Probucol Self-Emulsified Drug Delivery System: Stability Testing and Bioavailability Assessment in Human Volunteers

Author(s): Abdelazim Zaghloul*, Ahmed Lila, Fathy Abd-Allah, Aly Nada

Journal Name: Current Drug Delivery

Volume 16 , Issue 4 , 2019

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: Self-Emulsifying Drug Delivery System (SEDDS), if taken orally, is expected to self-emulsify in GIT and improve the absorption and bioavailability. Probucol (PB) is a highly lipophilic compound with very low and variable bioavailability.

Objective: The objectives of this study were to examine the stability and conduct bioavailability of the prepared Probucol Self-Emulsified Drug Delivery System (PBSEDDS) in human volunteers.

Methods: The methods included preparation of different PBSEDDS using soybean oil (solvent), Labrafil M1944CS (surfactant) and Capmul MCM-C8 (co-surfactant). The formulations were characterized in vitro for spontaneity of emulsification, droplet size, turbidity and dissolution in water after packing in HPMC capsules. The optimized formulations were evaluated for stability at different storage temperatures and human bioavailability compared with the drug dissolved in soybean oil (reference).

Results: The results showed that formulations (F1-F4) were stable if stored at 20 °C. The mean (n=3) pharmacokinetic parameters for stable formulations were: The Cmax, 1070.76, 883.16, 2876.43, 3513.46 and 1047.37 ng/ml; the Tmax, 7.93, 7.33, 3.96, 3.67 and 4.67 hr.; the AUC (0-t), 41043.41, 37763.23, 75006.26, 46731.36 and 26966.43 for F1, F2, F3, F4 and reference, respectively. The percentage relative bioavailability was in this order: F3> F4> F1> F2>.

Conclusion: In conclusion, the PBSEDDS formulations were stable at room temperature. F4 showed the highest Cmax and the shortest Tmax. All the formulations showed significant enhancement of bioavailability compared with the reference. The results illustrated the potential use of SEDDS for the delivery of probucol hydrophobic compound.

Keywords: Probucol, Self-Emulsified Drug-Delivery System (SEDDS), stability, human bioavailability, PBSEDDS, bioavailability, hydrophobic compound.

