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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

Solid Self-Emulsifying Drug Delivery System (Solid SEDDS) for Testosterone Undecanoate: In Vitro and In Vivo Evaluation

Author(s): Xi Liang, Yabing Hua, Qian Liu, Zhiguo Li, Fanglin Yu, Jing Gao, Hui Zhang* and Aiping Zheng*

Volume 18, Issue 5, 2021

Published on: 04 September, 2020

Page: [620 - 633] Pages: 14

DOI: 10.2174/1567201817666200904172626

Price: $65

Abstract

Objective: The current study aimed to investigate the potential of Solid Self-Emulsifying Drug Delivery Systems (solid SEDDS) loaded with Testosterone Undecanoate (TU) (solid TUSEDDS). The solid TU-SEDDS was composed of TU, Medium-Chain Triglycerides (MCT, oil), 2- Chloro-1-(chloromethyl) ethyl carbamate (EL-35, surfactant) and polyethylene glycol (PEG400, cosurfactant). It was expected to improve the dissolution and oral bioavailability of TU, as a result of investigating the feasibility of the clinical application of SEDDS.

Methods: First, a TU-SEDDS was developed by using rational blends of components with the good solubilizing ability for TU. Next, a ternary phase diagram was constructed to determine the self-emulsifying region, and the formulation was optimized. Then, the solid TU-SEDDS formulation was established by screening suitable solid adsorptions. Finally, the prepared SEDDS, TUSEDDS and solid TU-SEDDS formulations were evaluated in vitro and in vivo.

Results: The size of the solid TU-SEDDS was 189.1 ± 0.23 nm. The Transmission Electron Microscopy (TEM) results showed that the oil droplets were homogenous and spherical with good integrity. The Differential Scanning Calorimetry (DSC) and X-Ray Powder Dffraction (XRD) results indicated that the solid TU-SEDDS formulation almost preserves the amorphous state. Scanning Electron Microscopy (SEM) indicated that neusilin US2 successfully adsorbed the TU-SEDDS. Drug release indicated that the dissolution of the solid TU-SEDDS was faster than that of Andriol Testocaps ®. Furthermore, in vivo pharmacokinetic (PK) studies in Sprague-Dawley (SD) rats showed that the Area Under the Curve (AUC) of the solid TU-SEDDS (487.54±208.80 μg/L×h) was higher than that of Andriol Testocaps® (418.93±273.52 μg/L×h, P < 0.05). In beagles not fed a high-fat diet, the AUC of the solid TU-SEDDS (5.81±4.03 μg/L×h) was higher than that of Andriol Testocaps ® (5.53±3.43 μg/L×h, P > 0.05). In beagles fed a high-fat diet, the AUC of the solid TUSEDDS (38.18±21.90 μg/L×h) was higher than that of Andriol Testocaps® (37.17±13.79 μg/L×h, P > 0.05).

Conclusion: According to the results of this research, oral solid TU-SEDDS is expected to be another alternative delivery system for the late-onset hypogonadism. This is beneficial to the transformation of existing drug delivery systems into preclinical and clinical studies.

Keywords: Testosterone undecanoate, solid SEDDS, ternary phase diagram, neusilin US2, dissolution, pharmacokinetics.

