Development and Evaluation of a Novel Microemulsion Formulation of Elacridar to Improve its Bioavailability

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ABSTRACT

The study objective was to develop a formulation of elacridar to overcome its dissolution-rate-limited bioavailability. Elacridar is a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor that has been used to improve the brain distribution of drugs that are substrates of P-gp and BCRP. The chronic use of elacridar is restricted because of the poor solubility leading to poor oral bioavailability. A microemulsion formulation using Cremophor EL, Carbitol, and Captex 355 (6:3:1) was developed. The elacridar microemulsion was effective in the inhibition of P-gp and Bcrp in Madin-Darby canine kidney Il-transfected cells. Friend Leukemia Virus Strain B (FVB) mice were used to determine the bioavailability of elacridar after a 10 mg/kg dose of elacridar in the microemulsion, intraperitoneally (i.p.) and orally (p.o.); and the absolute bioavailability was determined to be 1.3 and 0.47, respectively. Coadministration of elacridar microemulsion i.p. with p.o. erlotinib in FVB mice improved the erlotinib brain penetration threefold. The current study shows that a microemulsion formulation of elacridar is effective in improving the bioavailability of elacridar and is an effective inhibitor of P-gp and Bcrp, in vitro and in vivo. It offers an alternative to the suspension and allows a decrease in the dose required to achieve a significant inhibitory effect at the blood–brain barrier.

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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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