Development of Solid Self-Emulsifying Formulation for Improving the Oral Bioavailability of Erlotinib.

Duy Hieu Truong,Han-Gon Choi,Hee Hyun Lee,Jong Oh Kim,Cheol Moon,Tuan Hiep Tran,Ju Yeon Choi,Chul Soon Yong,Thiruganesh Ramasamy

doi:10.1208/s12249-015-0370-5

Abstract

To improve the solubility and oral bioavailability of erlotinib, a poorly water-soluble anticancer drug, solid self-emulsifying drug delivery system (SEDDS) was developed using solid inert carriers such as dextran 40 and Aerosil® 200 (colloidal silica). The preliminary solubility of erlotinib in various oils, surfactants, and co-surfactants was determined. Labrafil M2125CS, Labrasol, and Transcutol HP were chosen as the oil, surfactant, and co-surfactant, respectively, for preparation of the SEDDS formulations. The ternary phase diagram was evaluated to show the self-emulsifying area. The formulations were optimized using the droplet size and polydispersity index (PDI) of the resultant emulsions. Then, the optimized formulation containing 5% Labrafil M2125CS, 65% Labrasol, and 30% Transcutol was spray dried with dextran or Aerosil® and characterized for surface morphology, crystallinity, and pharmacokinetics in rats. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) exhibited the amorphous form or molecular dispersion of erlotinib in the formulations. The pharmacokinetic parameters of the optimized formulations showed that the maximum concentration (C max) and area under the curve (AUC) of erlotinib were significantly increased, compared to erlotinib powder (p < 0.05). Thus, this SEDDS could be a promising method for enhancing the oral bioavailability of erlotinib.

Highlights

Erlotinib, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)4-quinazolinamine, is a synthetic anilinoquinazoline derivative that selectively and reversibly inhibits the epidermal growth factor receptor (EGFR) tyrosine kinase, preventing autophosphorylation of tyrosine residues and thereby inhibiting further downstream signaling [1]
Solubility studies of erlotinib in various vehicles were performed for selection of a suitable oil, surfactant, and cosurfactant for development of the optimal erlotinib-loaded self-emulsifying drug delivery systems (SEDDS) formulation
In this study, the aforementioned oil, surfactant, and co-surfactant were selected for formulation of erlotinib-loaded SEDDS

Summary

Introduction

N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)4-quinazolinamine, is a synthetic anilinoquinazoline derivative that selectively and reversibly inhibits the epidermal growth factor receptor (EGFR) tyrosine kinase, preventing autophosphorylation of tyrosine residues and thereby inhibiting further downstream signaling [1]. Erlotinib belongs to the Biopharmaceutical Classification System (BCS) class II, which is characterized by low solubility and high permeability (log P of 2.7) This may be one of the reasons for low bioavailability and a large intra- and inter-patient variability in peak plasma concentration and area under the curve (AUC) after the same oral dose [2,3,4]. SEDDS are anhydrous, isotropic mixtures of oil(s), surfactant(s), the lipophilic drug, and co-surfactant(s) or co-solvent(s), which spontaneously form oil-inwater emulsions upon aqueous dilution with gentle agitation These systems have some advantages over emulsions, compared to solid dosage forms, there are still some practical drawbacks associated with the conventional (liquid) SEDDS, including storage instability and interaction with hard or soft capsules. Solidification of liquid SEDDS has been used increasingly in an effort to overcome the abovementioned limitations and combine the advantages of conventional lipid-based drug delivery systems (i.e., increased solubility and bioavailability) with those of solid dosage forms (e.g., high stability and reproducibility, ease of process control, and relatively low production cost) [26,27,28,29,30,31,32,33,34]

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