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Current Drug Delivery

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ISSN (Print): 1567-2018
ISSN (Online): 1875-5704

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Research Article

Polymeric Precipitation Inhibitor Assisted Supersaturable SMEDDS of Efavirenz Based on Experimental Observations and Molecular Mechanics

Author(s): Manmeet Singh, Dilpreet Singh, Sundar Mahajan, Bilal Ahmed Sheikh and Neena Bedi*

Volume 18, Issue 4, 2021

Published on: 31 July, 2020

Page: [513 - 530] Pages: 18

DOI: 10.2174/1567201817666200731165508

Price: $65

Abstract

Background: Supersaturable SMEDDS, a versatile dosage form, was investigated for improving the biopharmaceutical attributes and eradicating the food effect of poorly water soluble drug efavirenz.

Objective: The present research pursues the development of efavirenz loaded Supersaturable Self- Microemulsifying Drug Delivery System (SS SMEDDS) for improving biopharmaceutical performance.

Methods: Preformulation studies were carried out to determine the optimized range of lipid excipients to develop stable supersaturated SMEDDS (ST SMEDDS). The SS SMEDD formulation was prepared by adding hydroxypropyl methylcellulose as a polymeric precipitation inhibitor. The developed SS SMEDDS were evaluated for supersaturation behavior by performing in vitro supersaturation studies and molecular simulations by in silico docking. Dissolution was performed in biorelevant media to simulate fed/fasted conditions in gastrointestinal regions. Absorption behavior was determined through in vivo pharmacokinetics approach.

Results: The optimized ST SMEDDS formulation containing Maisine® CC, Tween 80 and Transcutol-P exhibited thermodynamic stability with quick rate of emulsification. The optimized SS SMEDDS containing suitable polymeric precipitation inhibitor exhibited enhanced efavirenz concentration in in vitro supersaturation test. The theoretical simulations by molecular docking revealed strong intermolecular interactions with a docking score of -3.004 KJ/mol. The dissolution performance of marketed product in biorelevant dissolution media inferred the existence of food effect in the dissolution of efavirenz. However, in SS SMEDDS, no significant differences in drug release behavior under different fasted/fed conditions signify that the food effect was neutralized. In vivo pharmacokinetics revealed a significant increase in the absorption profile of efavirenz from SS SMEDDS than that of ST SMEDDS and marketed product.

Conclusion: The designed delivery system indicated promising results in developing an effectual EFV formulation for HIV treatment.

Keywords: Efavirenz, SMEDDS, biorelevant media, food effect, absorption, HIV, BCS.

