Abstract
Background: Nefopam hydrochloride (NPH) is a centrally acting non-opioid analgesic widely indicated for acute and chronic pain management. However, its therapeutic utility via the oral route is severely restricted by extensive hepatic first-pass metabolism, low oral bioavailability (~36%), and a short elimination half-life (~4 h) requiring frequent administration. Transdermal dissolving microneedle arrays present a minimally invasive, painless alternative that effectively circumvents hepatic degradation, improves patient compliance, and enables rapid onset with precise systemic drug delivery to overcome these pharmacokinetic limitations.
Objective: To design, fabricate, and evaluate a dissolving microneedle (DMN) patch for the transdermal delivery of Nefopam hydrochloride, offering a non-invasive, painless substitute for conventional hypodermic injections while bypassing first-pass hepatic clearance.
Method: NPH-loaded DMNs were fabricated via the solvent-casting micromolding technique using varying polymer ratios of hydroxypropyl methylcellulose (HPMC), cold water-soluble polyvinyl alcohol (PVA), and low molecular weight polyvinylpyrrolidone (PVP), combined with plasticizers (glycerin, propylene glycol, PEG 400) and Tween 80 as a release enhancer. Formulations were initially evaluated for needle morphology, drug content, axial fracture force, and in vitro drug release. The optimized formulation underwent comprehensive characterization, including surface pH, folding endurance, ex vivo skin permeation, field emission scanning electron microscopy (FE-SEM), solid-state drug–polymer compatibility, and physical stability testing.
Results: Sharp, uniform microneedles were successfully fabricated, with HPMC-dominant matrices displaying superior structural stability and mechanical resilience compared to PVA- and PVP-based formulations. The optimized formulation (F11) demonstrated excellent physicochemical attributes, including high drug content (98.25%), physiological surface pH (6.6), and minimal moisture absorbance (1.05%). Texture profile analysis confirmed high mechanical resistance, withstanding compressive forces up to 32 N across a 0 to 4 mm travel displacement and successfully penetrating skin-simulating Parafilm insertion models. In ex vivo skin permeation studies over 2 hours, the F11 DMN array dramatically reduced lag time (0.5 min vs. 8.0 min) and achieved a 63-fold enhancement in steady-state flux (0.7 mg/cm²·min) relative to the passive conventional F11 patch (0.011 mg/cm²·min). FE-SEM imaging revealed intact conical microstructures (height: 400.08 μm, base width: 188.3 μm) with smooth surface morphology and amorphous drug dispersion. Drug–polymer compatibility and stability testing demonstrated robust structural matrix integrity under storage.
Conclusion: Biocompatible HPMC/PVP/PVA dissolving microneedles were successfully engineered for rapid transdermal delivery of Nefopam hydrochloride. The optimized F11 formulation exhibited robust mechanical integrity, efficient skin insertion, and superior dissolution kinetics, presenting a highly effective, painless alternative to conventional hypodermic administration to enhance patient adherence.
| Intend to be published in the IJPS ? | Yes |
|---|---|
| Has the manuscript been published | not published |
