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WITHDRAWN: Improved pharmacokinetic and cytotoxicity characteristics of imatinib by utilizing nanostructured lipid carriers
Accepted Manuscript Title: Improved pharmacokinetic and cytotoxicity characteristics of Imatinib by utilizing nanostructured lipid carriers Author: Kyu Bong Woo, Biki Gupta, Pathak Shiva, Bijay Kumar Poudel, Nguyen Hanh Thuy, Raj Kumar Tapa, Han-Gon Choi, Jee-Heon Jeong, Jong Oh Kim, Chul Soon Yong PII: DOI: Reference:
S1818-0876(15)00219-6 http://dx.doi.org/doi: 10.1016/j.ajps.2015.11.056 AJPS 281
To appear in:
Asian Journal of Pharmaceutical Sciences
Please cite this article as: Kyu Bong Woo, Biki Gupta, Pathak Shiva, Bijay Kumar Poudel, Nguyen Hanh Thuy, Raj Kumar Tapa, Han-Gon Choi, Jee-Heon Jeong, Jong Oh Kim, Chul Soon Yong, Improved pharmacokinetic and cytotoxicity characteristics of Imatinib by utilizing nanostructured lipid carriers, Asian Journal of Pharmaceutical Sciences (2015), http://dx.doi.org/doi: 10.1016/j.ajps.2015.11.056. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
P-058 Improved pharmacokinetic and cytotoxicity characteristics of Imatinib by utilizing nanostructured lipid carriers Kyu Bong Wooa,*, Biki Guptaa, Pathak Shivaa, Bijay Kumar Poudela, Nguyen Hanh Thuya, Raj Kumar Tapaa, Han-Gon Choib, Jee-Heon Jeonga, Jong Oh Kima, Chul Soon Yonga a
College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyeongsan 712-749, South
Korea b
College of Pharmacy, Hanyang University, 55, Hanyangdaehak-ro, Sangnok-gu, Ansan 426-
791, South Korea Email: [email protected] Imatinib is a receptor tyrosine kinase inhibitor, whose clinical application is limited by its low aqueous solubility, extensive first pass metabolism, and rapid clearance [1, 2]. Nanostructured lipid carriers (NLC) offer advantages such as improved solubility and enhanced bioavailability of poorly soluble drugs, modulation of drug release and increased specificity and tumor targeting [3, 4]. The purpose of the current work is to prepare, optimize and characterize imatinib-loaded NLC (IMT-NLC), and evaluate its in vitro release, pharmacokinetics and in vitro cytotoxicity characteristics. An 11-factor Plackett-Burman design (PBD) at 2 levels was employed to screen the main effects of 8 variables on IMT-NLC characteristics. Furthermore, a 4-factor central composite design (CCD) was used to optimize the main effects, interaction effects and quadratic effects of formulation variables on in vitro performance of IMT-NLC, combined with desirability function approach for optimization of multiple responses. The optimized IMT-NLC was characterized by DLS, TEM, DSC and XRD. An in vitro release of the optimized IMT-NLC was evaluated by dialysis method in pH 7.4 phosphate buffered saline. An in vivo pharmacokinetic study was conducted in rats after oral as well as intravenous administration. PBD screening revealed significant main effects of organic to aqueous phase ratio (O/A), drug to lipid ratio (D/L), amount of lecithin (Lec) and amount of tween 20 (Tw20) on encapsulation efficiency (EE), D/L and O/A on drug loading (DL), and O/A and Tw20 on particle size, licensing the selection of these four variables for further optimization by CCD and desirability function which, thereby, yielded an optimized condition of 0.054, 6% w/w, 2.5% w/w and 1.25% w/v for O/A, D/L, Lec and Tw20, respectively. The optimized IMT-NLC exhibited a particle size, polydispersity index and zeta-potential of 148.8 ± 1.4 nm, 0.191 ± 0.017 and - 23.0 ± 1.5 mV, respectively, with a DL of 5.48 ± 0.01% w/w and EE of 97.93 ± 0.03% w/w. It displayed sustained release characteristics and significant enhancement of bioavailability of the drug after
Page 1 of 3
intravenous as well as oral administration with respective increase in AUC0-∞ by 2.5 and 2.4 times as compared with free drug. Hence, a combined DoE approach was capable of prompting accurate optimization of associated formulation variables leading to preparation of IMT-NLC with enhanced in vitro and in vivo characteristics. Keywords: Imatinib; Nanostructured lipid carriers; Plackett-Burman design; Central composite design
References [1] Deininger M, Buchdunger E, Druker B J. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 2005; 105:2640-2653. [2] Al-Hadiya B M H, Bakheit A H H, Abd-Elgalil A A. Imatinibmesylate. In: Brittain HG, editor. Profiles of drug substances, excipients, and related methodology 2014; 39:265-297. [3] Selvamuthukumar S, Velmurugan R. Nanostructured lipid carriers: a potential drug carrier for cancer chemotherapy. Lipids Health Dis 2012; 11:159. [4] Fang C L, Al-Suwayeh S A, Fang J Y. Nanostructured lipid carriers (NLCs) for drug delivery and targeting. Recent Pat Nanotechnol 2013; 7:41-55.