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[1]
Stegemann, S.; Leveiller, F.; Franchi, D.; de Jong, H.; Lindén, H. When poor solubility becomes an issue: from early stage to proof of concept. Eur. J. Pharm. Sci., 2007, 31(5), 249-261.
[http://dx.doi.org/10.1016/j.ejps.2007.05.110] [PMID: 17616376]
[2]
Custodio, J.M.; Wu, C.Y.; Benet, L.Z. Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption. Adv. Drug Deliv. Rev., 2008, 60(6), 717-733.
[http://dx.doi.org/10.1016/j.addr.2007.08.043] [PMID: 18199522]
[3]
Sathigari, S.; Chadha, G.; Lee, Y.H.P.; Wright, N.; Parsons, D.L.; Rangari, V.K.; Fasina, O.; Babu, R.J. Physicochemical characterization of efavirenz-cyclodextrin inclusion complexes. AAPS PharmSciTech, 2009, 10(1), 81-87.
[http://dx.doi.org/10.1208/s12249-008-9180-3] [PMID: 19148759]
[4]
Chiappetta, D.A.; Facorro, G.; de Celis, E.R.; Sosnik, A. Synergistic encapsulation of the anti-HIV agent efavirenz within mixed poloxamine/poloxamer polymeric micelles. Nanomedicine (Lond.), 2011, 7(5), 624-637.
[http://dx.doi.org/10.1016/j.nano.2011.01.017] [PMID: 21371572]
[5]
Lavra, Z.M.; Pereira de Santana, D.; Ré, M.I. Solubility and dissolution performances of spray-dried solid dispersion of Efavirenz in Soluplus. Drug Dev. Ind. Pharm., 2017, 43(1), 42-54.
[http://dx.doi.org/10.1080/03639045.2016.1205598] [PMID: 27349377]
[6]
Jain, S.; Sharma, J.M.; Agrawal, A.K.; Mahajan, R.R. Surface stabilized efavirenz nanoparticles for oral bioavailability enhancement. J. Biomed. Nanotechnol., 2013, 9(11), 1862-1874.
[http://dx.doi.org/10.1166/jbn.2013.1683] [PMID: 24059085]
[7]
Kotta, S.; Khan, A.W.; Ansari, S.H.; Sharma, R.K.; Ali, J. Anti HIV nanoemulsion formulation: optimization and in vitro-in vivo evaluation. Int. J. Pharm., 2014, 462(1-2), 129-134.
[http://dx.doi.org/10.1016/j.ijpharm.2013.12.038] [PMID: 24374067]
[8]
Taneja, S.; Shilpi, S.; Khatri, K. Formulation and optimization of efavirenz nanosuspensions using the precipitation-ultrasonication technique for solubility enhancement. Artif. Cells Nanomed. Biotechnol., 2016, 44(3), 978-984.
[PMID: 25724312]
[9]
Singh, B.; Bandopadhyay, S.; Kapil, R.; Singh, R.; Katare, O. Self-emulsifying drug delivery systems (SEDDS): formulation development, characterization, and applications. Crit. Rev. Ther. Drug Carrier Syst., 2009, 26(5), 427-521.
[http://dx.doi.org/10.1615/CritRevTherDrugCarrierSyst.v26.i5.10] [PMID: 20136631]
[10]
Kamble, R.N.; Mehta, P.P.; Kumar, A. Efavirenz Self-Nano-Emulsifying Drug Delivery System: in vitro and In Vivo Evaluation. AAPS PharmSciTech, 2016, 17(5), 1240-1247.
[http://dx.doi.org/10.1208/s12249-015-0446-2] [PMID: 26573159]
[11]
Kamboj, S.; Sethi, S.; Rana, V. Lipid based delivery of Efavirenz: An answer to its erratic absorption and food effect. Eur. J. Pharm. Sci., 2018, 123, 199-216.
[http://dx.doi.org/10.1016/j.ejps.2018.07.037] [PMID: 30031861]
[12]
Porter, C.J.; Trevaskis, N.L.; Charman, W.N. Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs. Nat. Rev. Drug Discov., 2007, 6(3), 231-248.
[http://dx.doi.org/10.1038/nrd2197] [PMID: 17330072]
[13]
Date, A.A.; Desai, N.; Dixit, R.; Nagarsenker, M. Self-nanoemulsifying drug delivery systems: formulation insights, applications and advances. Nanomedicine (Lond.), 2010, 5(10), 1595-1616.
[http://dx.doi.org/10.2217/nnm.10.126] [PMID: 21143036]
[14]
Mohsin, K.; Long, M.A.; Pouton, C.W. Design of lipid-based formulations for oral administration of poorly water-soluble drugs: precipitation of drug after dispersion of formulations in aqueous solution. J. Pharm. Sci., 2009, 98(10), 3582-3595.
[http://dx.doi.org/10.1002/jps.21659] [PMID: 19130605]
[15]
Dokania, S.; Joshi, A.K. Self-microemulsifying drug delivery system (SMEDDS): Challenges and Road Ahead. Drug Deliv., 2014, 32, 1-16.
[PMID: 24670091]
[16]
Singh, B.; Singh, R.; Bandyopadhyay, S.; Kapil, R.; Garg, B. Optimized nanoemulsifying systems with enhanced bioavailability of carvedilol. Colloids Surf. B Biointerfaces, 2013, 101, 465-474.
[http://dx.doi.org/10.1016/j.colsurfb.2012.07.017] [PMID: 23010056]
