AAPS PharmSciTech

, 20:44 | Cite as

Novel Drug Delivery Approach via Self-Microemulsifying Drug Delivery System for Enhancing Oral Bioavailability of Asenapine Maleate: Optimization, Characterization, Cell Uptake, and In Vivo Pharmacokinetic Studies

  • Mitali H. Patel
  • Veenu P. Mundada
  • Krutika K. SawantEmail author
Research Article


Asenapine maleate (AM)-loaded self-microemulsifying drug delivery system (AM-SMEDDS) was prepared to increase its oral bioavailability. AM-SMEDDS was developed using Capryol 90, Cremophor EL, and Transcutol HP as oil, surfactant, and cosurfactant, respectively, by spontaneous emulsification method. Pseudoternary diagram showed maximum region at 3:1 ratio of Cremophor EL/Transcutol HP. The AM-SMEDDS showed globule size and zeta potential of 21.1 ± 1.2 nm and − 19.3 ± 1.8 mV, respectively. Globules were found to be of spherical shape and uniformly distributed by transmission electron microscopy. In vitro drug release study showed 99.2 ± 3.3% of drug release at the end of 8 h in phosphate buffer pH 6.8. Ex vivo drug release study showed only 15% of drug diffusion through stomach and ~ 85% drug was diffused through intestinal membrane. Confocal and flow cytometry study showed that cellular uptake of coumarin-6 loaded SMEDDS was significantly enhanced by Caco-2 cells as that of coumarin-6 solution. The relative bioavailability of AM-SMEDDS was found to be 23.53 times greater than AM suspension. Intestinal lymphatic transport study using Cycloheximide (CHX) showed that the AUCtotal of AM-SMEDDS reduced about 35.67% compared with that without the treatment of CHX indicating involvement of lymphatic system in intestinal absorption of AM-loaded SMEDDS. These findings demonstrated the potential of SMEDDS for oral bioavailability improvement of AM via lymphatic uptake.

Graphical Abstract


Asenapine maleate Self-microemulsifying drug delivery system (SMEDDS) Cell uptake Bioavailability enhancement 



Mitali Patel thanks the Department of Science and Technology (DST), New Delhi, India for award of “Innovation in Science Pursuit for Inspired Research (INSPIRE)” Fellowship. Authors thank excipient companies—BASF India, Gattefosse India, HiMedia, and Sigma-Aldrich—for providing excipients and Alembic Pharmaceuticals Ltd, India for providing Asenapine maleate.


