title: Potential of erlotinib cyclodextrin nanosponge complex to enhance solubility, dissolution rate, in vitro cytotoxicity and oral bioavailability.
abstract: The present study was envisaged to evaluate the effect of erlotinib β-cyclodextrin nanosponge (ERL-NS) on the solubility, dissolution, in vitro cytotoxicity and oral bioavailability of erlotinib (ERL). Preliminary studies were conducted to select the optimized stoichiometry concentration of ERL and NS. The drug nanosponge complex comprising of 1:4 proportions of ERL and NS was prepared by freeze drying. ERL-NS formed nanoparticles of 372 ± 31 nm size with narrow size distribution (0.21 ± 0.07 PDI) and high zeta potential (-32.07 ± 4.58 mV). The complexation phenomenon was confirmed by DSC, SEM, PXRD, FTIR, and TEM studies. In vitro dissolution studies revealed an increased dissolution rate (2-folds) with an enhanced dissolution efficiency of the nanosponge complex in comparison to pure drug. In vitro cytotoxicity study and apoptosis assay in pancreatic cell lines (MIA PaCa-2 and PANC-1) indicates the increased toxicity of ERL-NS. Both, quantitative and qualitative cell uptake studies unveiled the higher uptake efficiency of ERL-NS than free drug. ERL-NS showed enhanced oral bioavailability with 1.8-fold higher Cmax (78.98 ± 6.2 vs. 42.36 ± 1.75 μg/ml), and ∼ 2-fold AUC0-∞ (1079.95 ± 41.38 vs. 580.43 ± 71.91), in comparison to pure ERL. Therefore, we conclude that the formation of a complex of nanosponge with ERL is a successful approach to increase its solubility, dissolution and oral bioavailability which may ultimately result in reduction in dose and dose related side-effects.
authors.affiliation: Department of Pharmaceutical Tech. (Formulations), National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India; Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
authors.forename: Chander Parkash
authors.initials: CP
authors.lastname: Dora
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Torino, Via P. Giuria, 7-10125, Torino, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Trotta
authors.affiliation: Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
authors.forename: Varun
authors.initials: V
authors.lastname: Kushwah
authors.affiliation: Department of Pharmaceutical Tech. (Formulations), National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
authors.forename: Naresh
authors.initials: N
authors.lastname: Devasari
authors.affiliation: Department of Pharmaceutical Tech. (Formulations), National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
authors.forename: Charan
authors.initials: C
authors.lastname: Singh
authors.affiliation: Department of Pharmaceutical Tech. (Formulations), National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India; Drug Design and Development Centre, Faculty of Pharmacy, MSR University of Applied Sciences, Bangalore, Karnataka 560054, India. Electronic address: sarasija_s@rediffmail.com.
authors.forename: Sarasija
authors.initials: S
authors.lastname: Suresh
authors.affiliation: Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India. Electronic address: sanyogjain@niper.ac.in.
authors.forename: Sanyog
authors.initials: S
authors.lastname: Jain
mesh_terms: D000284:Administration, Oral; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003505:Cyclodextrins / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D000069347:Erlotinib Hydrochloride / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012995:Solubility
chemical_list: D003505:Cyclodextrins; D004337:Drug Carriers; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; D011505:Protein-Tyrosine Kinases
keywords: Ammonium acetate (PubChem CID: 517165); Atorvastatin (PubChem CID: 60823); Carbonydiimidazole (PubChem CID: 68263); Coumarin-6 (PubChem CID: 100334); Erlotinib; Erlotinib hydrochloride (PubChem CID: 176871); In vitro cytotoxicity; Nanosponge; Oral bioavailability; Solubility enhancement; Tyrosine kinase inhibitor; β-Cyclodextrin (PubChem CID: 444041)