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Graphical Abstract

[1]
Garg, T.; Rath, G.; Goyal, A.K. Colloidal drug delivery systems: current status and future directions. Crit. Rev. Ther. Drug Carrier Syst., 2015, 32(2), 89-147.
[http://dx.doi.org/10.1615/CritRevTherDrugCarrierSyst.2015010159] [PMID: 25955882]
[2]
Singh, B.; Beg, S.; Khurana, R.K.; Sandhu, P.S.; Kaur, R.; Katare, O.P. Recent advances in self-emulsifying drug delivery systems (SEDDS). Crit. Rev. Ther. Drug Carrier Syst., 2014, 31(2), 121-185.
[http://dx.doi.org/10.1615/CritRevTherDrugCarrierSyst.2014008502] [PMID: 24940626]
[3]
Cherniakov, I.; Domb, A.J.; Hoffman, A. Self-nano-emulsifying drug delivery systems: an update of the biopharmaceutical aspects. Expert Opin. Drug Deliv., 2015, 12(7), 1121-1133.
[http://dx.doi.org/10.1517/17425247.2015.999038] [PMID: 25556987]
[4]
Chatterjee, B.; Hamed Almurisi, S.; Ahmed Mahdi Dukhan, A.; Mandal, U.K.; Sengupta, P. Controversies with self-emulsifying drug delivery system from pharmacokinetic point of view. Drug Deliv., 2016, 23(9), 3639-3652.
[http://dx.doi.org/10.1080/10717544.2016.1214990] [PMID: 27685505]
[5]
Franceschinis, E.; Voinovich, D.; Grassi, M.; Perissutti, B.; Filipovic-Grcic, J.; Martinac, A.; Meriani-Merlo, F. Self-emulsifying pellets prepared by wet granulation in high-shear mixer: influence of formulation variables and preliminary study on the in vitro absorption. Int. J. Pharm., 2005, 291(1-2), 87-97.
[http://dx.doi.org/10.1016/j.ijpharm.2004.07.046] [PMID: 15707735]
[6]
Chavda, H.; Patel, J.; Chavada, G. Self-nanoemulsifying powder of isotretinoin: preparation and characterization. Journal of Powder Technology, 2013, 1-9.
[7]
Chen, Y.; Chen, C.; Zheng, J.; Chen, Z.; Shi, Q.; Liu, H. Development of a solid supersaturatable self-emulsifying drug delivery system of docetaxel with improved dissolution and bioavailability. Biol. Pharm. Bull., 2011, 34(2), 278-286.
[http://dx.doi.org/10.1248/bpb.34.278] [PMID: 21415541]
[8]
Tang, B.; Cheng, G.; Gu, J.C.; Xu, C.H. Development of solid self-emulsifying drug delivery systems: preparation techniques and dosage forms. Drug Discov. Today, 2008, 13(13-14), 606-612.
[http://dx.doi.org/10.1016/j.drudis.2008.04.006] [PMID: 18598917]
[9]
Cole, E.T.; Cadé, D.; Benameur, H. Challenges and opportunities in the encapsulation of liquid and semi-solid formulations into capsules for oral administration. Adv. Drug Deliv. Rev., 2008, 60(6), 747-756.
[http://dx.doi.org/10.1016/j.addr.2007.09.009] [PMID: 18096270]
[10]
Shah, A.V.; Serajuddin, A.T.M. Development of solid self-emulsifying drug delivery system (SEDDS) I: use of poloxamer 188 as both solidifying and emulsifying agent for lipids. Pharm. Res., 2012, 29(10), 2817-2832.
[http://dx.doi.org/10.1007/s11095-012-0704-x] [PMID: 22371051]
[11]
Bakhle, S.S.; Avari, J.G. Development and characterization of solid self-emulsifying drug delivery system of cilnidipine. Chem. Pharm. Bull. (Tokyo), 2015, 63(6), 408-417.
[http://dx.doi.org/10.1248/cpb.c14-00326] [PMID: 26027464]
[12]
Gumaste, S.G.; Freire, B.O.S.; Serajuddin, A.T.M. Development of solid SEDDS, VI: Effect of precoating of Neusilin? US2 with PVP on drug release from adsorbed self-emulsifying lipid-based formulations. Drug Discov. Today, 2008, 13, 606-612.
[13]
Tan, A.; Davey, A.K.; Prestidge, C.A. Silica-Lipid Hybrid (SLH) versus non-lipid formulations for optimising the dose-dependent oral absorption of celecoxib. Pharm. Res., 2011, 28(9), 2273-2287.
[http://dx.doi.org/10.1007/s11095-011-0458-x] [PMID: 21560021]
[14]
