Formulation Development and Characterization of Lumefantrine Solid Dispersion with Piperine for Solubility Enhancement
Abstract
Lumefantrine low/variable bioavailability with low aqueous solubility is associated with their crystallinity and P-glycoprotein (P-gp) mediated efflux. Herein, to improve the dissolution and hence the oral bioavailability, amorphous solid dispersions (SD) of lumefantrine (LUMF) containing piperine (PIP), a P-gp and CYP3A4 inhibitor, were prepared with Copovidone/Kollidon® VA 64 (KOL) at three different ratios with increasing content of the polymer. The PIP-LUMF-KOL SD at ratio of 1:6:18 demonstrated higher aqueous solubility of LUMF and hence were characterized by DSC, FTIR and XRD. The improved dissolution resulting due to loss of crystallinity of LUMF was confirmed by DSC thermogram and XRD diffractogram of LUMF-PIP-SD while FTIR studies investigated the possible intermolecular interactions between LUMF and PIP and /or KOL. DSC and dissolution experiments validated the stability of LUMFPIP-Sol SD for 90 days under stressed humidity and temperature conditions. Overall, the data suggest that the SD of LUMF incorporated with P-gp inhibitor PIP, enhances dissolution and hence could improve the bioavailability of LUMF.
Keywords:
Lumefantrine; Piperine; Solid Dispersion; Solubility; ReleaseDOI
https://doi.org/10.25004/IJPSDR.2023.150318References
Du Plessis LH, Govender K, Denti P, Wiesner L. In vivo efficacy and bioavailability of lumefantrine : Evaluating the application of Pheroid technology. Eur J Pharm Biopharm. 2015; 97:68-77.
Patel K, Sarma V, Vavia P. Design and evaluation of lumefantrine–oleic acid self-nanoemulsifying ionic complex for enhanced dissolution. DARU J Pharm Sci. 2013; 21(1):1-11.
White NJ, vanVugt M, Ezzet FD. Clinical pharmacokinetics and pharmacodynamics of artemether-lumefantrine. Clin Pharmacokinet. 1999; 37(2):105-125.
Wahajuddin M, Raju KS, Singh SP, Taneja I. Investigation of the functional role of P-glycoprotein in limiting the oral bioavailability of lumefantrine. Antimicrob Agents Chemother. 2014; 58(1):489-494.
Gahoi S, Jain GK, Tripathi R, Pandey SK, Anwar M, Warsi MH, Singhal M, Khar RK, Ahmad, FJ. Enhanced antimalarial activity of lumefantrine nanopowder prepared by wet-milling DYNO MILL technique. Colloids Surf B Biointerfaces. 2012; 95:16-22.
Garg A, Bhalala K, Tomar DS. In-situ single pass intestinal permeability and pharmacokinetic study of developed lumefantrine loaded solid lipid nanoparticles. Int J Pharm. 2017; 516(1-2):120-130.
Bhatnagar P, Dhote V, Mahajan S, Mishra P, Mishra D. Solid dispersion in pharmaceutical drug development: from basics to clinical applications. Curr Drug Deliv. 2014; 11(2):155-171.
Baghel S, Cathcart H, O’Reilly NJ. Polymeric Amorphous Solid Dispersions: A Review of amorphization, crystallization, stabilization, solid-state characterization, and aqueous solubilization of biopharmaceutical classification system class II drugs. J Pharm Sci. 2016;105(9):2527–2544.
Huang S, Mao C, Williams III RO, Yang CY. Solubility advantage (and disadvantage) of pharmaceutical amorphous solid dispersions. J Pharm Sci. 2016; 105(12):3549-3561.
Sathigari SK, Radhakrishnan VK, Davis VA, Parsons DL, Babu RJ. Amorphous-state characterization of efavirenz—polymer hot-melt extrusion systems for dissolution enhancement. J Pharm Sci. 2012; 101(9):3456–3464.
Shah N, Sandhu H, Choi DS, Chokshi H, Malick AW. Amorphous Solid Dispersions: Theory and Practice. Springer, 2014.
Chiou, WL, Riegelman, S. Pharmaceutical applications of solid dispersion systems. J Pharm Sci. 1971; 60(9):1281-1302.
Serajddin AT. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci. 1999; 88(10):1058-1066.
Teja SB, Patil SP, Shete G, Patel S, Bansal AK. Drug-excipient behavior in polymeric amorphous solid dispersions. J Excip Food Chem. 2013; 4(3):70–94.
Li Y, Pang H, Guo Z, Lin L, Dong Y, Li, G, Lu M, Wu, C. Interactions between drugs and polymers influencing hot melt extrusion. J Pharm Pharmacol. 2014; 66(2):148-166.
Aso Y, Yoshioka S. Molecular mobility of nifedipine -PVP and phenobarbital-PVP solid dispersions as measured by 13C-NMR spin-lattice relaxation time. J Pharm Sci. 2006; 95(2):318-325.
Konno H, Handa T, Alonzo DE, Taylor LS. Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. Eur J Pharm Biopharm. 2008; 70(2) :493-499.
Bhardwaj V, Trasi NS, Zemlyanov DY, Taylor LS. Surface area normalized dissolution to study differences in itraconazole-copovidone solid dispersions prepared by spray-drying and hot melt extrusion. Int J Pharm. 2018; 540(1-2):106-119.
