Abstract
Background: Fenofibrate (FNB) is an effective drug for the treatment of hypertriglyceridemia, hypercholesterolemia as well as mixed hyperlipidemia. However, due to its poor aqueous solubility, FNB has the problem of poor oral absorption followed by low bioavailability.
Objective: The aim of this research was to construct FNB amorphous solid dispersion employing PVP VA64 as the carrier by hot-melt extrusion method, in order to improve the oral bioavailability. Additionally, the cell transport experiment was conducted to further investigate the mechanism of promoted osmotic absorption.
Methods: The physical state of the obtained solid dispersion was characterized using SEM, DSC and XRD. Besides, in vitro Caco-2 cells were used to evaluate the cytotoxicity of the carrier and mimic gastrointestinal drug permeation. At last, in vitro dissolution test and in vivo bioavailability study were also carried out.
Results: The prepared FNB solid dispersion was found to be an amorphous state after hot-melt extrusion process. In vitro cytotoxicity test on Caco-2 cells confirmed the excellent biocompatibility of the carrier PVP VA64. Besides, transwell cell transport assay and in vitro dissolution test revealed that FNB released from amorphous solid dispersion was equipped with an improved transmembrane transport and dissolution rate. Moreover, pharmacokinetic study in beagle dogs showed that comparing with commercial micronized product Lipanthyl®, the oral bioavailability of FNB solid dispersion was significantly enhanced (2.45 fold).
Conclusion: In conclusion, PVP VA64 can be regarded as a promising polymer to enhance the bioavailability of poorly water-soluble drugs such as FNB processed by hot-melt extrusion. Besides, investigations on the mechanism of the enhanced penetration are expected to lay a foundation on the subsequent development of effective and practical solid dispersion.
Keywords: Fenofibrate, PVP VA64, amorphous solid dispersion, hot-melt extrusion, cell transport, bioavailability.
Graphical Abstract
[1]
Zhang, M.; Li, H.; Lang, B.; O’Donnell, K.; Zhang, H.; Wang, Z.; Dong, Y.; Wu, C.; Williams, R.O., III Formulation and delivery of improved amorphous fenofibrate solid dispersions prepared by thin film freezing. Eur. J. Pharm. Biopharm., 2012, 82(3), 534-544.
[http://dx.doi.org/10.1016/j.ejpb.2012.06.016] [PMID: 22974985]
[http://dx.doi.org/10.1016/j.ejpb.2012.06.016] [PMID: 22974985]
[2]
Weng, T.; Qi, J.; Lu, Y.; Wang, K.; Tian, Z.; Hu, K.; Yin, Z.; Wu, W. The role of lipid-based nano delivery systems on oral bioavailability enhancement of fenofibrate, a BCS II drug: Comparison with fast-release formulations. J. Nanobiotechnol, 2014, 12, 39.
[http://dx.doi.org/10.1186/s12951-014-0039-3] [PMID: 25248304]
[http://dx.doi.org/10.1186/s12951-014-0039-3] [PMID: 25248304]
[3]
He, H.; Yang, R.; Tang, X. In vitro and in vivo evaluation of fenofibrate solid dispersion prepared by hot-melt extrusion. Drug Dev. Ind. Pharm., 2010, 36(6), 681-687.
[http://dx.doi.org/10.3109/03639040903449720] [PMID: 20136483]
[http://dx.doi.org/10.3109/03639040903449720] [PMID: 20136483]
[4]
Vogt, M.; Kunath, K.; Dressman, J.B. Dissolution enhancement of fenofibrate by micronization, cogrinding and spray-drying: Comparison with commercial preparations. Eur. J. Pharm. Biopharm., 2008, 68(2), 283-288.
[http://dx.doi.org/10.1016/j.ejpb.2007.05.010] [PMID: 17574403]
[http://dx.doi.org/10.1016/j.ejpb.2007.05.010] [PMID: 17574403]
[5]
Kerc, J.; Srcic, S.; Knez, Z.; Sencar-Bozic, P. Micronization of drugs using supercritical carbon dioxide. Int. J. Pharm., 1999, 182(1), 33-39.