Alinaghi, A.; Tan, A.; Rao, S.; Prestidge, C.A. Impact of solidification on the performance of lipid-based colloidal carriers: oil-based versus self-emulsifying systems. Curr. Drug Deliv., 2015, 12(1), 16-25.
[http://dx.doi.org/10.2174/1567201811666140716122644] [PMID: 25030115]
[15]
Hansen, T.; Holm, P.; Schultz, K. Process characteristics and compaction of spray-dried emulsions containing a drug dissolved in lipid. Int. J. Pharm., 2004, 287(1-2), 55-66.
[http://dx.doi.org/10.1016/j.ijpharm.2004.08.014] [PMID: 15541912]
[16]
Katla, V.M.; Veerabrahma, K. Cationic solid self micro emulsifying drug delivery system (SSMED) of losartan: Formulation development, characterization and in vivo evaluation. J. Drug Deliv. Sci. Technol., 2016, 35, 190-199.
[http://dx.doi.org/10.1016/j.jddst.2016.04.011]
[17]
Cheng, G.; Hu, R.; Ye, L.; Wang, B.; Gui, Y.; Gao, S.; Li, X.; Tang, J. Preparation and in vitro/in vivo evaluation of puerarin solid self-microemulsifying drug delivery system by spherical crystallization technique. AAPS PharmSciTech, 2016, 17(6), 1336-1346.
[http://dx.doi.org/10.1208/s12249-015-0469-8] [PMID: 26694058]
[18]
Yin, A.Y.; Htun, M.; Swerdloff, R.S.; Diaz-Arjonilla, M.; Dudley, R.E.; Faulkner, S.; Bross, R.; Leung, A.; Baravarian, S.; Hull, L.; Longstreth, J.A.; Kulback, S.; Flippo, G.; Wang, C. Reexamination of pharmacokinetics of oral testosterone undecanoate in hypogonadal men with a new self-emulsifying formulation. J. Androl., 2012, 33(2), 190-201.
[http://dx.doi.org/10.2164/jandrol.111.013169] [PMID: 21474786]
[19]
Köhn, F.M.; Schill, W.B. A new oral testosterone undecanoate formulation. World J. Urol., 2003, 21(5), 311-315.
[http://dx.doi.org/10.1007/s00345-003-0372-x] [PMID: 14579074]
[20]
Shackleford, D.M.; Faassen, W.A.; Houwing, N.; Lass, H.; Edwards, G.A.; Porter, C.J.; Charman, W.N. Contribution of lymphatically transported testosterone undecanoate to the systemic exposure of testosterone after oral administration of two andriol formulations in conscious lymph duct-cannulated dogs. J. Pharmacol. Exp. Ther., 2003, 306(3), 925-933.
[http://dx.doi.org/10.1124/jpet.103.052522] [PMID: 12807999]
[21]
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]
[22]
Inugala, S.; Eedara, B.B.; Sunkavalli, S.; Dhurke, R.; Kandadi, P.; Jukanti, R.; Bandari, S. Solid self-nanoemulsifying drug delivery system (S-SNEDDS) of darunavir for improved dissolution and oral bioavailability: In vitro and in vivo evaluation. Eur. J. Pharm. Sci., 2015, 74, 1-10.
[http://dx.doi.org/10.1016/j.ejps.2015.03.024] [PMID: 25845633]
[23]
Gamal, W.; Fahmy, R.H.; Mohamed, M.I. Development of novel amisulpride-loaded solid self-nanoemulsifying tablets: preparation and pharmacokinetic evaluation in rabbits. Drug Dev. Ind. Pharm., 2017, 43(9), 1539-1547.
[http://dx.doi.org/10.1080/03639045.2017.1322608] [PMID: 28447882]
[24]
Kharb, V.; Saharan, V.A.; Kharb, V.; Jadhav, H.; Purohit, S. Formulation and characterization of taste masked ondansetron-magnesium aluminum silicate adsorption systems. Drug Dev. Ind. Pharm., 2016, 42(8), 1291-1299.
[http://dx.doi.org/10.3109/03639045.2015.1128439] [PMID: 26641930]
[25]
Allgeier, M.C.; Piper, J.L.; Hinds, J.; Yates, M.H.; Kolodsick, K.J.; Meury, R.; Shaw, B.; Kulkarni, M.R.; Remick, D.M. Isolation and physical property optimization of an amorphous drug substance utilizing a high surface area magnesium aluminometasilicate (neusilin(®) us2). J. Pharm. Sci., 2016, 105(10), 3105-3114.
[http://dx.doi.org/10.1016/j.xphs.2016.06.019] [PMID: 27492963]
[26]
