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Pharmaceutical Nanotechnology

Editor-in-Chief

ISSN (Print): 2211-7385
ISSN (Online): 2211-7393

Research Article

Enhanced Pharmacokinetic Activity of Zotepine via Nanostructured Lipid Carrier System in Wistar Rats for Oral Application

Author(s): Cernam Tirumalesh, Dinesh Suram, Narendar Dudhipala and Nagaraj Banala *

Volume 8 , Issue 2 , 2020

Page: [148 - 160] Pages: 13

DOI: 10.2174/2211738508666200225113359

Price: $65

Abstract

Background: Zotepine (ZT) is a substituted dibenzothiepine tricyclic molecule and second generation antipsychotic drug. It is available as the parenteral and oral solid dosage form, but, orally administered ZT has a poor oral bioavailability (10%) that might be due to either poor water solubility, high lipophilicity (Log P 4) and also first-pass hepatic metabolism.

Objective: The oral bioavailability of ZT was improved by loading into a nanostructured lipid carriers (NLCs) system.

Methods: Hot homogenization with probe sonication method was used for the preparation of ZT-NLCs formulations and characterized for an optimal system based on physicochemical characteristics and in vitro release. Differential scanning calorimetry (DSC), X-ray diffraction (XRD) analysis, and scanning electron microscopy (SEM) studies were used to confirm the crystalline nature and shape of the optimized ZT-NLC formulation. The physical stability of the optimized ZT-NLC formulation was evaluated at the refrigerator and room temperature over two months. Furthermore, in vivo pharmacokinetic (PK) studies of optimized ZT-NLC and ZT coarse suspension (ZT-CS) as control formulation, were conducted in male Wistar rats.

Results: The optimized formulation of ZT-NLC showed Z-avg, PDI, ZP of 145.8 ± 2.5 nm, 0.18 ± 0.05, -31.6 ± 1.8 mV, respectively. In vitro release studies indicated the sustained release of ZT. DSC and XRD studies revealed the conversion of ZT into an amorphous form. SEM studies showed the spherical shape of the ZT-NLC formulation. PK studies showed 1.8-folds improvement (p<0.05) in oral bioavailability when compared with ZTCS formulation.

Conclusion: Overall, the results established that NLCs could be used as a new alternative delivery vehicle for the oral delivery of ZT.

Keywords: Bioavailability, in vitro release, nanostructured lipid carriers, Pharmacokinetics, SEM, Zotepine.