Yagi, N.; Terashima, Y.; Kenmotsu, H.; Sekikawa, H.; Takada, M. Dissolution behavior of probucol from solid dispersion systems of probucol polyvinylpyrrolidone. Chem. Pharm. Bull. (Tokyo), 1996, 44, 241-244.
Heel, R.C.; Brogden, R.N.; Speight, T.M.; Avery, G.S. Probucol: A review of its pharmacological properties and therapeutic use in patients with hypercholesterolemia. Drugs, 1978, 15, 409-428.
Li, G.; Yin, L.; Liu, T.; Zheng, X.; Xu, G.; Xu, Y.; Yuan, R.; Che, J.; Liu, H.; Zhou, L.; Chen, X.; He, M.; Li, Y.; Wu, L.; Liu, E. Role of probucol in preventing contrast-induced acute kidney injury after coronary interventional procedure. Am. J. Cardiol., 2009, 103, 512-514.
Liu, G.X.; Ou, D.M.; Li, L.X.; Chen, L.X.; Huang, H.L.; Liao, D.F.; Tang, C.S. Probucol inhibits oxidized-low density lipoprotein-induced adhesion of monocytes to endothelial cells in vitro. Acta Pharmacol. Sin., 2002, 23, 516-522.
Yamashita, S.; Matsuzawa, Y. Where are we with probucol: A new life for an old drug? Atherosclerosis, 2009, 207, 16-23.
Champagne, D.; Pearson, D.; Dea, D.; Rochford, J.; Poirier, J. The cholesterol-lowering drug probucol increases apolipoprotein E production in the hippocampus of aged rats: Implications for Alzheimer’s disease. Neuroscience, 2003, 121, 99-110.
Poirier, J. Apolipoprotein E and cholesterol metabolism in the pathogenesis and treatment of Alzheimer’s disease. Trends Mol. Med., 2003, 9, 94-101.
Endo, K.; Miyashita, Y.; Sasaki, H.; Ohira, M.; Saiki, A.; Koide, N.; Otsuka, M.; Oyama, T.; Takeyoshi, M.; Ito, Y.; Shirai, K. Probucol delays progression of diabetic nephropathy. Diabetes Res. Clin. Pract., 2006, 71, 156-163.
Zhou, G.; Wang, Y.; He, P.; Li, D. Probucol inhibited Nox2 expression and attenuated podocyte injury in type 2 diabetic nephropathy of db/db mice. Biol. Pharm. Bull., 2013, 36, 1883-1890.
Bagdade, J.D.; Lane, J.T.; Subbaiah, P.V. Probucol normalizes cholesteryl ester transfer in type 2 diabetes. Diabetes Res. Clin. Pract., 2016, 116, 29-35.
Gorogawa, S.; Kajimoto, Y.; Umayahara, Y.; Kaneto, H.; Watada, H.; Kuroda, A.; Kawamori, D.; Yasuda, T.; Matsuhisa, M.; Yamasaki, Y.; Hori, M. Probucol preserves pancreatic beta-cell function through reduction of oxidative stress in type 2 diabetes. Diabetes Res. Clin. Pract., 2002, 7, 1-10.
Liu, J.H.; Liu, D.F.; Wang, N.N.; Lin, H.L.; Mei, X. Possible role for the thioredoxin system in the protective effects of probucol in the pancreatic islets of diabetic rats. Clin. Exp. Pharmacol. Physiol., 2011, 38(8), 528-533.
Iqbal, M.; Okazaki, Y.; Okada, S. Probucol modulates iron nitrilotriacetate (Fe-NTA)-dependent renal carcinogenesis and hyperproliferative response: Diminution of oxidative stress. Mol. Cell. Biochem., 2007, 304, 61-69.
Jiang, Y.S.; Lei, J.A.; Feng, F.; Liang, Q.M.; Wang, F.R. Probucol suppresses human glioma cell proliferation in vitro via ROS production and LKB1-AMPK activation. Acta Pharmacologica Sinica, 2014, 35, 1556-1565.
Shudo, J.; Pongpeerapat, A.; Wanawongthai, C.; Moribe, K.; Yamamoto, K. In vivo assessment of oral administration of probucol nanoparticles in rats. Biol. Pharm. Bull., 2008, 31, 321-325.
Taha, E.; Ghorab, D.; Zaghloul, A. Bioavailability assessment of vitamin A self-nano emulsified drug delivery systems in rats: A comparative study. Med. Princ. Pract., 2007, 16, 355-359.
Nielsen, F.S.; Petersen, K.B.; Mullertz, A. Bioavailability of probucol from lipid and surfactant based formulations in minipigs: Influence of droplet size and dietary state. Eur. J. Pharm. Biopharm., 2008, 69, 553-562.
Zaghloul, A.; Abd-Allah, F.; Abu Seada, H.; Nada, A. Stability and human bioavailability of optimized self-emulsified drug delivery system of ibuprofen. Am. J. Pharm. Tech. Res, 2013, 3, 721-733.
Han, L.; Yang, Q.; Shen, T.; Qing, J.; Wang, J. Lymphatic transport of orally administered probucol-loaded mPEG-DSPE micelles. Drug Deliv., 2016, 23, 1955-1961.
Zaghloul, A.; Khattab, I.; Nada, A.; Al-Saidan, S. Preparation, characterization and optimization of probucol self-emulsified drug delivery system to enhance solubility and dissolution. Pharmazie, 2008, 63, 654-660.
Danafar, H.; Hamidi, M. Simple and sensitive high-performance liquid chromatography (HPLC) method with UV detection for mycophenolic acid assay in human plasma. Application to a bioequivalence study. Adv. Pharm. Bull., 2015, 5(4), 563-568.
Danafar, H.; Hamidi, M. Pharmacokinetics and bioequivalence study of amlodipine and atorvastatin in healthy male volunteers by LC-MS. Pharm. Sci., 2015, 21(Suppl. 1), 167-174C.
Ueyama, E.; Tamura, K.; Mizukawa, K.; Kano, K. Realistic prediction of solid pharmaceutical oxidation products by using a novel forced oxidation system. J. Pharm. Sci., 2014, 103, 1184-1193.
Komoda, M.; Onuki, N.; Harada, I. Studies on cause of color reversion of edible soybean oil and its prevention Part II. Tocored as a precursor of color reversion of soybean oil. Agric. Biol. Chem., 1967, 31(4), 461-469.
Kubo, Y.; Yagi, N.; Sekikawa, H. Stability of probucol-polyvinylpyrrolidone solid dispersion systems. Yakugaku Zasshi – J. Pharm. Soc. Japan, 2011, 131, 629-634.
Palin, K.J.; Wilson, C.G. The effect of different oils on the absorption of probucol in the rat. J. Pharm. Pharmacol., 1984, 36, 641-643.
Bardelmeijer, H.A.; Ouwehand, M.; Malingre, M.M.; Schellens, J.H.; Beijnen, J.H. van, O.T. Entrapment by Cremophor EL decreases the absorption of paclitaxel from the gut. Cancer Chemother. Pharmacol., 2002, 49, 119-125.
Malingre, M.M.; Schellens, J.H.; Tellingen, O.; van Ouwehand, M.; Bardelmeijer, H.A.; Rosing, H.; Koopman, F.J.; Schot, M.E. Ten, Bokkel, Huinink, W.W.; Beijnen, J.H. The co-solvent Cremophor EL limits absorption of orally administered paclitaxel in cancer patients. Br. J. Cancer, 2001, 85, 1472-1477.
Porter, C.J.; Kaukonen, A.M.; Boyd, B.J.; Edwards, G.A.; Charman, W.N. Susceptibility to lipase-mediated digestion reduces the oral bioavailability of danazol after administration as a medium-chain lipid-based microemulsion formulation. Pharm. Res., 2004, 2, 1405-1412.
Holm, R.; Porter, C.J.; Edwards, G.A.; Mullertz, A.; Kristensen, H.G.; Charman, W.N. Examination of oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in self-microemulsifying drug delivery systems (SMEDDS) containing structured triglycerides. Eur. J. Pharm. Sci., 2003, 20, 91-97.
Yamamoto, K.; Fukuda, N.; Shiroi, S.; Shiotsuki, Y.; Nagata, Y.; Tani, T.; Sakai, T. Effects of dietary fat levels on the absorption and tissue accumulation of probucol in the rat. Arzneimittelforschung, 1994, 44, 1059-1062.

open access plus

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 26 December, 2018
Page: [325 - 330]
Pages: 6
DOI: 10.2174/1567201816666181227111912

Article Metrics

PDF: 64
PRC: 1