Formulation and In Vitro Evaluation of Self Microemulsifying Drug Delivery System Containing Atorvastatin Calcium

Author(s): Mine Diril*, Gülbeyaz Yıldız Türkyılmaz, H. Yeşim Karasulu.

Journal Name: Current Drug Delivery

Volume 16 , Issue 8 , 2019

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Graphical Abstract:


Abstract:

Objective: The aim of this study was to develop a new dosage form as an alternative to the classical tablet forms of atorvastatin calcium (AtrCa). The formulation strategy was to prepare an optimum self micro emulsifying drug delivery system (SMEDDS) to overcome the problem of low solubility of the active substance.

Methods: In this study, pseudo ternary phase diagrams were plotted determined by the solubility studies. According to the solubility studies; oleic acid was used as the oil phase, Tween 20 and Span 80 were used as the surfactants and ethanol was used as the co-surfactant. SMEDDS formulations were characterized according to pH, electrical conductivity, density, refractive index, viscosity, emulsification time, dispersibility, robustness of dilution stability, droplet size, polidispersity index, zeta potential, transmittance %, cloud point, content quantification %, chemical and physical stability. The lipolysis study was conducted under fed and fasted conditions. In vitro release studies and kinetic evaluation were carried out. Permeability studies were also examined with Caco-2 cell culture.

Results: The droplet size of the optimized formulation did not change significantly in different medias over the test time period. Improved SMEDDS formulation will progress steadily without precipitating along the gastrointestinal tract. Lipolysis studies showed that the oil solution had been exposed to high amount of lipolysis compared to the SMEDDS formulation. The release rate of AtrCa from AtrCa- SMEDDS formulation (93.8%, at 15 minutes) was found as increased when the results were compared with commercial tablet formulation and pure drug. The permeability value of AtrCa from AtrCa- SMEDDS formulation was found higher than pure AtrCa and commercial tablet formulation, approximately 9.94 and 1.64 times, respectively.

Conclusion: Thus, lipid-based SMEDDS formulation is a potential formulation candidate for lymphatic route in terms of the increased solubility of AtrCa.

Keywords: Atorvastatin calcium, hypercholesterolemia, BCS classification, solubility, SMEDDS, lipolysis, Caco-2.