[http://dx.doi.org/10.1016/S0378-5173(99)00063-0] [PMID: 10332072]
[http://dx.doi.org/10.1016/S0378-5173(99)00063-0] [PMID: 10332072]
[6]
Kawakami, K.; Zhang, S.; Chauhan, R.S.; Ishizuka, N.; Yamamoto, M.; Masaoka, Y.; Kataoka, M.; Yamashita, S.; Sakuma, S. Preparation of fenofibrate solid dispersion using electrospray deposition and improvement in oral absorption by instantaneous post-heating of the formulation. Int. J. Pharm., 2013, 450(1-2), 123-128.
[http://dx.doi.org/10.1016/j.ijpharm.2013.04.006] [PMID: 23603098]
[http://dx.doi.org/10.1016/j.ijpharm.2013.04.006] [PMID: 23603098]
[7]
Nosrati, H.; Rakhshbahar, A.; Salehiabar, M.; Afroogh, S.; Kheiri Manjili, H.; Danafar, H. Davaran, S. Bovine serum albumin: An efficient biomacromolecule nanocarrier for improving the therapeutic efficacy of chrysin. J. Mol. Liq., 2018, 271, 639-646.
[http://dx.doi.org/10.1016/j.molliq.2018.06.066]
[http://dx.doi.org/10.1016/j.molliq.2018.06.066]
[8]
Nosrati, H.; Charmi, J.; Abedini, S.; Rashidi, N.; Attari, E.; Davaran, S.; Danafar, H. Kheiri Manjili, H. Preparation and characterization of magnetic theranostic nanoparticles for curcumin delivery and evaluation as MRI contrast agent. Appl. Organomet. Chem., 2018, 32(12), e4588.
[http://dx.doi.org/10.1002/aoc.4588]
[http://dx.doi.org/10.1002/aoc.4588]
[9]
Zuo, B.; Sun, Y.; Li, H.; Liu, X.; Zhai, Y.; Sun, J.; He, Z. Preparation and in vitro/in vivo evaluation of fenofibrate nanocrystals. Int. J. Pharm., 2013, 455(1-2), 267-275.
[http://dx.doi.org/10.1016/j.ijpharm.2013.07.021] [PMID: 23876497]
[http://dx.doi.org/10.1016/j.ijpharm.2013.07.021] [PMID: 23876497]
[10]
Mochalin, V.N.; Sagar, A.; Gour, S.; Gogotsi, Y. Manufacturing nanosized fenofibrate by salt assisted milling. Pharm. Res., 2009, 26(6), 1365-1370.
[http://dx.doi.org/10.1007/s11095-009-9846-x] [PMID: 19224343]
[http://dx.doi.org/10.1007/s11095-009-9846-x] [PMID: 19224343]
[11]
de Waard, H.; Hinrichs, W.L.; Frijlink, H.W. A novel bottom-up process to produce drug nanocrystals: controlled crystallization during freeze-drying. J. Control. Release, 2008, 128(2), 179-183.
[http://dx.doi.org/10.1016/j.jconrel.2008.03.002] [PMID: 18423767]
[http://dx.doi.org/10.1016/j.jconrel.2008.03.002] [PMID: 18423767]
[12]
Niu, X.; Wan, L.; Hou, Z.; Wang, T.; Sun, C.; Sun, J.; Zhao, P.; Jiang, T.; Wang, S. Mesoporous carbon as a novel drug carrier of fenofibrate for enhancement of the dissolution and oral bioavailability. Int. J. Pharm., 2013, 452(1-2), 382-389.
[http://dx.doi.org/10.1016/j.ijpharm.2013.05.016] [PMID: 23688621]
[http://dx.doi.org/10.1016/j.ijpharm.2013.05.016] [PMID: 23688621]
[13]
Zhao, Z.; Gao, Y.; Wu, C.; Hao, Y.; Zhao, Y.; Xu, J. Development of novel core-shell dual-mesoporous silica nanoparticles for the production of high bioavailable controlled-release fenofibrate tablets. Drug Dev. Ind. Pharm., 2016, 42(2), 199-208.
[http://dx.doi.org/10.3109/03639045.2015.1039018] [PMID: 26114553]
[http://dx.doi.org/10.3109/03639045.2015.1039018] [PMID: 26114553]
[14]
Van Speybroeck, M.; Mellaerts, R.; Mols, R.; Thi, T.D.; Martens, J.A.; Van Humbeeck, J.; Annaert, P.; Van den Mooter, G.; Augustijns, P. Enhanced absorption of the poorly soluble drug fenofibrate by tuning its release rate from ordered mesoporous silica. Eur. J. Pharm. Sci., 2010, 41(5), 623-630.