[17]
Beg, S.; Jena, S.S.; Patra, ChN.; Rizwan, M.; Swain, S.; Sruti, J.; Rao, M.E.; Singh, B. Development of solid self-nanoemulsifying granules (SSNEGs) of ondansetron hydrochloride with enhanced bioavailability potential. Colloids Surf. B Biointerfaces, 2013, 101, 414-423.
[http://dx.doi.org/10.1016/j.colsurfb.2012.06.031] [PMID: 23010049]
[18]
Zhang, S.; Sun, M.; Zhao, Y.; Song, X.; He, Z.; Wang, J.; Sun, J. Molecular mechanism of polymer-assisting supersaturation of poorly water-soluble loratadine based on experimental observations and molecular dynamic simulations. Drug Deliv. Transl. Res., 2017, 7(5), 738-749.
[http://dx.doi.org/10.1007/s13346-017-0401-8] [PMID: 28677032]
[19]
Jain, A.; Kaur, R.; Beg, S.; Kushwah, V.; Jain, S.; Singh, B. Novel cationic supersaturable nanomicellar systems of raloxifene hydrochloride with enhanced biopharmaceutical attributes. Drug Deliv. Transl. Res., 2018, 8(3), 670-692.
[http://dx.doi.org/10.1007/s13346-018-0514-8] [PMID: 29589250]
[20]
Kumar, M.; Singh, D.; Bedi, N. Mefenamic acid-loaded solid SMEDDS: an innovative aspect for dose reduction and improved pharmacodynamic profile. Ther. Deliv., 2019, 10(1), 21-36.
[http://dx.doi.org/10.4155/tde-2018-0053] [PMID: 30730824]
[21]
Gao, P.; Rush, B.D.; Pfund, W.P.; Huang, T.; Bauer, J.M.; Morozowich, W.; Kuo, M.S.; Hageman, M.J. Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability. J. Pharm. Sci., 2003, 92(12), 2386-2398.
[http://dx.doi.org/10.1002/jps.10511] [PMID: 14603484]
[22]
Rajpoot, B.S. Method development and validation of RP-HPLC method in the detection of efavirenz in bulk and tablet formulation. Int. Res. J. Pharm, 2012, 3(7), 297-300.
[23]
Chavan, R.B.; Thipparaboina, R.; Kumar, D.; Shastri, N.R. Evaluation of the inhibitory potential of HPMC, PVP and HPC polymers on nucleation and crystal growth. RSC Advances, 2016, 6, 77569-77576.
[http://dx.doi.org/10.1039/C6RA19746A]
[24]
Dash, R.N.; Mohammed, H.; Humaira, T. Design, optimization, and evaluation of ezetimibe solid supersaturatable self-nanoemulsifying drug delivery for enhanced solubility and dissolution. J. Pharm. Investig., 2016, 46, 153-168.
[http://dx.doi.org/10.1007/s40005-015-0225-9]
[25]
Singh, D.; Tiwary, A.K.; Bedi, N. Canagliflozin loaded SMEDDS: formulation optimization for improved solubility, permeability and pharmacokinetic performance. J. Pharm. Investig., 2019, 49, 67-85.
[http://dx.doi.org/10.1007/s40005-018-0385-5]
[26]
Klein, S. The use of biorelevant dissolution media to forecast the in vivo performance of a drug. AAPS J., 2010, 12(3), 397-406.
[http://dx.doi.org/10.1208/s12248-010-9203-3] [PMID: 20458565]
[27]
Constantinides, P.P. Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm. Res., 1995, 12(11), 1561-1572.
[http://dx.doi.org/10.1023/A:1016268311867] [PMID: 8592652]
[28]
Alves, L.D.S.; de La Roca Soares, M.F.; de Albuquerque, C.T.; da Silva, E.R.; Vieira, A.C.C.; Fontes, D.A.F.; Figueirêdo, C.B.; Soares Sobrinho, J.L.; Rolim Neto, P.J. Solid dispersion of efavirenz in PVP K-30 by conventional solvent and kneading methods. Carbohydr. Polym., 2014, 104, 166-174.
[http://dx.doi.org/10.1016/j.carbpol.2014.01.027] [PMID: 24607174]
[29]
Shakeel, F.; Haq, N.; Raish, M.; Siddiqui, N.A.; Alanazi, F.K.; Alsarra, I.A. Anti-oxidant and cytotoxic effects of vanillin via eucalyptus oil containing self-nanoemulsifying drug delivery system. J. Mol. Liq., 2016, 218, 233-239.
[http://dx.doi.org/10.1016/j.molliq.2016.02.077]
[30]
Paolino, D.; Ventura, C.A.; Nisticò, S.; Puglisi, G.; Fresta, M. Lecithin microemulsions for the topical administration of ketoprofen: percutaneous adsorption through human skin and in vivo human skin tolerability. Int. J. Pharm., 2002, 244(1-2), 21-31.
[http://dx.doi.org/10.1016/S0378-5173(02)00295-8] [PMID: 12204562]
[31]
Patel, R.B.; Patel, M.R.; Bhatt, K.K.; Patel, B.G. Formulation consideration and characterization of microemulsion drug delivery system for transnasal administration of carbamazepine. Bull. Fac. Pharm. Cairo Univ., 2013, 51(2), 243-253.
