Optimization of Solid Lipid Nanoparticles of Ezetimibe in Combination with Simvastatin Using Quality by Design (QbD)

Author(s): Kruti Borderwala, Ganesh Swain, Namrata Mange, Jaimini Gandhi, Manisha Lalan, Gautam Singhvi, Pranav Shah*

Journal Name: Nanoscience & Nanotechnology-Asia

Volume 10 , Issue 4 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Background: The objective of this study was to develop solid lipid nanoparticles (SLNs) of poorly water soluble anti-hyperlipidemic drugs-Ezetimibe in combination with Simvastatin.

Methods: This study describes a 32 full factorial experimental design to optimize the formulation of drug loaded lipid nanoparticles (SLN) by the high speed homogenization technique. The independent variables amount of lipid (GMS) and amount of surfactant (Poloxamer 188) were studied at three levels and arranged in a 32 factorial design to study the influence on the response variables- particle size, % entrapment efficiency (%EE) and cumulative drug release (% CDR) at 24 h.

Results: The particle size, % EE and % CDR at 24 h for the 9 batches (B1 to B9) showed a wide variation of 104.6-496.6 nm, 47.80-82.05% (Simvastatin); 48.60-84.23% (Ezetimibe) and 54.64-92.27% (Simvastatin); 43.8-97.1% (Ezetimibe), respectively. The responses of the design were analysed using Design Expert 10.0.2. (Stat-Ease, Inc, USA), and the analytical tools of software were used to draw response surface plots. From the statistical analysis of data, polynomial equations were generated. Optimized formulation showed particle size of 169.5 nm, % EE of 75.43% (Simvastatin); 79.10% (Ezetimibe) and 74.13% (Simvastatin); 77.11% (Ezetimibe) %CDR after 24 h. Thermal analysis of prepared solid lipid nanoparticles gave indication of solubilisation of drugs within lipid matrix.

Conclusion: Fourier Transformation Infrared Spectroscopy (FTIR) showed the absence of new bands for loaded solid lipid nanoparticles indicating no interaction between drugs and lipid matrix and being only dissolved in it. Electron microscope of transmission techniques indicated sphere form of prepared solid lipid nanoparticles with smooth surface with size approximately around 100 nm.

Keywords: Solid lipid nanoparticles, Ezetimibe, Simvastatin, factorial design, colloidal drug carrier system, loaded drugs.