[1]
Frohlich, E.D.; Quinlan, P.J. Coronary heart disease risk factors: Public impact of initial and later-announced risks. Ochsner J., 2014, 14(4), 532-537.
[PMID: 25598717]
[2]
Defesche, J.C.; Gidding, S.S.; Harada-Shiba, M.; Hegele, R.A.; Santos, R.D.; Wierzbicki, A.S. Familial hypercholesterolaemia. Nat. Rev. Dis. Primers, 2017, 3(February), 17093.
[http://dx.doi.org/10.1038/nrdp.2017.93] [PMID: 29219151]
[3]
Chong, P.H. Lack of therapeutic interchangeability of HMG-CoA reductase inhibitors. Ann. Pharmacother., 2002, 36(12), 1907-1917.
[http://dx.doi.org/10.1345/aph.1C116] [PMID: 12452755]
[4]
Mciver, L.A.; Siddique, M.S. Atorvastatin., 2019, 1-4.
[5]
U.S. Food and Drug Administration (FDA). Center For Drug Evaluation And Research “Lipitor”, 2017.
[6]
Hajare, A.A.; More, H.N. Design of the Lyophilization process of a doxorubicin formulation based on thermal properties. Indian J. Pharm. Sci., 2018, 79(6), 907-913.
[http://dx.doi.org/10.4172/pharmaceutical-sciences.1000307]
[7]
Talegaonkar, S.; Mustafa, G.; Akhter, S.; Iqbal, Z.I. Design and development of oral oil-in-water nanoemulsion formulation bearing atorvastatin: In vitro assessment. J. Dispers. Sci. Technol., 2010, 31(5), 690-701.
[http://dx.doi.org/10.1080/01932690903120540]
[8]
Chintalapudi, R.; Murthy, T.E.G.K.; Lakshmi, K.R.; Manohar, G.G. Formulation, optimization, and evaluation of self-emulsifying drug delivery systems of nevirapine. Int. J. Pharm. Investig., 2015, 5(4), 205-213.
[http://dx.doi.org/10.4103/2230-973X.167676] [PMID: 26682191]
[9]
Porter, C.J.H.; 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]
[10]
Hai, T.; Wan, X.; Yu, D.G.; Wang, K.; Yang, Y.; Liu, Z.P. electrospun lipid-coated medicated nanocomposites for an improved drug sustained-release profile. Mater. Des., 2019, 162, 70-79.
[http://dx.doi.org/10.1016/j.matdes.2018.11.036]
[11]
Baheti, A.; Srivastava, S.; Sahoo, D.; Lowalekar, R.; Panda, B.P.; Padhi, B.K.; Raghuvanshi, R. Development and pharmacokinetic evaluation of industrially viable self-microemulsifying drug delivery systems (SMEDDS) for terbinafine. Curr. Drug Deliv., 2015, 13(1), 65-75.
[http://dx.doi.org/10.2174/1567201812666150120153357] [PMID: 25600982]
[12]
Ahmed, M.; Manohara, Y.N.; Ravi, M.C. Rp-Hplc method development and validation for simultaneous estimation of atorvastatin calcium and amlodipine besylate. Int. J. Chemtech Res., 2012, 4(1), 337-345.
[13]
Singh, A.; Singh, V.; Rawat, G.; Juyal, D. Self emulsifying systems: A review. Asian J. Pharm., 2015, 9(1), 13.
[http://dx.doi.org/10.4103/0973-8398.150031]
[14]
Ansari, K.A.; Pagar, K.P.; Anwar, S.; Vavia, P.R. Design and optimization of self-microemulsifying drug delivery system (SMEDDS) of felodipine for chronotherapeutic application. Braz. J. Pharm. Sci., 2014, 50(1), 203-212.
[http://dx.doi.org/10.1590/S1984-82502011000100021]
[15]
Thomas, N.; Holm, R.; Rades, T.; Müllertz, A. Characterising lipid lipolysis and its implication in lipid-based formulation development. AAPS J., 2012, 14(4), 860-871.
[http://dx.doi.org/10.1208/s12248-012-9398-6] [PMID: 22956477]
[16]
Zhang, J.; Lv, Y.; Zhao, S.; Wang, B.; Tan, M.; Xie, H.; Lv, G.; Ma, X. Effect of lipolysis on drug release from self-microemulsifying drug delivery systems (SMEDDS) with different core/shell drug location. AAPS Pharm.Sci.Tech, 2014, 15(3), 731-740.
[http://dx.doi.org/10.1208/s12249-014-0096-9] [PMID: 24554238]
