Skip to main content
SpringerLink
Log in

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

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

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

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Bajaj H, Bisht S, Yadav M, Singh V. Bioavailability enhancement: a review. Int J Pharm Bio Sci. 2011;2(2):202–16.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  4. Gursoy RN, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother. 2004;58:173–82.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  6. Young AMJ. Evaluation of the clinical efficacy of asenapine in schizophrenia. Expert Opin Pharmacother. 2010;11(12):2107–15.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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. 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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Drug Delivery Research Laboratory, Shri G. H. Patel Pharmacy Building, Faculty of Pharmacy, The M. S. University of Baroda, Fatehgunj, Vadodara, Gujarat, 390002, India

    Mitali H. Patel, Veenu P. Mundada & Krutika K. Sawant

  2. Faculty of Pharmacy, The M.S. University of Baroda, Kalabhavan Campus, Vadodara, 390001, India

    Krutika K. Sawant

Authors
  1. Mitali H. Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Veenu P. Mundada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Krutika K. Sawant
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Krutika K. Sawant.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Patel, M.H., Mundada, V.P. & Sawant, K.K. 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. AAPS PharmSciTech 20, 44 (2019). https://doi.org/10.1208/s12249-018-1212-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-018-1212-z

KEY WORDS

Search

Navigation