title: Comparison of 2 strategies to enhance pyridoclax solubility: Nanoemulsion delivery system versus salt synthesis.
abstract: Pyridoclax is an original oligopyridine lead, very promising in treatment of chemoresistant cancers. However, from solubility measurement and permeability evaluation, it appeared that this compound can be considered as a BCS II drug, with a poor water solubility. To overcome this unfavorable property, two strategies were proposed and compared: pyridoclax di-hydrochloride salt synthesis and formulation of pyridoclax-loaded nanoemulsions (PNEs) efficiently performed by transposing the spontaneous emulsification process previously developed by our team. Whereas the salt improved the thermodynamic solubility of the drug by a factor 4, the apparent solubility of the encapsulated pyridoclax was 1000-fold higher. Their stability was assessed upon dilution in various complex biomimetic media relevant for oral administration (SGF, FaSSIF-V2, FeSSIF-V2) or for the intravenous route (PBS). The solubility of the salt was affected by the nature of the medium, indicating that it could precipitate after administration, negatively impacting its bioavailability and its efficiency in vivo. On the contrary, in all media, PNEs remained stable in terms of granulometric properties (determined by DLS), ζ-potential and encapsulation efficiency (measured by HPLC). Thus, such nanomedicines appear as a valuable option to perform preclinical studies on the promising pyridoclax.
authors.affiliation: Normandie Univ, UNICAEN, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), F-14000 Caen, France.
authors.forename: A-C
authors.initials: AC
authors.lastname: Groo
authors.affiliation: Normandie Univ, UNICAEN, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), F-14000 Caen, France.
authors.forename: M
authors.initials: M
authors.lastname: De Pascale
authors.affiliation: Normandie Univ, UNICAEN, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), F-14000 Caen, France. Electronic address: anne-sophie.voisin@unicaen.fr.
authors.forename: A-S
authors.initials: AS
authors.lastname: Voisin-Chiret
authors.affiliation: Normandie Univ, UNICAEN, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), F-14000 Caen, France.
authors.forename: S
authors.initials: S
authors.lastname: Corvaisier
authors.affiliation: Normandie Univ, UNICAEN, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), F-14000 Caen, France.
authors.forename: M
authors.initials: M
authors.lastname: Since
authors.affiliation: Normandie Univ, UNICAEN, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), F-14000 Caen, France. Electronic address: aurelie.malzert-freon@unicaen.fr.
authors.forename: A
authors.initials: A
authors.lastname: Malzert-Fréon
mesh_terms: D004339:Drug Compounding; D016503:Drug Delivery Systems / Q000379:methods*; D004655:Emulsions; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D011725:Pyridines / Q000008:administration & dosage / Q000138:chemical synthesis*; D012965:Sodium Chloride / Q000008:administration & dosage / Q000138:chemical synthesis*; D012995:Solubility
chemical_list: D004655:Emulsions; D011725:Pyridines; D012965:Sodium Chloride
keywords: Biomimetic media; Nanoemulsions; Oligopyridine; Preclinical studies; Solubility enhancement