Aceclofenac Delivery through Polymeric Nanoparticles loaded with Transdermal Hydrogel against Rheumatoid Arthritis

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory condition characterized by persistent joint inflammation, discomfort, and gradual deterioration of cartilage and bone [1]. RA affects around 0.46% to 1% of the worldwide population, with a higher prevalence among women and persons residing in industrialized nations 2, 3. Traditional therapies, such as nonsteroidal anti-inflammatory medications (NSAIDs) are prescribed for their analgesic and anti-inflammatory action. Still, they can cause adverse effects such as gastrointestinal problems and inconsistent drug concentrations leading to reduced effectiveness over time [4]. In RA, the molecular pathology is primarily driven by an overactive immune response that targets the synovial membrane leading to chronic inflammation. Pro-inflammatory cytokines mediators, including interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and prostaglandins play a pivotal role in perpetuating inflammation, synovial hyperplasia and joint destruction 5, 6. These inflammatory mediators cause the infiltration of immune cells into the joint space, eventually leading to cartilage degradation and bone erosion [7].

Aceclofenac, a widely used NSAID for RA therapy, exerts its anti-inflammatory and analgesic effects by inhibiting cyclooxygenase (COX) enzymes, particularly COX-2, which in turn reduces the synthesis of prostaglandins, inhabiting cytokines mediators of pain and inflammation [8]. This prostaglandin inhibition is resultantly linked to inhibiting the production of inflammatory cytokines such as IL-6 and TNF-α that further diminishing the inflammatory response [9]. Its ability to selectively reduce inflammation while minimizing gastrointestinal side effects, which are common with other NSAIDs, makes it a favourable option for the long-term management of RA. Nanoparticle based drug delivery systems offer a favourable alternative to traditional treatments by enabling precise and targeted release of medication. NPs improve the availability of drugs, minimise adverse effects throughout the body and enhanced the therapeutic efficacy by directly transporting drug molecule at the inflamed joints. For this purpose, various nanoparticles of ACE have been reported [10]. However, polymeric NPs of ACE loaded in hydrogels have several benefits compared to alternative nanoparticle systems, including solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). Although SLNs and NLCs are successful in enhancing drug stability and providing controlled release but still they frequently encounter drawbacks such as restricted drug loading capacity and the risk of drug ejection during storage 11, 12. On the other hand, hydrogels loaded with ACE-NPs offer increased drug encapsulation efficiency, improved control over drug release kinetics, and enhanced stability [13]. Moreover, the hydrogel matrix improves the ability of substances to pass through the skin. It enables the controlled and continuous release of ACE, making it a very suitable option for transdermal uses [14]. The hydrogel ability to retain moisture enhances its biocompatibility, resulting in less skin irritation and improved patient compliance compared to SLNs and NLCs.

The ACE-NPs encapsulated hydrogel presents a potential advancement over traditional therapies and previously documented nanoparticle systems due to its multifaceted benefits. It bypasses the adverse effects linked with oral treatments and provides superior entrapment and controlled release compared to other ACE-based therapies for RA. Encapsulating ACE in polymeric nanoparticles utilizing PCL enhances stability and bioavailability, enabling sustained release and maintaining therapeutic levels for a longer duration, thus reducing the need for frequent dosing. Incorporating these nanoparticles into a hydrogel ensures uniform drug distribution and better skin adherence, enhancing hydration for patients with RA. Additionally, argan oil (AO), used to amplify permeation, disrupts the lipid structure of the stratum corneum, increasing skin permeability and promoting deeper ACE penetration to reach the underlying tissues and joints, where it exerts its anti-inflammatory effects. This study also demonstrates that polymeric NPs of ACE, using a single drug loading approach, can provide comparable safety and efficacy to more complex coloaded formulations 15, 16. By focusing solely on ACE, the formulation simplifies the drug delivery system, potentially reducing the risk of drug interactions and enhancing the predictability of therapeutic outcomes while maintaining efficacy and safety.

The current research involved formulations, optimization studies and physicochemical characterization of ACE-NPs, an in vitro drug release profile and ex vivo permeation of ACE from a transdermal hydrogel. Furthermore, the prepared carrier system was also tested in vivo model, and investigated the potential therapeutic efficacy of ACE in terms of behavioral parameters, histopathological examination and radiological analyses was assessed.

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Materials

Poly-ε-caprolactone (PCL), Pluronic F127, acetone, triethanolamine, and polyacrylic acid (Carbopol 934) were procured from Sigma Aldrich. Aceclofenac (ACE) was a gift from Global Pharmaceuticals Islamabad. Potassium dihydrogen phosphate (KH2PO4) and sodium hydroxide (NaOH) were acquired from BDH laboratory supplies to prepare phosphate buffers.

Sana Rauf, Naveed Ahmed, Syeda Komal Fatima, Dildar Khan, Abid ur Rehman, Asim.ur. Rehman, Aceclofenac Delivery through Polymeric Nanoparticles loaded with Transdermal Hydrogel against Rheumatoid Arthritis, Journal of Drug Delivery Science and Technology, 2024, 106419, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2024.106419.

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