[http://dx.doi.org/10.1016/j.ejps.2010.09.002] [PMID: 20850527]
[http://dx.doi.org/10.1016/j.ejps.2010.09.002] [PMID: 20850527]
[15]
Tian, Z.; Yi, Y.; Yuan, H.; Han, J.; Zhang, X.; Xie, Y.; Lu, Y.; Qi, J.; Wu, W. Solidification of Nanostructured Lipid Carriers (NLCs) onto pellets by fluid-bed coating: Preparation, in vitro characterization and bioavailability in dogs. Powder Technol., 2013, 247, 120-127.
[http://dx.doi.org/10.1016/j.powtec.2013.07.010]
[http://dx.doi.org/10.1016/j.powtec.2013.07.010]
[16]
Borkar, N.; Xia, D.; Holm, R.; Gan, Y.; Müllertz, A.; Yang, M.; Mu, H. Investigating the correlation between in vivo absorption and in vitro release of fenofibrate from lipid matrix particles in biorelevant medium. Eur. J. Pharm. Sci., 2014, 51, 204-210.
[http://dx.doi.org/10.1016/j.ejps.2013.09.022] [PMID: 24134899]
[http://dx.doi.org/10.1016/j.ejps.2013.09.022] [PMID: 24134899]
[17]
Kawabata, Y.; Wada, K.; Nakatani, M.; Yamada, S.; Onoue, S. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: Basic approaches and practical applications. Int. J. Pharm., 2011, 420(1), 1-10.
[http://dx.doi.org/10.1016/j.ijpharm.2011.08.032] [PMID: 21884771]
[http://dx.doi.org/10.1016/j.ijpharm.2011.08.032] [PMID: 21884771]
[18]
Hugo, M.; Kunath, K.; Dressman, J. Selection of excipient, solvent and packaging to optimize the performance of spray-dried formulations: Case example fenofibrate. Drug Dev. Ind. Pharm., 2013, 39(2), 402-412.
[http://dx.doi.org/10.3109/03639045.2012.685176] [PMID: 22591213]
[http://dx.doi.org/10.3109/03639045.2012.685176] [PMID: 22591213]
[19]
Zhao, Y.M.; Zhao, H.Y.; Ma, C. Preparation of nimesulide solid dispersion by hot melt extrusion technology. J. Chin. Pharm. Sci., 2013, 48(3), 185-190.
[http://dx.doi.org/10.11669/cpj.2013.03.007]
[http://dx.doi.org/10.11669/cpj.2013.03.007]
[20]
Zhefei, G.; Yongcheng, L.; Xu, L.; Ming, L.; Chuanbin, W. Study on the preparation technology and quality evaluation of diflunisal solid dispersion. Guangdong Yaoxueyuan Xuebao, 2013, (04), 357-362.
[21]
Patterson, J.E.; James, M.B.; Forster, A.H.; Lancaster, R.W.; Butler, J.M.; Rades, T. Preparation of glass solutions of three poorly water soluble drugs by spray drying, melt extrusion and ball milling. Int. J. Pharm., 2007, 336(1), 22-34.
[http://dx.doi.org/10.1016/j.ijpharm.2006.11.030] [PMID: 17174493]
[http://dx.doi.org/10.1016/j.ijpharm.2006.11.030] [PMID: 17174493]
[22]
Won, D.H.; Kim, M.S.; Lee, S.; Park, J.S.; Hwang, S.J. Improved physicochemical characteristics of felodipine solid dispersion particles by supercritical anti-solvent precipitation process. Int. J. Pharm., 2005, 301(1-2), 199-208.
[http://dx.doi.org/10.1016/j.ijpharm.2005.05.017] [PMID: 16024189]
[http://dx.doi.org/10.1016/j.ijpharm.2005.05.017] [PMID: 16024189]
[23]
Ibrahim, A.H.; Ibrahim, H.M.; Ismael, H.R.; Samy, A.M. Optimization and evaluation of lyophilized fenofibrate nanoparticles with enhanced oral bioavailability and efficacy. Pharm. Dev. Technol., 2018, 23(4), 358-369.
[http://dx.doi.org/10.1080/10837450.2017.1295065] [PMID: 29069712]
[http://dx.doi.org/10.1080/10837450.2017.1295065] [PMID: 29069712]
[24]
Repka, M.A.; Shah, S.; Lu, J.; Maddineni, S.; Morott, J.; Patwardhan, K.; Mohammed, N.N. Melt extrusion: Process to product. Expert Opin. Drug Deliv., 2012, 9(1), 105-125.