Graphical Abstract
[1]
Green B. Zotepine: a clinical review. Expert Opin Drug Metab Toxicol 2009; 5(2): 181-6.
[http://dx.doi.org/10.1517/17425250802670482] [PMID: 19199377]
[2]
Tanaka O. [Pharmacokinetics of zotepine and various factors affecting that of zotepine]. Nihon Shinkei Seishin Yakurigaku Zasshi 1996; 16(2): 49-52.
[PMID: 8905790]
[3]
Palem CR, Narendar D, Satyanarayana G, Varsha BP. Development and optimization of Atorvastatin calcium-cyclodextrin inclusion complexed oral disintegrating tablets for enhancement of solubility, dissolution, pharmacokinetic and pharmacodynamic activity by central composite design. Int J Pharm Sci Nanotech 2016; 9(2): 1-11.
[4]
Swetha E, Narendar D. Influence of β-cyclodextrin and hydroxypropyl-β-cyclodextrin on enhancement of solubility and dissolution of isradipine. Int J Pharm Sci Nanotech 2017; 10(3): 3752-7.
[5]
McFall H, Sarabu S, Shankar V, et al. Formulation of aripiprazole-loaded pH-modulated solid dispersions via hot-melt extrusion technology: In vitro and in vivo studies. Int J Pharm 2019; 554: 302-11.
[http://dx.doi.org/10.1016/j.ijpharm.2018.11.005] [PMID: 30395959]
[6]
Nagaraj K, Narendar D, Kishan V. Development of olmesartan medoxomil optimized nanosuspension using the Box-Behnken design to improve oral bioavailability. Drug Dev Ind Pharm 2017; 43(7): 1186-96.
[http://dx.doi.org/10.1080/03639045.2017.1304955] [PMID: 28271908]
[7]
Palem CR, Dudhipala NR, Battu SK, Repka MA, Rao Yamsani M. Development, optimization and in vivo characterization of domperidone-controlled release hot-melt-extruded films for buccal delivery. Drug Dev Ind Pharm 2016; 42(3): 473-84.
[http://dx.doi.org/10.3109/03639045.2015.1104346] [PMID: 26530127]
[8]
William NC, Christopher JHP. Lipophilic prodrugs designed for intestinal lymphatic transport. Adv Drug Deliv Rev 1996; 19: 149-69.
[http://dx.doi.org/10.1016/0169-409X(95)00105-G]
[9]
Müller RH, Radtke M, Wissing SA. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv Drug Deli. Rev 2002; 54: 131-55.
[10]
Müller RH, Mäder K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery - a review of the state of the art. Eur J Pharm Biopharm 2000; 50(1): 161-77.
[http://dx.doi.org/10.1016/S0939-6411(00)00087-4] [PMID: 10840199]
[11]
Das S, Chaudhury A. Recent advances in lipid nanoparticle formulations with solid matrix for oral drug delivery. AAPS PharmSciTech 2011; 12(1): 62-76.
[http://dx.doi.org/10.1208/s12249-010-9563-0] [PMID: 21174180]
[12]
Domingo C, Saurina J. An overview of the analytical characterization of nanostructured drug delivery systems: towards green and sustainable pharmaceuticals: a review. Anal Chim Acta 2012; 744: 8-22.
[http://dx.doi.org/10.1016/j.aca.2012.07.010] [PMID: 22935368]
[13]
Dudhipala N, Veerabrahma K. Candesartan cilexetil loaded solid lipid nanoparticles for oral delivery: characterization, pharmacokinetic and pharmacodynamic evaluation. Drug Deliv 2016; 23(2): 395-404.
[http://dx.doi.org/10.3109/10717544.2014.914986] [PMID: 24865287]
[14]
Fathi HA, Allam A, Elsabahy M, Fetih G, El-Badry M. Nanostructured lipid carriers for improved oral delivery and prolonged antihyperlipidemic effect of simvastatin. Colloids Surf B Biointerfaces 2018; 162: 236-45.
[http://dx.doi.org/10.1016/j.colsurfb.2017.11.064] [PMID: 29197789]
[15]
Ling Tan JS, Roberts CJ, Billa N. Mucoadhesive chitosan-coated nanostructured lipid carriers for oral delivery of amphotericin B. Pharm Dev Technol 2019; 24(4): 504-12.
[http://dx.doi.org/10.1080/10837450.2018.1515225] [PMID: 30132723]
[16]
Pailla SR, Talluri S, Rangaraj N, et al. Intranasal Zotepine Nanosuspension: intended for improved brain distribution in rats. Daru 2019; 27(2): 541-56.
[http://dx.doi.org/10.1007/s40199-019-00281-4] [PMID: 31256410]
[17]
Dalvadi H, Patel N, Parmar K. Systematic development of design of experiments (DoE) optimised self-microemulsifying drug delivery system of Zotepine. J Microencapsul 2017; 34(3): 308-18.
[http://dx.doi.org/10.1080/02652048.2017.1324920] [PMID: 28452252]
[18]
Dudhipala N, Janga KY, Gorre T. Comparative study of nisoldipine-loaded nanostructured lipid carriers and solid lipid nanoparticles for oral delivery: preparation, characterization, permeation and pharmacokinetic evaluation. Artif Cells Nanomed Biotechnol 2018; 46(sup2): 616-25.
[http://dx.doi.org/10.1080/21691401.2018.1465068] [PMID: 29688077]
[19]
