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

• Published in: International 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
• Language: English
• Published: Amsterdam Elsevier B.V 01.11.2007; Elsevier
• Subjects: 1,2-Dipalmitoylphosphatidylcholine; Administration, Oral; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - chemistry; Biological and medical sciences; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Didanosine; Didanosine - administration & dosage; Didanosine - chemistry; Drug Stability; DSC; Emulsions; Freeze Drying; General pharmacology; Glycerolipidic prodrug; Liposomes; Lymphatic System; Medical sciences; Micelles; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Prodrugs - administration & dosage; Prodrugs - chemistry; Triglycerides - chemistry; X-Ray Diffraction; XRDT; Glycerolipidic prodrug; XRDT; Liposomes; Didanosine; DSC; Purine nucleoside; Antiretroviral agent; RNA-directed DNA polymerase; Drug carrier; Reverse transcriptase inhibitor; Formulation; Nucleoside analog; Antiviral; Differential scanning calorimetry; Lymphatic system; Pharmaceutical technology; Enzyme; Transferases; Oral administration; Enzyme inhibitor; Liposome; Lymphatic; Bioavailability; Prodrug; Nucleotidyltransferases; Dideoxynucleoside
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2007.05.064

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.