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C
Fig. 1. Plasma concentration-time profiles after (A) intravenous and (B) oral administration of free IMT and IMT-NLC and In vitro cytotoxicity characteristics of free IMT and IMT-NLC. [*p <0.05 as compared with free IMT.] (C)
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S1818-0876(15)00219-6 http://dx.doi.org/doi: 10.1016/j.ajps.2015.11.056 AJPS 281
To appear in:
Asian Journal of Pharmaceutical Sciences
Please cite this article as: Kyu Bong Woo, Biki Gupta, Pathak Shiva, Bijay Kumar Poudel, Nguyen Hanh Thuy, Raj Kumar Tapa, Han-Gon Choi, Jee-Heon Jeong, Jong Oh Kim, Chul Soon Yong, Improved pharmacokinetic and cytotoxicity characteristics of Imatinib by utilizing nanostructured lipid carriers, Asian Journal of Pharmaceutical Sciences (2015), http://dx.doi.org/doi: 10.1016/j.ajps.2015.11.056. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
P-058 Improved pharmacokinetic and cytotoxicity characteristics of Imatinib by utilizing nanostructured lipid carriers Kyu Bong Wooa,*, Biki Guptaa, Pathak Shivaa, Bijay Kumar Poudela, Nguyen Hanh Thuya, Raj Kumar Tapaa, Han-Gon Choib, Jee-Heon Jeonga, Jong Oh Kima, Chul Soon Yonga a
College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyeongsan 712-749, South
Korea b
College of Pharmacy, Hanyang University, 55, Hanyangdaehak-ro, Sangnok-gu, Ansan 426-
791, South Korea Email: [email protected] Imatinib is a receptor tyrosine kinase inhibitor, whose clinical application is limited by its low aqueous solubility, extensive first pass metabolism, and rapid clearance [1, 2]. Nanostructured lipid carriers (NLC) offer advantages such as improved solubility and enhanced bioavailability of poorly soluble drugs, modulation of drug release and increased specificity and tumor targeting [3, 4]. The purpose of the current work is to prepare, optimize and characterize imatinib-loaded NLC (IMT-NLC), and evaluate its in vitro release, pharmacokinetics and in vitro cytotoxicity characteristics. An 11-factor Plackett-Burman design (PBD) at 2 levels was employed to screen the main effects of 8 variables on IMT-NLC characteristics. Furthermore, a 4-factor central composite design (CCD) was used to optimize the main effects, interaction effects and quadratic effects of formulation variables on in vitro performance of IMT-NLC, combined with desirability function approach for optimization of multiple responses. The optimized IMT-NLC was characterized by DLS, TEM, DSC and XRD. An in vitro release of the optimized IMT-NLC was evaluated by dialysis method in pH 7.4 phosphate buffered saline. An in vivo pharmacokinetic study was conducted in rats after oral as well as intravenous administration. PBD screening revealed significant main effects of organic to aqueous phase ratio (O/A), drug to lipid ratio (D/L), amount of lecithin (Lec) and amount of tween 20 (Tw20) on encapsulation efficiency (EE), D/L and O/A on drug loading (DL), and O/A and Tw20 on particle size, licensing the selection of these four variables for further optimization by CCD and desirability function which, thereby, yielded an optimized condition of 0.054, 6% w/w, 2.5% w/w and 1.25% w/v for O/A, D/L, Lec and Tw20, respectively. The optimized IMT-NLC exhibited a particle size, polydispersity index and zeta-potential of 148.8 ± 1.4 nm, 0.191 ± 0.017 and - 23.0 ± 1.5 mV, respectively, with a DL of 5.48 ± 0.01% w/w and EE of 97.93 ± 0.03% w/w. It displayed sustained release characteristics and significant enhancement of bioavailability of the drug after
Page 1 of 3
intravenous as well as oral administration with respective increase in AUC0-∞ by 2.5 and 2.4 times as compared with free drug. Hence, a combined DoE approach was capable of prompting accurate optimization of associated formulation variables leading to preparation of IMT-NLC with enhanced in vitro and in vivo characteristics. Keywords: Imatinib; Nanostructured lipid carriers; Plackett-Burman design; Central composite design
References [1] Deininger M, Buchdunger E, Druker B J. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 2005; 105:2640-2653. [2] Al-Hadiya B M H, Bakheit A H H, Abd-Elgalil A A. Imatinibmesylate. In: Brittain HG, editor. Profiles of drug substances, excipients, and related methodology 2014; 39:265-297. [3] Selvamuthukumar S, Velmurugan R. Nanostructured lipid carriers: a potential drug carrier for cancer chemotherapy. Lipids Health Dis 2012; 11:159. [4] Fang C L, Al-Suwayeh S A, Fang J Y. Nanostructured lipid carriers (NLCs) for drug delivery and targeting. Recent Pat Nanotechnol 2013; 7:41-55.
Page 2 of 3
C
Fig. 1. Plasma concentration-time profiles after (A) intravenous and (B) oral administration of free IMT and IMT-NLC and In vitro cytotoxicity characteristics of free IMT and IMT-NLC. [*p <0.05 as compared with free IMT.] (C)
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