Formulation and Comparative Evaluation of Naproxen-Based Transdermal Gels

Abstract

This research centered on creating and analyzing transdermal gel formulations containing naproxen, with the goal of offering a more tolerable and user-friendly substitute for oral NSAID therapy. Oral naproxen is often linked to gastrointestinal irritation, systemic reactions, and low compliance due to repeated dosing needs. To overcome these limitations, six unique gel compositions (F1–F6) were prepared using varying amounts of Carbopol 940 as the base polymer and two skin penetration enhancers: propylene glycol and oleic acid. The prepared gels were tested for their physical and chemical behavior, including pH level, viscosity, ease of spreading, consistency of drug content, and release rate of naproxen through synthetic membranes using a Franz diffusion setup. Among all, formulation F4, which included 15% propylene glycol, showed the best performance. It featured excellent spreadability (70 cm), a smooth application texture, skin-compatible pH (6.8), and high uniformity in drug distribution (97.5%). This formulation also allowed a prolonged release of the drug over an 8-hour period, following a release trend consistent with the Higuchi model (R² = 0.98). Moreover, it remained stable under accelerated storage conditions and dried within 3 minutes, supporting patient comfort and ease of use. To conclude, the optimized naproxen gel for transdermal application presents a practical and efficient method for delivering NSAIDs locally, combining effective pain relief with reduced side effects and better user adherence.

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed medications globally for managing pain, inflammation, and musculoskeletal disorders such as arthritis, osteoarthritis, and rheumatoid arthritis. Naproxen, a commonly used NSAID, is particularly effective due to its dual action in reducing both pain and inflammation by inhibiting cyclooxygenase (COX) enzymes responsible for prostaglandin synthesis. Despite its therapeutic benefits, the oral administration of naproxen is associated with several significant drawbacks. These include gastrointestinal complications such as ulcers, bleeding, and dyspepsia, which result from the drug’s irritant effect on the stomach lining. Additionally, systemic side effects like renal impairment and cardiovascular risks are linked to the prolonged oral use of NSAIDs. Naproxen also undergoes extensive first-pass metabolism in the liver, which reduces its bioavailability and necessitates frequent dosing—often leading to poor patient compliance [1-3].

To address these limitations, transdermal drug delivery (TDD) has emerged as a promising alternative. TDD offers several advantages over oral administration. Firstly, it bypasses the gastrointestinal tract and hepatic metabolism, thereby avoiding first-pass effects and enhancing bioavailability [4]. Secondly, it provides sustained and controlled drug release, prolonging the therapeutic effect and reducing the frequency of dosing. Thirdly, it minimizes systemic side effects by delivering the drug directly to the target site, making it more suitable for long-term use. Lastly, TDD is non-invasive and patient-friendly, improving adherence to treatment regimens. Among various transdermal formulations, gels are particularly advantageous due to their ease of application, good adhesion to the skin, enhanced drug permeation, and customizable viscosity and spreadability [5].

Figure 1: Transdermal drug delivery — **Figure 1:** Transdermal drug delivery

Figure 2: How to optimize the transdermal gel formulation — **Figure 2:** How to optimize the transdermal gel formulation

Transdermal Drug Delivery Systems (TDDS) have emerged as a transformative strategy in pharmaceutical science, offering a non-invasive alternative to oral and injectable routes. Using the skin’s extensive surface area, these systems enable the controlled release of therapeutics into systemic circulation, bypassing hepatic first-pass metabolism and gastrointestinal degradation. This method is especially beneficial for drugs like nonsteroidal anti-inflammatory drugs (NSAIDs), where sustained exposure with minimized systemic toxicity is desirable [6-7].

Naproxen, a propionic acid derivative classified as an NSAID, inhibits both COX-1 and COX-2 enzymes, thereby reducing prostaglandin synthesis responsible for pain and inflammation. It is widely prescribed for osteoarthritis, rheumatoid arthritis, and acute gout. However, long-term oral use is linked with significant adverse effects—approximately 30-50% of users develop gastrointestinal complications such as ulcers and bleeding [8]. These are attributed to both local mucosal irritation and systemic COX-1 inhibition that diminishes protective prostaglandins.

Naproxen’s pharmacokinetics, characterized by a long half-life (12-17 hours) and high plasma protein binding (~95%), also complicates dosage optimization and elevates the risk of systemic side effects.

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Table 1: Ingredient used in formulation

P.V. Purohit, P.S. Pakhar, V.B. Pawar, S.S. Dandade, M.S. Waghmare, F.A. Shaikh, R.H. Kale, Formulation and Comparative Evaluation of Naproxen-Based Transdermal Gels. J. Pharm. Sci. Comput. Chem. 2025, 1 [2], 83-105., https://doi.org/10.48309/jpscc.2025.522940.1009