title: Solubilization of poorly water-soluble drugs by mixed micelles based on hydrogenated phosphatidylcholine.
abstract: A remarkable part of newly developed active pharmaceutical ingredients is rejected in early phase development and will never find a way to a patient because of poor water solubility which is often paired with poor bioavailability. Considering such arising solubility problems the development of application vehicles like mixed micelles (MM) is a challenging research topic in pharmaceutical technology. While known classical MM systems are composed of phosphatidylcholine and bile salts, it was the aim of this study to investigate if alternatively developed MM systems were superior in solubilization of different hydrophobic drugs. The novel MM were also comprised of phosphatidylcholine and (contrarily to bile salts) different other suitable surfactants forming binary MM. As model water-insoluble drug substances two benzodiazepines, diazepam and tetrazepam, and the steroid estradiol were chosen. In this study the solubilization capacities of newly developed MM were compared to those of classical lecithin/bile salt MM systems and different other surfactant containing systems. The MM system with sucrose laurate and hydrogenated PC (hPC) at a weight fraction of 0.5 was found to be superior in drug solubilization of all investigated drugs compared to the classical lecithin/bile salt mixed micelles. Further, a polysorbate 80 solution, also at 5%, was inferior with regard to solubilize the investigated hydrophobic drugs. The MM sizes of the favorite developed MM system, before and after drug incorporation, were analysed by dynamic light scattering (DLS) to evaluate the influence of the drug incorporation. Here, the particle sizes, before and after drug incorporation, remained constant, indicating a stable formation of the solubilizate. Further the critical micelle concentration (CMC) of MM before and after drug incorporation was analysed by three different determination techniques. Constant CMC-values could be obtained regardless if diazepam was encapsulated within the MM or unloaded MM were analysed.
authors.affiliation: Department of Pharmaceutics and Biopharmaceutics, Christian Albrecht University Kiel, Gutenbergstrasse 76, 24118 Kiel, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Rupp
authors.forename: Hartwig
authors.initials: H
authors.lastname: Steckel
authors.forename: Bernd W
authors.initials: BW
authors.lastname: Müller
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D001569:Benzodiazepines / Q000737:chemistry*; D001647:Bile Acids and Salts / Q000737:chemistry; D003975:Diazepam / Q000737:chemistry*; D004958:Estradiol / Q000737:chemistry*; D006865:Hydrogenation; D057927:Hydrophobic and Hydrophilic Interactions; D054709:Lecithins / Q000737:chemistry; D008027:Light; D008823:Micelles; D010316:Particle Size; D010713:Phosphatidylcholines / Q000737:chemistry*; D011136:Polysorbates / Q000737:chemistry; D012542:Scattering, Radiation; D012995:Solubility; D013395:Sucrose / Q000031:analogs & derivatives / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D001647:Bile Acids and Salts; D054709:Lecithins; D008823:Micelles; D010713:Phosphatidylcholines; D011136:Polysorbates; D013501:Surface-Active Agents; D047392:beta-Cyclodextrins; C018152:sucrose monolaurate; D001569:Benzodiazepines; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D004958:Estradiol; D013395:Sucrose; C005245:tetrazepam; D003975:Diazepam