Owing to its slightly aqueous solubility, loratadine (LOR) is used in high doses in different marketed formulations to achieve its desirable bioavailability. The aim of this work is to formulate novel LOR-glycerin nanoparticles (LOR-GNPs) to increase LOR bioavailability. LOR-GNPs were prepared by a precipitation method and then evaluated for such size and morphology using dynamic scattering spectroscopy (DLS) and scanning electron microscopy (SEM), as well as the percentage entrapment efficiency (EE%) of free LOR from GNPs formulations was performed using titration method. Furthermore, the GNPs were formulated in hydrogel. The hydrogel viscosity, spreadability, homogeneity and abdominal rat skin permeation were studied and optimized DLS indicated a successful coating of LOR with glycerin surface that recorded an average size of 334 ± 30 nm with uniform particle size, while SEM showed LOR-NPs in different shapes. The EE% free LOR was found to be satisfactory with a mean content of 98.1 ± 0.3 and a relative standard deviation below 2.0% indicates the reproducibility of the LOR release. LOR-GNPs were formulated as a hydrogel to check their suitability for a dosage form usage. The hydrogel showed accepted viscosity, spreadability, and homogeneity. The results proved that the GNPs penetrated abdominal rat skin. The obtained results showed that LOR-GNPs are considered a new addition for improvement of LOR solubility when applied as a hydrogel. The developed method could be used for different insoluble candidates.