Dudhipala N, Veerabrahma K. Improved anti-hyperlipidemic activity of Rosuvastatin Calcium via lipid nanoparticles: Pharmacokinetic and pharmacodynamic evaluation. Eur J Pharm Biopharm 2017; 110: 47-57.
[http://dx.doi.org/10.1016/j.ejpb.2016.10.022] [PMID: 27810472]
[20]
Run B, Narendar D, Veerabrahma K. Development of olmesartan medoxomil lipid-based nanoparticles and nanosuspension: preparation, characterization and comparative pharmacokinetic evaluation. Artif Cells Nanomed Biotechnol 2018; 46(1): 126-37.
[http://dx.doi.org/10.1080/21691401.2017.1299160] [PMID: 28290712]
[21]
Dudhipala N, Puchchakayala G. Capecitabine lipid nanoparticles for anti-colon cancer activity in 1,2-dimethylhydrazine-induced colon cancer: preparation, cytotoxic, pharmacokinetic, and pathological evaluation. Drug Dev Ind Pharm 2018; 44(10): 1572-82.
[http://dx.doi.org/10.1080/03639045.2018.1445264] [PMID: 29493289]
[22]
Dudhipala N, Veerabrahma K. Pharmacokinetic and pharmacodynamic studies of nisoldipine-loaded solid lipid nanoparticles developed by central composite design. Drug Dev Ind Pharm 2015; 41(12): 1968-77.
[http://dx.doi.org/10.3109/03639045.2015.1024685] [PMID: 25830370]
[23]
Thirumalesh C. Lipid nanocarriers of zotepine for enhanced oral bioavailability (master’s thesis). Warangal (India): Kakatiya University 2018.
[24]
Mandpe L, Pokharkar V. Quality by design approach to understand the process of optimization of iloperidone nanostructured lipid carriers for oral bioavailability enhancement. Pharm Dev Technol 2015; 20(3): 320-9.
[http://dx.doi.org/10.3109/10837450.2013.867445] [PMID: 24328553]
[25]
Almeida H, Lobão P, Frigerio C, et al. Preparation, characterization and biocompatibility studies of thermoresponsive eyedrops based on the combination of nanostructured lipid carriers (NLC) and the polymer Pluronic F-127 for controlled delivery of ibuprofen. Pharm Dev Technol 2017; 22(3): 336-49.
[http://dx.doi.org/10.3109/10837450.2015.1125922] [PMID: 28240141]
[26]
Tatke A, Dudhipala N, Janga KY, et al. In-situ gel of triamcinolone acetonide-loaded solid lipid nanoparticles for improved topical ocular delivery: tear kinetics and ocular disposition studies. Nanomaterials (Basel) 2018; 9(1) E33
[http://dx.doi.org/10.3390/nano9010033] [PMID: 30591688]
[27]
Jia LJ, Zhang DR, Li ZY, et al. Preparation and characterization of silybin-loaded nanostructured lipid carriers. Drug Deliv 2010; 17(1): 11-8.
[http://dx.doi.org/10.3109/10717540903431586] [PMID: 19941406]
[28]
Hu FQ, Jiang SP, Du YZ, Yuan H, Ye YQ, Zeng S. Preparation and characterization of stearic acid nanostructured lipid carriers by solvent diffusion method in an aqueous system. Colloids Surfaces B Biointer 2005; 45: 167-73.
[http://dx.doi.org/10.1016/j.colsurfb.2005.08.005]
[29]
Dudhipala N, Janga KY. Lipid nanoparticles of zaleplon for improved oral delivery by Box-Behnken design: optimization, in vitro and in vivo evaluation. Drug Dev Ind Pharm 2017; 43(7): 1205-14.
[http://dx.doi.org/10.1080/03639045.2017.1304957] [PMID: 28274147]
[30]
Kalofonos I, Kalfonos D, Martin-Doyle W, Hanko JA, Hagen EJ. Crystalline forms of zotepine hydrochloride United states patent WO2009152347A2. 2009.
[31]
Kudarha R, Dhas NL, Pandey A, Belgamwar VS, Ige PP. Box-Behnken study design for optimization of bicalutamide-loaded nanostructured lipid carrier: stability assessment. Pharm Dev Technol 2015; 20(5): 608-18.
[http://dx.doi.org/10.3109/10837450.2014.908305] [PMID: 24785784]
[32]
Bummer PM. Physical chemical considerations of lipid-based oral drug delivery--solid lipid nanoparticles. Crit Rev Ther Drug Carrier Syst 2004; 21(1): 1-20.
[http://dx.doi.org/10.1615/CritRevTherDrugCarrierSyst.v21.i1.10] [PMID: 15099183]
[33]
Beloqui A, Solinís MÁ, Rodríguez-Gascón A, Almeida AJ, Préat V. Nanostructured lipid carriers: Promising drug delivery systems for future clinics. Nanomedicine (Lond) 2016; 12(1): 143-61.
[http://dx.doi.org/10.1016/j.nano.2015.09.004] [PMID: 26410277]
[34]
Aljaeid BM, Hosny KM. Fabrication and evaluation of Phytomenadione as a nanostructure lipid carrier for enhancement of bioavailability. Pharm Dev Technol 2018; 23(4): 382-6.
[http://dx.doi.org/10.1080/10837450.2017.1312440] [PMID: 28346840]
[35]
Narendar D. A comprehensive review on solid lipid nanoparticles as delivery vehicle for enhanced pharmacokinetic and pharmacodynamic activity of poorly soluble drugs. Int J Pharm Sci Nanotech 2019; 12(2): 4421-40.

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