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Proniosomes are drug-encapsulated, nanoscale vesicular structures that generate multilamellar niosomal dispersions upon hydration. This study aimed to develop enalapril maleate nanoproniosomal gels and assess their effectiveness in experimental hypertensive rat models. The gels were synthesized based on the coacervation phase separation method, using lecithin, cholesterol, and various nonionic surfactants as formulation components, along with the drug. The developed gels were then subjected to various analyses, such as pH, viscosity, rate of spontaneity, entrapment efficiency, vesicle size, ex vivo permeation, skin irritation, scanning electron microscopy, stability, in vivo bio-availability, in vivo antihypertensive activity, and in vitro–in vivo correlation studies. Results revealed that all synthesized gel formulations maintained good physical characteristics, within permissible limits. The results of the ex vivo skin permeation analysis revealed non-Fickian release kinetics and zero-order penetration behaviors of the drug formulations with diffusion, achieving a cumulative permeation rate of 58.75%–89.72% through albino rat skin over 24 h. Moreover, skin irritation tests revealed that the topical application of the drug formulations did not cause any signs of irritation, indicating their safety. Furthermore, in vivo bio-availability studies revealed that one particular formulation, EMNP7, demonstrated an approximately 188.99-fold greater bio-availability compared to the Vasotec tablet. Additionally, in vivo antihypertensive analysis revealed that this formulation effectively restored elevated rat blood pressures to the normal range. Furthermore, the in vitro–in vivo correlation analysis suggested that the ex vivo (in vitro) data could accurately replicate in vivo physiological conditions. Overall, our findings indicate that enalapril maleate encapsulated within nanoproniosomal gels can effectively function as controlled drug delivery systems, releasing the drug once per day for effective hypertension management.
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