Eedara, B.B.; Kallakunta, V.R.; Bandari, S. Self-nanoemulsifying powders for improved oral delivery of poorly water-soluble drugs. Ther. Deliv., 2015, 6(8), 899-901.
[http://dx.doi.org/10.4155/tde.15.43] [PMID: 26488495]
[27]
Zhou, C.; Renbo, A.; Hui, Z. Dissolution detection of testosterone undecanoate capsule in vitro. Int. J. Pharm. Sci. Res., 2016, 43, 566-570.
[28]
Shao, B.; Cui, C.; Ji, H.; Tang, J.; Wang, Z.; Liu, H.; Qin, M.; Li, X.; Wu, L. Enhanced oral bioavailability of piperine by self-emulsifying drug delivery systems: in vitro, in vivo and in situ intestinal permeability studies. Drug Deliv., 2015, 22(6), 740-747.
[http://dx.doi.org/10.3109/10717544.2014.898109] [PMID: 24670090]
[29]
Kim, M.S.; Kim, J.S.; Park, H.J.; Cho, W.K.; Cha, K.H.; Hwang, S.J. Enhanced bioavailability of sirolimus via preparation of solid dispersion nanoparticles using a supercritical antisolvent process. Int. J. Nanomedicine, 2011, 6, 2997-3009.
[PMID: 22162657]
[30]
Fernandez-Tarrio, M.; Yañez, F.; Immesoete, K.; Alvarez-Lorenzo, C.; Concheiro, A. Pluronic and tetronic copolymers with polyglycolyzed oils as self-emulsifying drug delivery systems. AAPS PharmSciTech, 2008, 9(2), 471-479.
[http://dx.doi.org/10.1208/s12249-008-9070-8] [PMID: 18431654]
[31]
Borhade, V.B.; Nair, H.A.; Hegde, D.D. Development and characterization of self-microemulsifying drug delivery system of tacrolimus for intravenous administration. Drug Dev. Ind. Pharm., 2009, 35(5), 619-630.
[http://dx.doi.org/10.1080/03639040802498856] [PMID: 18979309]
[32]
Muchow, M.; Maincent, P.; Müller, R.H.; Keck, C.M. Production and characterization of testosterone undecanoate-loaded NLC for oral bioavailability enhancement. Drug Dev. Ind. Pharm., 2011, 37(1), 8-14.
[http://dx.doi.org/10.3109/03639045.2010.489559] [PMID: 21138344]
[33]
Hua, Y.; Li, W.; Cheng, Z.; Zhao, Z.; Yin, X.; Li, Y.; Sun, J.; Gao, J.; Zhang, H.; Zheng, A. Solidification of nanostructured lipid carriers loaded testosterone undecanoate: in vivo and in vitro study. Drug Res. (Stuttg.), 2018, 68(8), 457-464.
[http://dx.doi.org/10.1055/a-0573-9132] [PMID: 29589341]
[34]
Heshmati, N.; Cheng, X.; Dapat, E.; Sassene, P.; Eisenbrand, G.; Fricker, G.; Müllertz, A. In vitro and in vivo evaluations of the performance of an indirubin derivative, formulated in four different self-emulsifying drug delivery systems. J. Pharm. Pharmacol., 2014, 66(11), 1567-1575.
[http://dx.doi.org/10.1111/jphp.12286] [PMID: 24961657]
[35]
Subramanian, N.; Ray, S.; Ghosal, S.K.; Bhadra, R.; Moulik, S.P. Formulation design of self-microemulsifying drug delivery systems for improved oral bioavailability of celecoxib. Biol. Pharm. Bull., 2004, 27(12), 1993-1999.
[http://dx.doi.org/10.1248/bpb.27.1993] [PMID: 15577219]
[36]
Sruti, J.; Patra, ChN.; Swain, S.K.; Beg, S.; Palatasingh, H.R.; Dinda, S.C.; Rao, M.E. Improvement in dissolution rate of cefuroxime axetil by using poloxamer 188 and neusilin us2. Indian J. Pharm. Sci., 2013, 75(1), 67-75.
[http://dx.doi.org/10.4103/0250-474X.113551] [PMID: 23901163]
[37]
Khaled, S.A.; Burley, J.C.; Alexander, M.R.; Yang, J.; Roberts, C.J. 3D printing of tablets containing multiple drugs with defined release profiles. Int. J. Pharm., 2015, 494(2), 643-650.
[http://dx.doi.org/10.1016/j.ijpharm.2015.07.067] [PMID: 26235921]
[38]
Sun, C.; Gui, Y.; Hu, R.; Chen, J.; Wang, B.; Guo, Y.; Lu, W.; Nie, X.; Shen, Q.; Gao, S.; Fang, W. Preparation and pharmacokinetics evaluation of Solid Self-Microemulsifying Drug Delivery System (S-SMEDDS) of osthole. AAPS PharmSciTech, 2018, 19(5), 2301-2310.
