title: Liposomal formulation of a glycerolipidic prodrug for lymphatic delivery of didanosine via oral route.
abstract: Didanosine is a polar drug with poor membrane absorption and high hepatic first pass metabolism. This study aimed at developing a lipidic formulation of a glycerolipidic prodrug of didanosine in order to improve its bioavailability. In the course of a preformulation study, the glycerolipidic prodrug of didanosine was characterized by microscopy, DSC and XRDT. In anhydrous conditions, the prodrug displayed a polymorphic behaviour similar to that of triglycerides. Then, we evaluated three types of lipidic formulations (emulsions, mixed micelles and liposomes) in order to encapsulate the prodrug. Solubilities in water - even in the presence of taurocholate micelles - but also in some oils were very low (max 244 microg/mL) as the prodrug was found to be amphiphilic (log P=2). On the contrary, the prodrug was found to be perfectly incorporated in dipalmitoylphosphatidylcholine (DPPC) multilamellar liposomes up to a ratio of 1:5 (mol:mol) prodrug:DPPC as suggested by HPLC-UV and DSC experiments. Moreover, these liposomes could be freeze-dried whereas the chemical integrity of the prodrug was preserved. Then, the freeze-dried liposomal preparation could be formulated as gastro-resistant capsules to prevent didanosine from acidic degradation. Further experiments are on the way to evaluate in vitro the absorption of prodrug incorporated in liposomes by enterocytes.
authors.affiliation: Univ. Paris-Sud, UMR CNRS 8612, IFR 141, F-92296 Châtenay-Malabry, France.
authors.forename: M
authors.initials: M
authors.lastname: Lalanne
authors.forename: K
authors.initials: K
authors.lastname: Andrieux
authors.forename: A
authors.initials: A
authors.lastname: Paci
authors.forename: M
authors.initials: M
authors.lastname: Besnard
authors.forename: M
authors.initials: M
authors.lastname: Ré
authors.forename: C
authors.initials: C
authors.lastname: Bourgaux
authors.forename: M
authors.initials: M
authors.lastname: Ollivon
authors.forename: D
authors.initials: D
authors.lastname: Desmaele
authors.forename: P
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine; D000284:Administration, Oral; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D016049:Didanosine / Q000008:administration & dosage / Q000737:chemistry; D004355:Drug Stability; D004655:Emulsions; D005612:Freeze Drying; D008081:Liposomes; D008208:Lymphatic System; D008823:Micelles; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry; D014280:Triglycerides / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D019380:Anti-HIV Agents; D004655:Emulsions; D008081:Liposomes; D008823:Micelles; D011355:Prodrugs; D014280:Triglycerides; D015060:1,2-Dipalmitoylphosphatidylcholine; D016049:Didanosine