  1. 1.
    Bajaj H, Bisht S, Yadav M, Singh V. Bioavailability enhancement: a review. Int J Pharm Bio Sci. 2011;2(2):202–16.Google Scholar
  2. 2.
    Jannin V, Musakhanian J, Marchaud D. Approaches for the development of solid and semi-solid lipid-based formulations. Adv Drug Deliv Rev. 2008;60:734–46.CrossRefGoogle Scholar
  3. 3.
    Kohli K, Chopra S, Dhar D, Arora S, Khar RK. Self-emulsifying drug delivery system: an approach to enhance oral bioavailability. Drug Discov Today. 2010;15(21/22):958–65.CrossRefGoogle Scholar
  4. 4.
    Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother. 2004;58:173–82.CrossRefGoogle Scholar
  5. 5.
    Negi LM, Tariq M, Talegaonkar S. Nano scale self-emulsifying oil based carrier system for improved oral bioavailability of camptothecin derivative by P-glycoprotein modulation. Colloids Surf B. 2013;111:346–53.CrossRefGoogle Scholar
  6. 6.
    Young AMJ. Evaluation of the clinical efficacy of asenapine in schizophrenia. Expert Opin Pharmacother. 2010;11(12):2107–15.CrossRefGoogle Scholar
  7. 7.
    Kulkarni JA, Avachat AA. Pharmacodynamic and pharmacokinetic investigation of cyclodextrin mediated asenapine maleate in situ nasal gel for improved bioavailability. Drug Dev Ind Pharm. 2017;43(2):234–45.CrossRefGoogle Scholar
  8. 8.
    Shreya AB, Managuli RS, Menon J, Kondapalli L, Hegde AR, Avadhani K, et al. Nano-transfersomal formulations for transdermal delivery of asenapine maleate: in vitro and in vivo performance evaluations. J Liposome Res. 2016;26(3):221–32.CrossRefGoogle Scholar
  9. 9.
    Singh B, Singh R, Bandyopadhyay S, Kapil R, Garg B. Optimized nanoemulsifying systems with enhanced bioavailability of carvedilol. Colloids Surf B. 2013;101:465–74.CrossRefGoogle Scholar
  10. 10.
    Prajapati ST, Joshi H, Patel CN. Preparation and characterization of self microemulsifying drug delivery system of olmesartan medoxomil for bioavailability improvement. Aust J Pharm. 2013;2013:1–9.Google Scholar
  11. 11.
    Singh S, Pathak K, Bali V. Product development studies on surface-adsorbed nanoemulsion of olmesartan medoxomil as a capsular dosage form. AAPS PharmSciTech. 2012;13(4):1212–21.CrossRefGoogle Scholar
  12. 12.
    Patel MR, Patel MH, Patel RB. Preparation and in vitro/ex vivo evaluation of nanoemulsion for transnasal delivery of paliperidone. Appl Nanosci. 2016;6(8):1095–104.CrossRefGoogle Scholar
  13. 13.
    Balakumar K, Raghavan CV, selvana NT, Hari prasad R, Abdu S. Self nanoemulsifying drug delivery system (SNEDDS) of rosuvastatin calcium: design, formulation, bioavailability and pharmacokinetic evaluation. Colloids Surf B. 2013;112:337–43.CrossRefGoogle Scholar
  14. 14.
    Jaisamut P, Wiwattanawongsa K, Graidist P, Sangsen Y, Wiwattanapatapee R. Enhanced oral bioavailability of curcumin using a supersaturatable self-microemulsifying system incorporating a hydrophilic polymer; in vitro and in vivo investigations. AAPS PharmSciTech. 2018;19(2):730–40.CrossRefGoogle Scholar
  15. 15.
    Bandyopadhyay S, Katare OP, Singh B. Optimized self nano-emulsifying systems of ezetimibe with enhanced bioavailability potential using long chain and medium chain triglycerides. Colloids Surf B. 2012;100:50–61.CrossRefGoogle Scholar
  16. 16.
    Calcagno AM, Ludwig JA, Fostel JM, Gottesman MM, Ambudkar SV. Comparison of drug transporter levels in normal colon, colon cancer, and Caco-2 cells: impact on drug disposition and discovery. Mol Pharmacol. 2006;3(1):87–93.CrossRefGoogle Scholar
  17. 17.
    Rivolta I, Panariti A, Lettiero B, Sesana S, Gasco P, Gasco MR, et al. Cellular uptake of coumarin-6 as a model drug loaded in solid lipid nanoparticles. J Physiol Pharmacol. 2011;62(1):45–53.PubMedGoogle Scholar
  18. 18.
    Fenyvesi F, Reti-Nagy K, Bacso Z, Gutay-Toth Z, Malanga M, Fenyvesi E, et al. Fluorescently labeled methyl-beta-cyclodextrin enters intestinal epithelial Caco-2 cells by fluid-phase endocytosis. PLoS One. 2014;9(1):1–11.CrossRefGoogle Scholar
  19. 19.
    Wu L, Qiao Y, Wang L, Guo J, Wang G, He W, et al. A self-microemulsifying drug delivery system (SMEDDS) for a novel medicative compound against depression: a preparation and bioavailability study in rats. AAPS PharmSciTech. 2015;16(5):1051–8.CrossRefGoogle Scholar
  20. 20.