[17]
Artursson, P.; Palm, K.; Luthman, K. Caco-2 monolayers in experimental and theoretical predictions of drug transport. Adv. Drug Deliv. Rev., 2012, 64(Suppl.), 280-289.
[http://dx.doi.org/10.1016/j.addr.2012.09.005] [PMID: 11259831]
[18]
Steffansen, B.; Pedersen, M.D.L.; Laghmoch, A.M.; Nielsen, C.U. SGLT1-mediated transport in Caco-2 cells is highly dependent on cell bank origin. J. Pharm. Sci., 2017, 106(9), 2664-2670.
[http://dx.doi.org/10.1016/j.xphs.2017.04.033] [PMID: 28454747]
[19]
Pérez-Sánchez, A.; Borrás-Linares, I.; Barrajón-Catalán, E.; Arráez-Román, D.; González-Álvarez, I.; Ibáñez, E.; Segura-Carretero, A.; Bermejo, M.; Micol, V. Evaluation of the intestinal permeability of rosemary (Rosmarinus officinalis L.) extract polyphenols and terpenoids in Caco-2 cell monolayers. PLoS One, 2017, 12(2)e0172063
[http://dx.doi.org/10.1371/journal.pone.0172063] [PMID: 28234919]
[20]
Parhizkar, E.; Emadi, L.; Alipour, S. Development and evaluation of midazolam in situ nasal gel properties in presence of solubility enhancers at cilia-friendly pH. Macromol. Res., 2017, 25(3), 255-261.
[http://dx.doi.org/10.1007/s13233-017-5031-y]
[21]
Berginc, K.; Kristl, A. Transwell-grown HepG2 cell monolayers as in vitro permeability model to study drug-drug or drug-food interactions. J. Med. Food, 2011, 14(1-2), 135-139.
[http://dx.doi.org/10.1089/jmf.2010.0041] [PMID: 21138349]
[22]
Szumała, P. Structure of microemulsion formulated with monoacylglycerols in the presence of polyols and ethanol. J. Surfactants Deterg., 2015, 18(1), 97-106.
[http://dx.doi.org/10.1007/s11743-014-1618-x] [PMID: 25580075]
[23]
Rowe, R.C.; Sheskey, P.J.; Quinn, M.E. Handbook of Pharmaceutical Excipients, 6th ed; , 2009.
[24]
Food and Drug Administration (FDA). Bioanalytical Method Validation: Guidance for Industry, 2018.
[25]
Food and Drug Administration (FDA). Anaytical Procedures and Methods Validation for Drugs and Biologics, 2015.
[26]
Jaiswal, P.; Aggarwal, G.; Harikumar, S.L.; Singh, K. Development of self-microemulsifying drug delivery system and solid-self-microemulsifying drug delivery system of telmisartan. Int. J. Pharm. Investig., 2014, 4(4), 195-206.
[http://dx.doi.org/10.4103/2230-973X.143123] [PMID: 25426441]
[27]
Karasulu, H.Y.; Karabulut, B.; Göker, E.; Güneri, T.; Gabor, F. Controlled release of methotrexate from w/o microemulsion and its in vitro antitumor activity. Drug Deliv., 2007, 14(4), 225-233.
[http://dx.doi.org/10.1080/10717540601067760] [PMID: 17497355]
[28]
Patel, P.V.; Patel, H.K.; Panchal, S.S.; Mehta, T.A. Self micro-emulsifying drug delivery system of tacrolimus: Formulation, in vitro evaluation and stability studies. Int. J. Pharm. Investig., 2013, 3(2), 95-104.
[http://dx.doi.org/10.4103/2230-973X.114899] [PMID: 24015381]
[29]
Akula, S.; Gurram, A.K.; Devireddy, S.R. Self-microemulsifying drug delivery systems: An attractive strategy for enhanced therapeutic profile. Int. Sch. Res. Notices, 2014, 2014964051
[http://dx.doi.org/10.1155/2014/964051] [PMID: 27382619]
[30]
Caliph, S.M.; Charman, W.N.; Porter, C.J.H. Effect of short-, medium-, and long-chain fatty acid-based vehicles on the absolute oral bioavailability and intestinal lymphatic transport of halofantrine and assessment of mass balance in lymph-cannulated and non-cannulated rats. J. Pharm. Sci., 2000, 89(8), 1073-1084.