Trasi NS, Bhujbal SV, Zemlyanov DY, Zhou QT, Taylor LS. Physical stability and release properties of lumefantrine amorphous solid dispersion granules prepared by a simple solvent evaporation approach. Int J Pharm. 2020; 2:100052.
Bhujbal SV, Pathak V, Zemlyanov DY, Taylor LS, Zhou QT. Physical stability and dissolution of lumefantrine amorphous solid dispersions produced by spray anti-solvent precipitation. J Pharm Sci. 2021: 110(6):2423-2431.
Valkama E, Haluska O, Lehto VP, Korhonen O, Pajula K. Production and stability of amorphous solid dispersions produced by a Freeze-drying method from DMSO. Int J Pharm. 2021; 606:120902.
Vo CLN, Park C, Lee BJ. Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. Eur J Pharm Biopharm. 2013; 85(3):799-813.
Mehanna MM, Motawaa AM, Samaha MW. In sight into tadalafil–block copolymer binary solid dispersion: mechanistic investigation of dissolution enhancement. Int J Pharm. 2010; 402(1-2):78-88.
Di L, Fish PV, Mano T. Bridging solubility between drug discovery and development. Drug Discov Today. 2012; 17(9-10):486-495.
Savjani KT, Gajjar AK, Savjani JK. Drug solubility: importance and enhancement techniques. Int Sch Res Notices. 2012; 3:1-10.
Varma MV, Panchagnula R. Enhanced oral paclitaxel absorption with vitamin E-TPGS: effect on solubility and permeability in vitro, in situ and in vivo. Eur J Pharm Sci. 2005; 25(4-5):445-453.
Ayrton A, Morgan P. Role of transport proteins in drug absorption, distribution and excretion. Xenobiotica. 2001; 31:469–497.
Kaur V, Garg T, Rath G, Goyal AK. Therapeutic potential of nanocarrier for overcoming to P-glycoprotein. J Drug Target. 2014; 22(10):859-870.
Athukuri BL, Neerati P, 2017 Enhanced oral bioavailability of domperidone with piperine in male wistar rats: involvement of CYP3A1 and P-gp inhibition. J Pharm Pharm Sci. 2017; 20:28-37.
Han Y, Tan TMC, Lim LY. In vitro and in vivo evaluation of the effects of piperine on P-gp function and expression. Toxicol Appl Pharmacol. 2008; 230(3):283-289.
Singh DV, Godbole MM, Misra K. A plausible explanation for enhanced bioavailability of P-gp substrates in presence of piperine: simulation for next generation of P-gp inhibitors. J Mol Model. 2013; 19(1):227-238.
Zhou S, Lim LY, Chowbay B. Herbal modulation of P‐glycoprotein. Drug Metab Rev. 2004; 36(1): 57-104.
Jain JP, Leong FJ, Chen L, Kalluri S, Koradia V, Stein DS, Wolf MC, Sunkara G, Kota J. Bioavailability of lumefantrine is significantly enhanced with a novel formulation approach, an outcome from a randomized, open-label pharmacokinetic study in healthy volunteers. Antimicrob Agents Chemother. 2017; 61(9):e00868-17.
Majeed M, Badmaev V, Rajendran R. Use of piperine as a bioavailability enhancer. 1998. United States Patent Number, US005744161A.
Wdowiak K, Miklaszewski A, Pietrzak R, Cielecka-Piontek J. Amorphous system of hesperetin and piperine—improvement of apparent solubility, permeability, and biological Activities. Int J Mol Sci. 2023; 24(5):48-59.
Fule R, Meer T, Sav A, Amin, P. Solubility and dissolution rate enhancement of lumefantrine using hot melt extrusion technology with physicochemical characterization. J Pharma Invest. 2013; 43:305-321.
Grohganz H, Priemel PA, Löbmann K, Nielsen LH, Laitinen R, Mullertz A, Van den Mooter G, Rades, T. Refining stability and dissolution rate of amorphous drug formulations. Expert Opin Drug Deliv. 2014; 11(6):977-989.
Fule R, Dhamecha D, Maniruzzaman M, Khale A, Amin P. Development of hot melt co-formulated antimalarial solid dispersion system in fixed dose form (ARLUMELT): evaluating amorphous state and in vivo performance. Int J Pharm. 2015; 496(1):137-156.
Chokshi RJ, Zia H, Sandhu HK, Shah NH, Malick, WA. Improving the dissolution rate of poorly water-soluble drug by solid dispersion and solid solution—pros and cons. Drug Deliv. 2007; 14(1):33-45.
Liu J, Cao F, Zhang C, Ping Q. Use of polymer combinations in the preparation of solid dispersions of a thermally unstable drug by hot-melt extrusion. Acta Pharmaceutica Sinica B. 2013; 3(4):263-272.
Ashour EA, Majumdar S, Alsheteli A, Alshehri S, Alsulays B, Feng X, Gryczke A, Kolter K, Langley N, Repka, MA. Hot melt extrusion as an approach to improve solubility, permeability and oral absorption of a psychoactive natural product, piperine. J Pharm Pharm. 2016; 68(8):989-998.
Published
Abstract Display: 374 
PDF Downloads: 388 