[http://dx.doi.org/10.1016/j.bfopcu.2013.07.002]
[32]
Hong, E.P.; Kim, J.Y.; Kim, S.H.; Hwang, K.M.; Park, C.W.; Lee, H.J.; Kim, D.W.; Weon, K.Y.; Jeong, S.Y.; Park, E.S. Formulation and evaluation of a self-microemulsifying drug delivery system containing bortezomib. Chem. Pharm. Bull. (Tokyo), 2016, 64(8), 1108-1117.
[http://dx.doi.org/10.1248/cpb.c16-00035] [PMID: 27477648]
[33]
Kallakunta, V.R.; Eedara, B.B.; Jukanti, R.; Ajmeera, R.K.; Bandari, S.A. Gelucire 44/14 and Labrasol Based Solid Self Emulsifying Drug Delivery System: Formulation and Evaluation. J. Pharm. Investig., 2013, 43, 185-196.
[http://dx.doi.org/10.1007/s40005-013-0060-9]
[34]
Cui, J.; Yu, B.; Zhao, Y.; Zhu, W.; Li, H.; Lou, H.; Zhai, G. Enhancement of oral absorption of curcumin by self-microemulsifying drug delivery systems. Int. J. Pharm., 2009, 371(1-2), 148-155.
[http://dx.doi.org/10.1016/j.ijpharm.2008.12.009] [PMID: 19124065]
[35]
Fusao, U.; Kazuko, M.; Akira, K.; Kenji, N.; Keiji, Y. Inhibitory effects of water-soluble polymers on precipitation of RS-8359. Int. J. Pharm., 1997, 154, 59-66.
[http://dx.doi.org/10.1016/S0378-5173(97)00129-4]
[36]
Raghavan, S.L.; Trividic, A.; Davis, A.F.; Hadgraft, J. Effect of cellulose polymers on supersaturation and in vitro membrane transport of hydrocortisone acetate. Int. J. Pharm., 2000, 193(2), 231-237.
[http://dx.doi.org/10.1016/S0378-5173(99)00345-2] [PMID: 10606787]
[37]
Stillhart, C.; Imanidis, G.; Kuentz, M. Insights into drug precipitation kinetics during in vitro digestion of a lipid-based drug delivery system using in-line raman spectroscopy and mathematical modeling. Pharm. Res., 2013, 30(12), 3114-3130.
[http://dx.doi.org/10.1007/s11095-013-0999-2] [PMID: 23456098]
[38]
Vithani, K.; Hawley, A.; Jannin, V.; Pouton, C.; Boyd, B.J. Solubilisation behaviour of poorly water-soluble drugs during digestion of solid SMEDDS. Eur. J. Pharm. Biopharm., 2018, 130, 236-246.
[http://dx.doi.org/10.1016/j.ejpb.2018.07.006] [PMID: 29981444]
[39]
Phan, S.; Salentinig, S.; Prestidge, C.A.; Boyd, B.J. Self-assembled structures formed during lipid digestion: characterization and implications for oral lipid-based drug delivery systems. Drug Deliv. Transl. Res., 2014, 4(3), 275-294.
[http://dx.doi.org/10.1007/s13346-013-0168-5] [PMID: 25786882]
[40]
Sassene, P.; Kleberg, K.; Williams, H.D.; Bakala-N’Goma, J.C.; Carrière, F.; Calderone, M.; Jannin, V.; Igonin, A.; Partheil, A.; Marchaud, D.; Jule, E.; Vertommen, J.; Maio, M.; Blundell, R.; Benameur, H.; Porter, C.J.; Pouton, C.W.; Müllertz, A. Toward the establishment of standardized in vitro tests for lipid-based formulations, part 6: effects of varying pancreatin and calcium levels. AAPS J., 2014, 16(6), 1344-1357.
[http://dx.doi.org/10.1208/s12248-014-9672-x] [PMID: 25274609]
[41]
Thomas, N.; Holm, R.; Müllertz, A.; Rades, T. in vitro and in vivo performance of novel supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS). J. Control. Release, 2012, 160(1), 25-32.
[http://dx.doi.org/10.1016/j.jconrel.2012.02.027] [PMID: 22405903]
[42]
Vandecruys, R.; Peeters, J.; Verreck, G.; Brewster, M.E. Use of a screening method to determine excipients which optimize the extent and stability of supersaturated drug solutions and application of this system to solid formulation design. Int. J. Pharm., 2007, 342(1-2), 168-175.
[http://dx.doi.org/10.1016/j.ijpharm.2007.05.006] [PMID: 17573214]
[43]
Nekkanti, V.; Karatgi, P.; Prabhu, R.; Pillai, R. Solid self-microemulsifying formulation for candesartan cilexetil. AAPS PharmSciTech, 2010, 11(1), 9-17.
[http://dx.doi.org/10.1208/s12249-009-9347-6] [PMID: 20013081]
[44]
Gao, P.; Akrami, A.; Alvarez, F.; Hu, J.; Li, L.; Ma, C.; Surapaneni, S. Characterization and optimization of AMG 517 supersaturatable self-emulsifying drug delivery system (S-SEDDS) for improved oral absorption. J. Pharm. Sci., 2009, 98(2), 516-528.
[http://dx.doi.org/10.1002/jps.21451] [PMID: 18543293]

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