[http://dx.doi.org/10.1002/1520-6017(200008)89:8<1073:AID-JPS12>3.0.CO;2-V] [PMID: 10906731]
[31]
Jones, D. Pharmaceutical solution for oral administration. Pharmaceutical solution for oral administration, 2008, 1-24
[32]
Thakkar, H.; Nangesh, J.; Parmar, M.; Patel, D. Formulation and characterization of lipid-based drug delivery system of raloxifene-microemulsion and self-microemulsifying drug delivery system. J. Pharm. Bioallied Sci., 2011, 3(3), 442-448.
[http://dx.doi.org/10.4103/0975-7406.84463] [PMID: 21966167]
[33]
Sundari, P.T.; Mounika, P. Formulation and evaluation of SMEDDS containing ezetimibe by employing arachis oil as oil and Tween 80, Peg 400 as surfactant system. Eur. J. Biomed. Pharm. Sci., 2018, 5(7), 431-440.
[34]
Christophersen, P.C.; Christiansen, M.L.; Holm, R.; Kristensen, J.; Jacobsen, J.; Abrahamsson, B.; Müllertz, A. Fed and fasted state gastro-intestinal in vitro lipolysis: In vitro in vivo relations of a conventional tablet, a SNEDDS and a solidified SNEDDS. Eur. J. Pharm. Sci., 2014, 57(1), 232-239.
[http://dx.doi.org/10.1016/j.ejps.2013.09.007] [PMID: 24056027]
[35]
U.S. Food and Drug Administration (FDA). Dissolution Methods, http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_getallData.cfm
[36]
Weibull, W. A statistical distribution function of wide applicability. J. Appl. Mech., 1951, 103, 293-297.
[37]
Langenbucher, F. Linearization of dissolution rate curves by the Weibull distribution. J. Pharm. Pharmacol., 1972, 24(12), 979-981.
[http://dx.doi.org/10.1111/j.2042-7158.1972.tb08930.x] [PMID: 4146531]
[38]
Ramteke, K.H.; Dighe, P.A.; Kharat, A.R.; Patil, S.V. Mathematical models of drug dissolution: A review. Sch. Acad. J. Pharm., 2014, 3(5), 388-396.
[39]
Medina, J.R.; Salazar, D.K.; Hurtado, M.; Cortés, A.R.; Domínguez-Ramírez, A.M. Comparative in vitro dissolution study of carbamazepine immediate-release products using the USP paddles method and the flow-through cell system. Saudi Pharm. J., 2014, 22(2), 141-147.
[http://dx.doi.org/10.1016/j.jsps.2013.02.001] [PMID: 24648826]
[40]
Zhang, L.; Strong, J.M.; Qiu, W.; Lesko, L.J.; Huang, S.M. Scientific perspectives on drug transporters and their role in drug interactions. Mol. Pharm., 2006, 3(1), 62-69.
[http://dx.doi.org/10.1021/mp050095h] [PMID: 16686370]
[41]
Gonzalez-Mariscal, L.; Contreras, R.G.; Bolívar, J.J.; Ponce, A.; Chávez De Ramirez, B.; Cereijido, M. Role of calcium in tight junction between epithelial cells formation. Am. J. Physiol., 1990, 259, 978-986.
[http://dx.doi.org/10.1152/ajpcell.1990.259.6.C978] [PMID: 2124417]
[42]
Gundogdu, E.; Mangas-Sanjuan, V.; Gonzalez-Alvarez, I.; Bermejo, M.; Karasulu, E. In vitro-in situ permeability and dissolution of fexofenadine with kinetic modeling in the presence of sodium dodecyl sulfate. Eur. J. Drug Metab. Pharmacokinet., 2012, 37(1), 65-75.
[http://dx.doi.org/10.1007/s13318-011-0059-4] [PMID: 21833762]
[43]
Tretiach, M.; van Driel, D.; Gillies, M.C. Transendothelial electrical resistance of bovine retinal capillary endothelial cells is influenced by cell growth patterns: An ultrastructural study. Clin. Exp. Ophthalmol., 2003, 31(4), 348-353.
[http://dx.doi.org/10.1046/j.1442-9071.2003.00670.x] [PMID: 12880462]


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VOLUME: 16
ISSUE: 8
Year: 2019
Page: [768 - 779]
Pages: 12
DOI: 10.2174/1567201816666190820143957
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