Development and Evaluation of a Novel Microemulsion Formulation of Elacridar to Improve its Bioavailability
Section snippets
INTRODUCTION
One of the major hurdles that has to be overcome for effective treatment of brain disorders is the blood–brain barrier (BBB). Efflux transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), work at the level of the BBB to actively efflux drugs from the brain, thus limiting distribution to their target site. Pharmacological inhibition of these efflux transporters may overcome this inadequate delivery of drug therapy to the brain. Elacridar (GF 120918) was
Chemicals and Reagents
Elacridar (GF 120918) [N-(4-(2-(1,2,3,4-tetrahydro-6, 7-dimethoxy-2-isoquinolinyl)ethyl)phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide] of molecular weight 563.64 g/mol was purchased from Toronto Research Chemicals (Ontario, Canada). Cremophor EL, Cremophor RH40, Solutol HS, Captex 355, and Captex 300 were obtained from Abitech (Janesville, Wisconsin). Carbitol [2-(2-ethoxyethoxy) ethanol] was purchased from Sigma–Aldrich (St. Louis, Missouri). Erlotinib was purchased from LC
Solubility Studies
The components evaluated for the microemulsion were first examined for their capability to dissolve elacridar. The results are listed in Table 1. The components selected for further development of the formulation were chosen on the basis of solubility of elacridar in those components. Cremophor EL provided the best solubilization capacity and was therefore chosen for use in the microemulsion. Cremophor itself is an inhibitor of P-gp19; therefore, appropriate controls have been used in all
DISCUSSION
The use of elacridar in preclinical models, as well as in clinical settings, for chronic administration is limited by its poor p.o. absorption and lack of injectable formulations. The poor solubility of elacridar in aqueous solvents has been limiting in formulating an injectable dosage form. The use of surfactants and lipids can enhance the solubility and permeability of poorly soluble drugs.26., 27. This strategy has been used to improve the p.o. bioavailability of drugs such as antiviral
ACKNOWLEDGMENTS
This work was supported by National Institutes of Health–National Cancer Institute [CA138437] (W.F.E.) and an AHC Faculty Development grant at the University of Minnesota (W.F.E.). Financial support for R.S. was provided by the Ronald J. Sawchuk Fellowship and Rowell Fellowship.
Author Contributions: R.S. and W.F.E. participated in the research design. R.S. and R.K.M. conducted the experiments. R.S., R.K.M., and W.F.E. contributed for the new reagents or analytic tools. R.S., R.K.M., and W.F.E.
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