title: Parenteral formulation of an antileishmanial drug candidate--tackling poor solubility, chemical instability, and polymorphism.
abstract: The paullon chalcone derivative KuRei300 is active against Leishmania donovani, the protozoans causing visceral leishmaniasis. The aim of this study was the development of a parenteral formulation of the virtually water insoluble compound in order to enable future studies in mice. Mixed lecithin/bile salt micelles, liposomes, supercooled smectic cholesterol myristate nanoparticles, cubic phase nanoparticles and a triglyceride emulsion were screened for their solubilizing properties. Due to the limited available amount of KuRei300 a passive loading approach with pre-formulated carriers that were incubated with drug substance deposited onto the walls of glass vials was used. The loading capacities of the nanocarriers, the influence of the solid state properties of the drug and its deposits on the loading results and chemical stability aspects of KuRei300 were investigated. Employed methods included HPLC, UV spectroscopy, (1)H NMR, XRPD, and DSC. All nanocarriers substantially improved the solubility of KuRei300; the mixed micelles exhibited the highest drug load. Related to the lipid matrix, however, the smectic nanoparticles solubilized the significantly highest amount of drug. Loading from physically altered drug deposits improved the obtainable concentration to the threefold compared with untreated drug powder. Formulations with KuRei300 must be stored excluded from light under a nitrogen atmosphere as the substance is susceptible to photoisomerization and decomposition.
authors: Institute of Pharmaceutical Technology, Technische Universität Braunschweig, Braunschweig, Germany. Electronic address: e.kupetz@tu-braunschweig.de.
authors: Eva
authors: E
authors: Kupetz
authors: Lutz
authors: L
authors: Preu
authors: Conrad
authors: C
authors: Kunick
authors: Heike
authors: H
authors: Bunjes
mesh_terms: D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000737:chemistry; D001552:Benzazepines / Q000008:administration & dosage* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D002788:Cholesterol Esters / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D004355:Drug Stability; D004356:Drug Storage; D004655:Emulsions; D007211:Indoles / Q000008:administration & dosage* / Q000737:chemistry; D007267:Injections; D008055:Lipids / Q000737:chemistry; D008081:Liposomes; D008823:Micelles; D053758:Nanoparticles; D012995:Solubility; D014280:Triglycerides / Q000737:chemistry
chemical_list: D000981:Antiprotozoal Agents; D001552:Benzazepines; D002788:Cholesterol Esters; D004337:Drug Carriers; D004655:Emulsions; D007211:Indoles; C000591227:KuRei300; D008055:Lipids; D008081:Liposomes; D008823:Micelles; D014280:Triglycerides; C032561:cholesteryl myristate
keywords: Cubic phase nanoparticles; Formulation screening; Lipid nanocarriers; Liposomes; Mixed micelles; Passive loading; Photoisomerization; Supercooled smectic cholesterol myristate nanoparticles; Triglyceride emulsion