[http://dx.doi.org/10.1208/s12249-018-1067-3] [PMID: 29845504]
[39]
Shakeel, F.; Haq, N.; Alanazi, F.K.; Alsarra, I.A. Surface-adsorbed reverse micelle-loaded solid self-nanoemulsifying drug delivery system of talinolol. Pharm. Dev. Technol., 2016, 21(2), 131-139.
[http://dx.doi.org/10.3109/10837450.2014.971379] [PMID: 25318634]
[40]
Bahloul, B.; Lassoued, M.A.; Sfar, S. A novel approach for the development and optimization of self emulsifying drug delivery system using HLB and response surface methodology: application to fenofibrate encapsulation. Int. J. Pharm., 2014, 466(1-2), 341-348.
[http://dx.doi.org/10.1016/j.ijpharm.2014.03.040] [PMID: 24657287]
[41]
Jain, S.; Jain, A.K.; Pohekar, M.; Thanki, K. Novel self-emulsifying formulation of quercetin for improved in vivo antioxidant potential: implications for drug-induced cardiotoxicity and nephrotoxicity. Free Radic. Biol. Med., 2013, 65, 117-130.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.05.041] [PMID: 23792276]
[42]
Gursoy, R.N.; Benita, S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed. Pharmacother., 2004, 58(3), 173-182.
[http://dx.doi.org/10.1016/j.biopha.2004.02.001] [PMID: 15082340]
[43]
Kumar, A.; Sharma, S.; Kamble, R. Self-emulsifying drug delivery system (SEDDS): Future aspects. Int. J. Pharm. Pharm. Sci., 2010, 2, 7-13.
[44]
Puglia, C.; Damiani, E.; Offerta, A.; Rizza, L.; Tirendi, G.G.; Tarico, M.S.; Curreri, S.; Bonina, F.; Perrotta, R.E. Evaluation of Nanostructured Lipid Carriers (NLC) and nanoemulsions as carriers for UV-filters: characterization, in vitro penetration and photostability studies. Eur. J. Pharm. Sci., 2014, 51, 211-217.
[http://dx.doi.org/10.1016/j.ejps.2013.09.023] [PMID: 24157543]
[45]
Sodalee, K.; Sapsuphan, P.; Wongsirikul, R. Preparation and evaluation of alpha-mangostin solid self-emulsifying drug delivery system. Asian J Pharm SCI., 2015, 11(1), 225-226. [J].
[http://dx.doi.org/10.1016/j.ajps.2015.11.024]
[46]
Balakrishnan, P.; Lee, B.J.; Oh, D.H.; Kim, J.O.; Hong, M.J.; Jee, J.P.; Kim, J.A.; Yoo, B.K.; Woo, J.S.; Yong, C.S.; Choi, H.G. Enhanced oral bioavailability of dexibuprofen by a novel Solid Self-Emulsifying Drug Delivery System (SEDDS). Eur. J. Pharm. Biopharm., 2009, 72(3), 539-545.
[http://dx.doi.org/10.1016/j.ejpb.2009.03.001] [PMID: 19298857]
[47]
Mallappa, M.K.; Kesarla, R.; Banakar, S. Calcium alginate-neusilin us2 nanocomposite microbeads for oral sustained drug delivery of poor water soluble drug aceclofenac sodium. J. Drug Deliv., 2015, 2015, 826981.
[http://dx.doi.org/10.1155/2015/826981] [PMID: 25802761]
[48]
Quan, G.; Wu, Q.; Zhang, X.; Zhan, Z.; Zhou, C.; Chen, B.; Zhang, Z.; Li, G.; Pan, X.; Wu, C. Enhancing in vitro dissolution and in vivo bioavailability of fenofibrate by solid self-emulsifying matrix combined with SBA-15 mesoporous silica. Colloids Surf. B Biointerfaces, 2016, 141, 476-482.
[http://dx.doi.org/10.1016/j.colsurfb.2016.02.013] [PMID: 26896653]
[49]
Schnabel, P.G.; Bagchus, W.; Lass, H.; Thomsen, T.; Geurts, T.B. The effect of food composition on serum testosterone levels after oral administration of Andriol Testocaps. Clin. Endocrinol. (Oxf.), 2007, 66(4), 579-585.
[http://dx.doi.org/10.1111/j.1365-2265.2007.02781.x] [PMID: 17371478]
[50]
Bagchus, W.M.; Hust, R.; Maris, F.; Schnabel, P.G.; Houwing, N.S. Important effect of food on the bioavailability of oral testosterone undecanoate. Pharmacotherapy, 2003, 23(3), 319-325.
[http://dx.doi.org/10.1592/phco.23.3.319.32104] [PMID: 12627930]

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