    Parthasarathi TR, Srinivas TS, Sri MV, Ram SS, Basha MM, Pudi R. Quantitative determination of asenapine maleate using reverse phase-high performance liquid chromatography. In J Pharm Bio Sci. 2012;3(4):360–6.Google Scholar
  21. 21.
    Sun M, Zhai X, Xue K, Hu L, Yang X, Li G, et al. Intestinal absorption and intestinal lymphatic transport of sirolimus from self-microemulsifying drug delivery systems assessed using the single-pass intestinal perfusion (SPIP) technique and a chylomicron flow blocking approach: linear correlation with oral bioavailabilities in rats. Eur J Pharm Sci. 2011;43:132–40.CrossRefGoogle Scholar
  22. 22.
    El-Laithy HM, Basalious EB, El-Hosiny BM, Adel MM. Novel self-nanoemulsifying self-nanosuspension (SNESNS) for enhancing oral bioavailability of diacerein: simultaneous portal blood absorption and lymphatic delivery. Int J Pharm. 2015;490(1–2):146–54.CrossRefGoogle Scholar
  23. 23.
    Pouton CW, Porter CJ. Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies. Adv Drug Deliv Rev. 2008;60(6):625–37.CrossRefGoogle Scholar
  24. 24.
    Seo YG, Kim DH, Ramasamy T, Kim JH, Marasini N, Oh YK, et al. Development of docetaxel-loaded solid self-nanoemulsifying drug delivery system (SNEDDS) for enhanced chemotherapeutic effect. Int J Pharm. 2013;452:412–20.CrossRefGoogle Scholar
  25. 25.
    Borhade V, Nair H, Hegde D. Design and evaluation of self-microemulsifying drug delivery system (SMEDDS) of tacrolimus. AAPS PharmSciTech. 2008;9(1):13–21.CrossRefGoogle Scholar
  26. 26.
    Singh AK, Chaurasiya A, Singh S, Upadhyay SC, Mukherjee R, Khar RK. Exemestane loaded self-microemulsifying drug delivery system (SMEDDS): development and optimization. AAPS PharmSciTech. 2008;9(2):628–34.CrossRefGoogle Scholar
  27. 27.
    Nepal PR, Han HK, Choi HK. Preparation and in vitro–in vivo evaluation of Witepsol® H35 based self-nanoemulsifying drug delivery systems (SNEDDS) of coenzyme Q10. Eur J Pharm Sci. 2010;39:224–32.CrossRefGoogle Scholar
  28. 28.
    Elnaggar YS, El-Massik MA, Abdallah OY. Self-nanoemulsifying drug delivery systems of tamoxifen citrate: design and optimization. Int J Pharm. 2009;380(1–2):133–41.CrossRefGoogle Scholar
  29. 29.
    McConville C, Friend D. Development and characterisation of a self-microemulsifying drug delivery systems (SMEDDSs) for the vaginal administration of the antiretroviral UC-781. Eur J Pharm Biopharm. 2013;83:322–9.CrossRefGoogle Scholar
  30. 30.
    Avachat AM, Patel VG. Self nanoemulsifying drug delivery system of stabilized ellagic acid–phospholipid complex with improved dissolution and permeability. Saudi Pharm J. 2015;23(3):276–89.CrossRefGoogle Scholar
  31. 31.
    Zhang P, Liu Y, Feng N, Xu J. Preparation and evaluation of self microemulsifying drug delivery system of oridonin. Int J Pharm. 2008;355:269–76.CrossRefGoogle Scholar
  32. 32.
    Zhao G, Huang J, Xue K, Si L, Li G. Enhanced intestinal absorption of etoposide by self-microemulsifying drug delivery systems: roles of P-glycoprotein and cytochrome P450 3A inhibition. Eur J Pharm Sci. 2013;50:429–39.CrossRefGoogle Scholar
  33. 33.
    Gursoy RN, Çevik O. Design, characterization and in vitro evaluation of SMEDDS containing an anticancer peptide, linear LyP-1. Pharm Dev Technol. 2014;19(4):486–90.CrossRefGoogle Scholar
  34. 34.
    Ji H, Tang J, Li M, Ren J, Zheng N, Wu L. Curcumin-loaded solid lipid nanoparticles with Brij78 and TPGS improved in vivo oral bioavailability and in situ intestinal absorption of curcumin. Drug Deliv. 2016;23(2):549–470.CrossRefGoogle Scholar
  35. 35.
    Rege BD, Kao JPY, Polli JE. Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. Eur J Pharm Sci. 2002;16:237–46.CrossRefGoogle Scholar
  36. 36.
    Lim SK, Banerjee A, Onyuksel H. Improvement of drug safety by the use of lipid-based nanocarriers. J Control Release. 2012;163:34–45.CrossRefGoogle Scholar
  37. 37.
    Kou L, Sun J, Zhai Y, He Z. The endocytosis and intracellular fate of nanomedicines: implication for rational design. Asian J Pharm Sci. 2013;8:1–10.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Mitali H. Patel
    • 1
  • Veenu P. Mundada
    • 1
  • Krutika K. Sawant
    • 1
    • 2
    Email author
  1. 1.Drug Delivery Research Laboratory, Shri G. H. Patel Pharmacy Building, Faculty of PharmacyThe M. S. University of BarodaVadodaraIndia
  2. 2.Faculty of PharmacyThe M.S. University of BarodaVadodaraIndia

Personalised recommendations