Liposomal formulation of a glycerolipidic prodrug for lymphatic delivery of didanosine via oral route

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...

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Published inInternational journal of pharmaceutics Vol. 344; no. 1; pp. 62 - 70
Main Authors Lalanne, M., Andrieux, K., Paci, A., Besnard, M., Ré, M., Bourgaux, C., Ollivon, M., Desmaele, D., Couvreur, P.
Format Journal Article Conference Proceeding
LanguageEnglish
Published Amsterdam Elsevier B.V 01.11.2007
Elsevier
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Summary: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 μg/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.
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ISSN:0378-5173
1873-3476
DOI:10.1016/j.ijpharm.2007.05.064