[http://dx.doi.org/10.1517/17425247.2012.642365] [PMID: 22145932]
[http://dx.doi.org/10.1517/17425247.2012.642365] [PMID: 22145932]
[25]
Breitenbach, J. Melt extrusion: from process to drug delivery technology. Eur. J. Pharm. Biopharm., 2002, 54(2), 107-117.
[http://dx.doi.org/10.1016/S0939-6411(02)00061-9] [PMID: 12191680]
[http://dx.doi.org/10.1016/S0939-6411(02)00061-9] [PMID: 12191680]
[26]
Vynckier, A.K.; Dierickx, L.; Saerens, L.; Voorspoels, J.; Gonnissen, Y.; De Beer, T.; Vervaet, C.; Remon, J.P. Hot-melt co-extrusion for the production of fixed-dose combination products with a controlled release ethylcellulose matrix core. Int. J. Pharm., 2014, 464(1-2), 65-74.
[http://dx.doi.org/10.1016/j.ijpharm.2014.01.028] [PMID: 24486558]
[http://dx.doi.org/10.1016/j.ijpharm.2014.01.028] [PMID: 24486558]
[27]
Almeida, A.; Brabant, L.; Siepmann, F.; De Beer, T.; Bouquet, W.; Van Hoorebeke, L.; Siepmann, J.; Remon, J.P.; Vervaet, C. Sustained release from hot-melt extruded matrices based on ethylene vinyl acetate and polyethylene oxide. Eur. J. Pharm. Biopharm., 2012, 82(3), 526-533.
[http://dx.doi.org/10.1016/j.ejpb.2012.08.008] [PMID: 22986082]
[http://dx.doi.org/10.1016/j.ejpb.2012.08.008] [PMID: 22986082]
[28]
Chen, M.W.; Chen, W.R.; Chen, T.K.; Chen, R.E.; Wang, Y.T. [Application research of hot-melt extrusion in preparation of solid
dispersion] Yao Xue Xue Bao, 2012, 47(2), 163-167.
[PMID: 22512025]
[PMID: 22512025]
[29]
Fule, R.; Paithankar, V.; Amin, P. Hot melt extrusion based solid solution approach: Exploring polymer comparison, physicochemical characterization and in-vivo evaluation. Int. J. Pharm., 2016, 499(1-2), 280-294.
[http://dx.doi.org/10.1016/j.ijpharm.2015.12.062] [PMID: 26746801]
[http://dx.doi.org/10.1016/j.ijpharm.2015.12.062] [PMID: 26746801]
[30]
Feng, J.; Xu, L.; Gao, R.; Luo, Y.; Tang, X. Evaluation of polymer carriers with regard to the bioavailability enhancement of bifendate solid dispersions prepared by hot-melt extrusion. Drug Dev. Ind. Pharm., 2012, 38(6), 735-743.
[http://dx.doi.org/10.3109/03639045.2011.623703] [PMID: 21999610]
[http://dx.doi.org/10.3109/03639045.2011.623703] [PMID: 21999610]
[31]
Sarode, A.L.; Sandhu, H.; Shah, N.; Malick, W.; Zia, H. Hot Melt Extrusion (HME) for amorphous solid dispersions: predictive tools for processing and impact of drug-polymer interactions on supersaturation. Eur. J. Pharm. Sci., 2013, 48(3), 371-384.
[http://dx.doi.org/10.1016/j.ejps.2012.12.012] [PMID: 23267847]
[http://dx.doi.org/10.1016/j.ejps.2012.12.012] [PMID: 23267847]
[32]
Auch, C.; Harms, M.; Mäder, K. Melt-based screening method with improved predictability regarding polymer selection for amorphous solid dispersions. Eur. J. Pharm. Sci., 2018, 124, 339-348.