Padhye, S.G.; Nagarsenker, M.S. Simvastatin solid lipid nanoparticle for oral delivery: Formulation development and in vivo evaluation. Indian J. Pharm. Sci., 2013, 75(5), 591-598.
Uner, M.; Yener, G. Importance of solid lipid nanoparticles (SLN) in various administration routes and future perspectives. Int. J. Nanomedicine, 2007, 2(3), 289.
Muller, R.; Radtke, M.; Wissing, S. Nanostructured lipid matrices for improved microencapsulation of drugs. Int. J. Pharm., 2002, 242(1), 121-128.
Muller, R.H.; Maeder, 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), 161-177.
Kossena, G.A.; Charman, W.N.; Wilson, C.G.; O’Mahony, B.; Lindsay, B.; Hempenstall, J.M. Low dose lipid formulations: Effects on gastric emptying and biliary secretion. Pharmaceut. Sci. Res., 2007, 24(11), 2084-2096.
Zur Mühlen, A.; Schwarz, C.; Mehnert, W. Solid lipid nanoparticles (SLN) for controlled drug delivery– Drug release and release mechanism. Eur. J. Pharm. Biopharm., 1998, 45(2), 149-155.
Jawahar, N.; Meyyanathan, S.; Reddy, G.; Sood, S. Solid lipid nanoparticles for oral delivery of poorly soluble drugs. Cheminform. J. Pharmaceut. Sci. Res., 2013, 44(27), 123-127.
Mehnert, W.; Mader, K. Solid lipid nanoparticles: Production, characterization and applications. Adv. Drug Deliv. Rev., 2001, 47(2), 165-196.
Yang, S.; Zhu, J.; Lu, Y.; Liang, B.; Yang, C. Body distribution of camptothecin solid lipid nanoparticles after oral administration. Pharmaceut. Sci. Res., 1999, 16(5), 751-761.
Mukherjee, S.; Ray, S.; Thakur, R. Solid lipid nanoparticles: A modern formulation approach in drug delivery system. Indian J. Pharmaceut. Sci. Res., 2009, 71(4), 349.
Jain, S.; Chourasia, M.; Masuriha, R.; Soni, V.; Jain, A.; Jain, N.K. Solid lipid nanoparticles bearing flurbiprofen for transdermal delivery. Drug Deliv., 2005, 12(4), 207-215.
Jenning, V.; Schäfer-Korting, M.; Gohla, S. Vitamin A-loaded solid lipid nanoparticles for topical use: Drug release properties. J. Control. Release, 2000, 66(2), 115-126.
Nußbaumer, B.; Glechner, A.; Kaminski-Hartenthaler, A.; Mahlknecht, P.; Gartlehner, G. Ezetimibe-statin combination therapy: Efficacy and safety as compared with statin monotherapy—a systematic review. Dtsch. Arztebl. Int., 2016, 113, 445-453.
Schubert, M.A.; Muller-Goymann, C.C. Solvent injection as a new approach for manufacturing lipid nanoparticles—evaluation of the method and process parameters. Eur. J. Pharm. Biopharm., 2003, 55, 121-131.
Ijioma, N.; Robinson, J.G. Lipid-lowering effects of Ezetimibe and Simvastatin in combination. Expert Rev. Cardiovasc. Ther., 2011, 9(2), 131-145.
Bays, H.; Sapre, A.; Taggart, W.; Liu, J.; Capece, R.; Tershakovec, A. Long-term (48-Week) safety of Ezetimibe 10 Mg/Day coadministered with Simvastatin compared to Simvastatin alone in patients with primary hypercholesterolemia. Curr. Med. Res. Opin., 2008, 24(10), 2953-2966.
Kastelein, J.J.; Sankatsing, R.R. Ezetimibe/Simvastatin (INEGY™) In the treatment of hyperlipidaemia. Int. J. Clin. Pract., 2005, 59(12), 1464-1471.
Kumari, N.; Srivasatva, B. Optimization and evaluation of immediate release tablet in combination of Ezetimibe and Simvastatin drugs. Int. J. Pharm. Nat. Med., 2013, 1, 1-13.
Mane, V.B.; Babar, S.; Kulkarni, N. Development of UV spectrophotometric method for the simultaneous estimation of Simvastatin and Ezetimibe in tablet dosage form by simultaneous equation and absorbance ratio method. Int. J. Pharm. Tech. Res., 2011, 3(3), 1459-1466.
Verma, R.V.; Shanmukha, J.V.; Reddy, S. Estimation Of Simvastatin and Ezetimibe in combined tablet formulation by stability indicating high performance liquid chromatography. Der. Pharm. Lett., 2015, 7(8), 204-212.
Leroux, J.C.; Allemann, E.; Doelker, E.; Gurny, R. New approach for the preparation of nanoparticles by an emulsification–diffusion method. Eur. J. Pharm. Biopharm., 1994, 41, 14-18.
Zhang, N.; Ping, Q.; Huang, G.; Xu, W.; Cheng, Y.; Han, X. Lectin-modified solid lipid nanoparticles as carriers for oral administration of insulin. Int. J. Pharm., 2006, 327(1), 153-159.
Yu, B-T.; Sun, X.; Zhang, Z-R. Enhanced liver targeting by synthesis of N 1-Stearyl-5-Fu and incorporation into solid lipid nanoparticles. Arch. Pharm. Res., 2003, 26(12)1096101
Patel, S.; Chavhan, S.; Soni, H.; Babbar, A.; Mathur, R.; Mishra, A. Brain targeting of Risperidone loaded solid lipid nanoparticles by intranasal route. J. Drug Target., 2011, 19(6), 468-474.
Wong, H.L.; Rauth, A.M.; Bendayan, R.; Manias, J.L.; Ramaswamy, M.; Liu, Z. A new polymer–lipid hybrid nanoparticle system increases cytotoxicity of Doxorubicin against multidrug-resistant human breast cancer cells. Pharm. Res., 2006, 23(7), 1574-1585.
Pandey, R.; Zahoor, A.; Sharma, S.; Khuller, G. Nanoparticle encapsulated antitubercular drugs as a potential oral drug delivery system against murine tuberculosis. Tuberculosis, 2003, 83(6), 373-388.
Domb, A.J. Nanoparticles for pharmaceutical applications; USA, 2007.
Khan, A.A.; Mudassir, J.; Mohtar, N.; Darwis, Y. Advanced drug delivery to the lymphatic system: Lipid based nanoformulations. Int. J. Nanomedicine, 2013, 8(1), 2733-2744.
