Skip to Main content Skip to Navigation
Theses

Mise en forme et amélioration de la biodisponibilité d'un anticancéreux destiné à la voie orale : exemple du mitotane

Abstract : Mitotane or o, p'-DDD is a organochlorine drug, very slightly soluble in water. It is used in the treatment of non resectable and metastasized adrenocortical carcinoma (Lysodren®). In therapy, to achieve therapeutic plasma level, high cumulative doses of mitotane were usually used during 3-5 months. This regimen causes gastrointestinal and neuromuscular side effects and make patients to be less compliants.The main objective of this work is to developp differents formulations of mitotane in order to improve the relative bioavailability when compared with conventional form Lysodren®. To shorten this equilibration time and reduce side effects, it's necessary to develop a new formulation. In order to increase mitotane solubility and make it more bioavailable, we encapsulated mitotane in polymeric particles and microemulsions.We prepared nanocapsules with biodegradable polymers (poly-epsilon-caprolactone) (PCL) and an association of PCL and non-biodegradable polymers (Eudragit®RL). We have also prepared PCL microparticles and a Self Microemulsifying Drug Delivery System or SMEDDS.Nanocapsules and microparticles diameters were respectively 300 nm and 40 to 76 µm. The zeta potential is negative for PCL particles wheras particles combining PCL and Eudragit®RL polymers exhibited positive zêta potential. For microemulsions, we investigated by constructing ternary phase diagrams and choosing the optimal formulation consisted of a mixture of Capryol®, Tween® 20 and Cremophor® EL (33, 33, 33%) with an emulsion diameter of 40 nm. The release of mitotane from SMEDDS and particles was higher and faster than from the conventional form Lysodren®.Pharmacokinetics after single-dose of oral mitotane formulations (100 mg/kg) in rabbits showed a 339% increase of relative bioavailability with microemulsions, 195% with the nanocapsules and 187% with the microparticles. Caco-2 cell culture showed a complete absorption of mitotane after 4h with microemulsions. For microparticles and nanocapsules, 50 and 45% of the initial dose, were respectively absorbed by Caco-2 cells. Caco-2 cells evaluation confirmed the low absorption of the mitotane powder (10%). Finally, Ussing chamber showed that microemulsions pass through the intestinal barrier 5 times higher than a solution of mitotane. In conclusion, microemulsions showed improvement of bioavailability of mitotane by a factor 3 in rabbits and could allow cost effective production. Microemulsions are a real alternative to Lysodren® which is currently available on the European market
Document type :
Theses
Complete list of metadata

Cited literature [145 references]  Display  Hide  Download

https://hal.univ-lorraine.fr/tel-01748564
Contributor : Thèses Ul Connect in order to contact the contributor
Submitted on : Thursday, March 29, 2018 - 11:38:26 AM
Last modification on : Friday, September 10, 2021 - 1:04:03 PM
Long-term archiving on: : Friday, September 14, 2018 - 9:44:31 AM

File

SCD_T_2010_0022_ATTIVI.pdf
Files produced by the author(s)

Identifiers

  • HAL Id : tel-01748564, version 1

Citation

David Attivi. Mise en forme et amélioration de la biodisponibilité d'un anticancéreux destiné à la voie orale : exemple du mitotane. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2010. Français. ⟨NNT : 2010NAN10022⟩. ⟨tel-01748564⟩

Share

Metrics

Record views

128

Files downloads

2725