Schiano_2025_Eur.J.Pharm.Biopharm__114832

The carrier prodrug approach is a well-established medicinal chemistry strategy adopted to refine the physicochemical and biopharmaceutical properties of parent drugs. In the present work, this strategy was applied to improve the transdermal delivery of butyric acid (BA) by employing D-glucosamine (N-Glc), a natural and non-toxic molecule, as a carrier. Accordingly, the design and synthesis of a new carrier prodrug, N-glucosamine tetrabutyrate (3-amino-6-((butyryloxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl tributyrate, N-Glc-BE) is reported. The physicochemical profile of N-Glc-BE was comprehensively evaluated, including its chemical and enzymatic stability under different pH conditions and in human serum, as well as its lipophilicity and solubility. N-Glc-BE exhibited chemical stability across a wide pH range but underwent enzymatic hydrolysis in the presence of esterase, with a half-life of 8 min in human serum. The prodrug also showed favorable solubility and lipophilicity for transdermal application. Skin permeation studies using Franz diffusion cells demonstrated that N-Glc-BE primarily accumulated in the epidermis and dermis and gradually reached the receptor compartment, allowing sustained release of the parent compound, BA. Furthermore, N-Glc-BE was shown to be biocompatible in preclinical human skin models, including primary skin cell cultures. In conclusion, the novel, odorless prodrug N-Glc-BE represents a promising candidate for the transdermal delivery of BA, a molecule with recognized biological activity but poor physicochemical properties. The use of N-Glc as a carrier not only provides a non-toxic delivery platform but also capitalizes on its kwon role in skin health and function.