Solomon, D.H.; Bitton, A.; Katz, J.N.; Radner, H.; Brown, E.M.; Fraenkel, L. Review: Treat to target in rheumatoid arthritis: Fact, fiction, or hypothesis. Arthritis Rheumatol., 2014, 66(4), 775-782.
Dhoranwala, K.; Shah, P.; Shah, S. Formulation optimization of Rosuvastatin calcium loaded solid lipid nanoparticles by 32 full-factorial design. Nanoworld J., 2015, 1(4), 110-119.
Patel, K.P.; Pathak, C.J.; Patel, R.P. Formulation, development and in-vitro evaluation of Lopinavir loaded solid lipid nanoparticles. Int. J. Pharm. Sci. Res., 2015, 6(1), 442.
Parvin, S.; Rafshanjani, M.A.; Kader, M.A. Formulation and evaluation of Dexamethasone loaded stearic acid nanoparticles by hot homogenization method. Int. Curr. Pharm. J., 2014, 3(12), 331-335.
Mosallaei, N.; Jaafari, M.R.; Hanafi-Bojd, M.Y.; Golmohammadzadeh, S.; Malaekeh-Nikouei, B. Docetaxel-loaded solid lipid nanoparticles: Preparation, characterization, in vitro, and in vivo evaluations. J. Pharm. Sci., 2013, 102(6), 1994-2004.
Kushwaha, A.K.; Vuddanda, P.R.; Karunanidhi, P.; Singh, S.K.; Singh, S. Development and evaluation of solid lipid nanoparticles of Raloxifene hydrochloride for enhanced bioavailability. Biomed Res. Int., 2013, 2013, 584549
Madhushri, M.; Thakur, R.S.; Jadhav, K.K.; Patel, R.N. Formulation and evaluation of solid lipid nanoparticles containing Clotrimazole. American J. Pharm. Tech. Res., 2012, 2, 3.
Nair, R.; Kumar, A.C.; Priya, V.K.; Yadav, C.M.; Raju, P.Y. Formulation and evaluation of chitosan solid lipid nanoparticles of Carbamazepine. Lipids Health Dis., 2012, 11(1), 72.
Chalikwar, S.S.; Belgamwar, V.S.; Talele, V.R.; Surana, S.J.; Patil, M.U. Formulation and evaluation of nimodipine-loaded solid lipid nanoparticles delivered via lymphatic transport system. Colloids Surf. B Biointerfaces, 2012, 97, 109-116.
Silva, A.C.; González-Mira, E.; García, M.L.; Egea, M.A.; Fonseca, J.; Silva, R.; Santos, D.; Souto, E.B.; Ferreira, D. Preparation, characterization and biocompatibility studies on Risperidone-loaded solid lipid nanoparticles (SLN): High pressure homogenization versus ultrasound. Colloids Surf. B Biointerfaces, 2011, 86(1), 158-165.
Ekambaram, P.; Sathali, A.A. Formulation and evaluation of solid lipid nanoparticles of Ramipril. J. Young Pharm., 2011, 3(3), 216-220.
Lv, Q.; Yu, A.; Xi, Y.; Li, H.; Song, Z.; Cui, J.; Cao, F.; Zhai, G. Development and evaluation of Penciclovir loaded solid lipid nanoparticles for topical delivery. Int. J. Pharm., 2009, 372(1)191198
Dixit, R.P.; Nagarsenker, M.S. Formulation and in vivo evaluation of self-nanoemulsifying granules for oral delivery of a combination of Ezetimibe and Simvastatin. Drug Dev. Ind. Pharm., 2008, 34(12), 1285-1296.
Padhye, S.G.; Nagarsenker, M.S. Simvastatin solid lipid nanoparticles for oral delivery: Formulation development and in vivo evaluation. Indian J. Pharm. Sci., 2013, 75(5), 591.
Ali, Y.A.; Abd-Alhammid, S.N. Formulation and evaluation of Ezetimibe nanoparticles. Iraqi J. Pharm Sci., 2017, 24(2), 11-21.
Singh, B.; Diwan, A. Effect of process parameters on formulation of solid lipid nanoparticle of protease inhibitor. Atazanavir Sulphate. Indian J. Pharmaceut. Res., 2005, 1, 21-29.
Yoo, J-W. Doshi. N.; Mitragotri. S. Adaptive micro and nanoparticles: Temporal control over carrier properties to facilitate drug delivery. Adv. Drug Deliv. Rev., 2011, 63(14), 1247-1256.
Srivalli, K.M.R.; Mishra, B. Preparation and pharmacodynamic assessment of Ezetimibe nanocrystals: Effect of P-Gp inhibitory stabilizer on particle size and oral absorption. Colloids Surf. B Biointerfaces, 2015, 135, 756-764.
Patel, R.; Bhimani, D.; Patel, J.; Patel, D. Solid-state characterization and dissolution properties of Ezetimibe–Cyclodextrins inclusion complexes. J. Incl. Phenom. Macrocycl. Chem., 2008, 60, 241-251.
Yasir, M.; Sara, U. Preparation and optimization of Haloperidol loaded solid lipid nanoparticles by Box–Behnken design. J. Pharm. Res., 2013, 7(6), 551-558.
Thode, K.; Müller, R.H.; Kresse, M. Two-time window and multiangle photon correlation spectroscopy size and zeta potential analysis—highly sensitive rapid assay for dispersion stability. J. Pharm. Sci., 2000, 89, 10.
Gasper, M.; Blanco, D.; Cruz, M.; Alonso, M. Formulation ofL-asparaginase-loaded poly(lactidecoglycolide) nanoparticles: Influence of polymer properties on enzyme loading, activity and in vitro release. J. Control. Release, 1998, 52(1-2), 53-62.
Dunne, M.; Corrigan, I.; Ramtoola, Z. Influence of particle size and dissolution conditions on the degradation properties of polylactideco-glycolide particles. Biomaterials, 2002, 21(16), 1659-1668.
Del, P.A.; Solinis, M.A.; Gascon, A.R.; Pedraz, J.L. Short- and long-term stability study of lyophilized solid lipid nanoparticles for gene therapy. Eur. J. Pharm. Biopharm., 2008, 71(2), 181-189.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 26 August, 2020
Page: [404 - 418]
Pages: 15
DOI: 10.2174/2210681209666190218143736
Price: $25

Article Metrics

PDF: 23