quick drug uptake and prolonged release, maintaining drug levels in tissues for up to 72 h. With a systemic bioavailability of 57 %, these patches prove to be an effective means of transdermal drug delivery. This study highlights the potential of this novel microneedle delivery system in enhancing the treatment of chronic pain with reduced systemic side effects.

Highlights

• Diclofenac nanoparticles loaded microneedles target localised pain relief effectively.
• Ex vivo studies confirm enhanced skin permeation with microneedle patches.
• In vivo research demonstrates rapid absorption and 72-hour prolonged release.
• Microneedle technology outperforms traditional topical treatments.

Introduction

Osteoarthritis (OA) is a prevalent condition that primarily affects the elderly population and results in various symptoms, including pain and joint dysfunction [1,2]. It poses a considerable public health challenge globally and is often associated with obesity and aging [3]. Several nonpharmacological and pharmacological interventions are currently available to alleviate pain and improve the patient’s quality of life [4,5]. Nonpharmacological therapies include exercise and weight management, while pharmacologic treatment options include oral and topical administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular injection of corticosteroids according to the osteoarthritis research society international (OARSI) guidelines [6]. Microneedles (MN) have emerged as a promising technology for drug delivery, enabling efficient drug delivery that is painless and minimally invasive, making them an attractive alternative to traditional injections or topical formulations for both localised and systemic delivery in the treatment of OA [7,8].

Diclofenac (DCF) is one of the most studied NSAIDs in the treatment of OA [10]. Several commercial products have been practically applied including topical gel, topical solution and topical plaster. To date, the increasing number of topical DCF products introduced to the market (Olfen®, Voltaren®, Flector® etc.) is an indication of growing appeal of transdermal delivery of DCF. Nevertheless, delivering DCF via the transdermal route suffers several challenges, as the drug is intrinsically hydrophobic (log P: 4.51), which limits the amount of the drug that can be delivered across the skin through topical formulations [11]. Owing to these drawbacks, diclofenac sodium (DS), a soluble salt form, is utilized in various formulations, including topical applications, to enhance solubility and skin permeability.

In recent years, the convergence of nanoparticles and MN patches has emerged as a breakthrough in drug delivery [[12], [13], [14], [15], [16], [17], [18]]. This innovative approach addresses challenges such as the hydrophobicity and poor permeability of drugs, creating a sophisticated composite pharmaceutical platform that is capable of delivering drugs in a localised and extended manner for the management of disease [[19], [20], [21]].

Despite the growing interest in the topical delivery of DCF among scientists and the pharmaceutical industry, research into the combination of DCF nanoparticles (DCF-NPs) and MN systems currently remains limited [22]. Pireddu et al. conducted a study in which a DERMA-Q roller was used to pretreat the skin before applying DCF nanosuspensions stabilised with poloxamer-188 and Tween-80 to enhance delivery [23]. The current study fabricated DCF-NPs with satisfactory stability and a small particle size. Our MN fabrication method leverages the “nano-in-micro” strategy to encapsulate these nanoparticles within the tips of MNs, utilizing preformed PLA baseplates for improved precision and reliability (as illustrated in Fig. 1). The integration of these preformed baseplates streamlines the fabrication process, significantly reduces preparation time, and ensures consistent drug delivery and structural integrity across the MN arrays. This study also includes a comprehensive investigation to compare MNs loaded with DCF, DCF-NP and DS, with commercial Voltarol® gel as well as oral DCF administration. This investigation provides valuable insights into the transdermal delivery of DCF. It is hoped that the pharmaceutical system developed in this study offers a potential solution for delivering DCF both locally and systemically in a sustained and patient-friendly manner, thereby improving the management and treatment of OA.

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Materials

DCF and DS were purchased from Tokyo Chemical Industry (Oxford, UK). Poly(vinyl alcohol) (PVA, MW 9000–10,000) was purchased from Sigma–Aldrich (St. Louis, MO, U.S.). Plasdone™ K-29/32 (Povidone, PVP, 60 kDa) was obtained from Ashland (Wilmington, Delaware, U.S.). Phosphate buffered saline (PBS) tablets (pH 7.3–7.5) and Tween® 80 (reagent grade) were purchased from VWR Life Science (Basingstoke, UK). Acetonitrile (HPLC grade) and methanol (HPLC grade) were purchased from Sigma–Aldrich (St. Louis, MO, U.S.). All other chemicals were of analytical reagent grade. Heparin sodium flushing solution, 100 I.U./mL (200 units in 2 mL) was obtained from Wockhardt (Wrexham, UK). The depilatory cream Veet® was purchased from Reckitt (Slough, UK). Stillborn piglets were obtained from a local farm immediately after birth and stored at −20 °C until further use.

Mingshan Li, Lalitkumar K. Vora, Ke Peng, Akmal H.B. Sabri, Nuoya Qin, Marco Abbate, Alejandro J. Paredes, Helen O. McCarthy, Ryan F. Donnelly, Novel nano-in-micro fabrication technique of diclofenac nanoparticles loaded microneedle patches for localised and systemic drug delivery, Biomaterials Advances, Volume 161, 2024, 213889, ISSN 2772-9508, https://doi.org/10.1016/j.bioadv.2024.213889.

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