[http://dx.doi.org/10.1016/j.ejps.2018.08.035] [PMID: 30172803]
[http://dx.doi.org/10.1016/j.ejps.2018.08.035] [PMID: 30172803]
[33]
Li, Y.; Lu, M. PVP VA64 as a novel release-modifier for sustained-
release mini-matrices prepared via hot melt extrusion. 2018,
8(6), 1670-1678
[http://dx.doi.org/10.1007/s13346-017-0437-9]
[http://dx.doi.org/10.1007/s13346-017-0437-9]
[34]
Nosrati, H.; Abbasi, R.; Charmi, J.; Rakhshbahar, A.; Aliakbarzadeh, F.; Danafar, H.; Davaran, S. Folic acid conjugated bovine serum albumin: An efficient smart and tumor targeted biomacromolecule for inhibition folate receptor positive cancer cells. Int. J. Biol. Macromol., 2018, 117, 1125-1132.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.06.026] [PMID: 29885392]
[http://dx.doi.org/10.1016/j.ijbiomac.2018.06.026] [PMID: 29885392]
[35]
Salehiabar, M.; Nosrati, H.; Javani, E.; Aliakbarzadeh, F.; Kheiri Manjili, H.; Davaran, S.; Danafar, H. Production of biological nanoparticles from bovine serum albumin as controlled release carrier for curcumin delivery. Int. J. Biol. Macromol., 2018, 115, 83-89.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.04.043] [PMID: 29653171]
[http://dx.doi.org/10.1016/j.ijbiomac.2018.04.043] [PMID: 29653171]
[36]
Konno, H.; Handa, T.; Alonzo, D.E.; Taylor, L.S. Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. Eur. J. Pharm. Biopharm., 2008, 70(2), 493-499.
[http://dx.doi.org/10.1016/j.ejpb.2008.05.023] [PMID: 18577451]
[http://dx.doi.org/10.1016/j.ejpb.2008.05.023] [PMID: 18577451]
[37]
Greenhalgh, D.J.; Williams, A.C.; Timmins, P.; York, P. Solubility parameters as predictors of miscibility in solid dispersions. J. Pharm. Sci., 1999, 88(11), 1182-1190.
[http://dx.doi.org/10.1021/js9900856] [PMID: 10564068]
[http://dx.doi.org/10.1021/js9900856] [PMID: 10564068]
[38]
Nosrati, H.; Adibtabar, M.; Sharafi, A.; Danafar, H.; Hamidreza Kheiri, M. PAMAM-modified citric acid-coated magnetic nanoparticles as pH sensitive biocompatible carrier against human breast cancer cells. Drug Dev. Ind. Pharm., 2018, 44(8), 1377-1384.
[http://dx.doi.org/10.1080/03639045.2018.1451881] [PMID: 29560737]
[http://dx.doi.org/10.1080/03639045.2018.1451881] [PMID: 29560737]
[39]
Nosrati, H.; Salehiabar, M.; Kheiri Manjili, H.; Davaran, S.; Danafar, H. Theranostic nanoparticles based on magnetic nanoparticles: Design, preparation, characterization, and evaluation as novel anticancer drug carrier and MRI contrast agent. Drug Dev. Ind. Pharm., 2018, 44(10), 1668-1678.
[http://dx.doi.org/10.1080/03639045.2018.1483398] [PMID: 29848101]
[http://dx.doi.org/10.1080/03639045.2018.1483398] [PMID: 29848101]
[40]
Mellert, W.; Deckardt, K.; Gembardt, C.; Hildebrand, B.; Schulte, S. Carcinogenicity and chronic toxicity of copovidone (Kollidon VA 64) in Wistar rats and Beagle dogs. Food Chem. Toxicol., 2004, 42(10), 1573-1587.
[http://dx.doi.org/10.1016/j.fct.2004.05.003] [PMID: 15304304]
[http://dx.doi.org/10.1016/j.fct.2004.05.003] [PMID: 15304304]
[41]
Linn, M.; Collnot, E.M.; Djuric, D.; Hempel, K.; Fabian, E.; Kolter, K.; Lehr, C.M. Soluplus® as an effective absorption enhancer of poorly soluble drugs in vitro and in vivo. Eur. J. Pharm. Sci., 2012, 45(3), 336-343.
[http://dx.doi.org/10.1016/j.ejps.2011.11.025] [PMID: 22172603]
[http://dx.doi.org/10.1016/j.ejps.2011.11.025] [PMID: 22172603]
Related Books
Localized Micro/Nanocarriers for Programmed and On-Demand Controlled Drug Release
Mixed Polymeric Micelles for Osteosarcoma Therapy: Development and Characterization
A Comprehensive Text Book on Self-emulsifying Drug Delivery Systems
Nanomaterials: Evolution and Advancement towards Therapeutic Drug Delivery (Part II)
Nanomaterials: Evolution and Advancement Towards Therapeutic Drug Delivery (Part I)
Article Metrics
75
10
2
1