Novel Naproxen Salts with Increased Skin Permeability

Area of Science:

• Pharmaceutical Chemistry
• Drug Delivery Systems
• Medicinal Chemistry

Background:

• Naproxen, a widely used non-steroidal anti-inflammatory drug (NSAID), suffers from poor water solubility and limited skin permeability, hindering effective topical delivery.
• Developing novel formulations and derivatives is crucial to enhance naproxen's therapeutic efficacy and patient compliance.

Purpose of the Study:

• To synthesize and characterize novel naproxen salts derived from L-proline alkyl esters.
• To evaluate the physicochemical properties, in vitro skin permeation, and cytotoxicity of these new naproxen derivatives.

Main Methods:

• Synthesis of L-proline alkyl ester naproxenates ([ProOR][NAP]) with varying alkyl chains (R=ethyl to butyl, including isopropyl).
• Comprehensive characterization using Nuclear Magnetic Resonance (NMR), Fourier transform infrared spectroscopy (FTIR), X-ray powder diffractometry (XRD), and in vitro dissolution studies.
• Assessment of lipophilicity, permeability, and accumulation in pigskin, alongside specific rotation, melting point, thermal stability, and cytotoxicity assays against L929 fibroblast cells.

Main Results:

• All synthesized [ProOR][NAP] salts were fully identified and characterized.
• The naproxen derivatives exhibited improved solubility and enhanced absorption across biological membranes compared to parent naproxen.
• The isopropyl ester derivative ([ProiPr][NAP]) demonstrated the highest permeability through pigskin, achieving a nearly four-fold increase in naproxen permeation.
• Lipophilicity increased with the alkyl chain length, while permeability was optimal with the isopropyl ester.
• Cytotoxicity studies revealed no significant difference in cell viability compared to naproxen, indicating a favorable safety profile.

Conclusions:

• L-proline alkyl ester naproxenates represent a promising strategy for improving naproxen's topical delivery and efficacy.
• The isopropyl ester derivative shows exceptional potential for enhancing transdermal drug delivery due to its high skin permeability and safety.
• These findings suggest a viable approach to developing more effective naproxen-based topical formulations.