Skip to main content
SpringerLink
Log in

Using Self-Nanoemulsifying System to Improve Oral Bioavailability of a Pediatric Antiepileptic Agent Stiripentol: Formulation and Pharmacokinetics Studies

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

Abstract

This study aimed to develop a self-nanoemulsifying drug delivery system (SNEDDS) for poorly water-soluble drug stiripentol (STP) with enhanced oral bioavailability. Optimal excipients were selected by constructing pseudo-ternary phase diagrams using determined solubilities of STP, and then the proper composition of SNEDDS was investigated by employing a central composite design method. The optimized SNEDDS was composed of oil (ethyl oleate 39.61%), surfactant (Cremophor® RH 40 43.18%), co-surfactant (1,2-propanediol 17.21%), and STP of 50 mg/mL. The hydrodynamic size, zeta potential, and polydispersity index (PDI) were found to be 45.52 ± 1.99 nm, − 21.67 ± 0.24 mV, and 0.076 ± 0.011, respectively. The optimized STP-SNEDDS showed good stability in accelerated and dilution stability studies. It was also helpful to suppress STP degradation in acidic solution. Compared with STP suspension, STP-SNEDDS presented much faster dissolution rate. STP-SNEDDS successfully resulted in superior levels of Cmax and AUC0 → 6 h (4048.38 ± 704.54 μg/L and 7754.58 ± 1489.37 h μg/L, respectively) to STP suspension (1894.09 ± 1077.64 μg/L and 3556.93 ± 2470.01 h μg/L, respectively). The relative oral bioavailability of STP was 218.01%. The brain biodistribution studies showed that STP-SNEDDS presented significantly higher STP concentrations in the brain at 0.5 h and 1 h than that of STP suspension after administration. These findings indicated that a SNEDDS-based oral formulation of STP would be helpful for increasing its therapeutic potential.

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
Fig. 8

Similar content being viewed by others

References

  1. De Liso P, Chemaly N, Laschet J, et al. Patients with Dravet syndrome in the era of stiripentol: a French cohort cross-sectional study. Epilepsy Res. 2016;125:42–6.

    PubMed  Google Scholar 

  2. Arends RH, Zhang K, Levy RH, Baillie TA, Shen DD. Stereoselective pharmacokinetics of stiripentol: an explanation for the development of tolerance to anticonvulsant effect. Epilepsy Res. 1994;18(2):91–6.

    CAS  PubMed  Google Scholar 

  3. Strzelczyk A, Kortland LM, Knake S, Rosenow F. Stiripentol for the treatment of super-refractory status epilepticus. Acta Neurol Scand. 2015;132(6):435–9.

    CAS  PubMed  Google Scholar 

  4. Quilichini PP, Chiron C, Ben-Ari Y, Gozlan H. Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABAA-receptor channels. Epilepsia. 2006;47(4):704–16.

    CAS  PubMed  Google Scholar 

  5. Nickels KC, Wirrell EC. Stiripentol in the management of epilepsy. CNS Drugs. 2017;31(5):405–16.

    CAS  PubMed  Google Scholar 

  6. Sada N, Lee S, Katsu T, Otsuki T, Inoue T. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science. 2015;347(6228):1362–7.

    CAS  PubMed  Google Scholar 

  7. Inoue Y, Ohtsuka Y. Long-term safety and efficacy of stiripentol for the treatment of Dravet syndrome: a multicenter, open-label study in Japan. Epilepsy Res. 2015;113:90–7.

    CAS  PubMed  Google Scholar 

  8. Zhang X, Wang H, Zhang T, Zhou X, Wu B. Exploring the potential of self-assembled mixed micelles in enhancing the stability and oral bioavailability of an acid-labile drug. Eur J Pharm Sci. 2014;62:301–8.

    CAS  PubMed  Google Scholar 

  9. Afifi S. Solid dispersion approach improving dissolution rate of stiripentol: a novel antiepileptic drug. Iran J Pharm Res. 2015;14(4):1001–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Diacomit 250 mg powder for oral suspension in sachet. Alan Pharmaceuticals. https://www.medicines.org.uk/emc/product/10304/smpc/print. Accessed 31, May 2019.

  11. Lu R, Liu S, Wang Q, Li X. Nanoemulsions as novel oral carriers of stiripentol: insights into the protective effect and absorption enhancement. Int J Nanomedicine. 2015;10:4937–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Chatterjee B, Hamed Almurisi S, Ather AMD, et al. Controversies with self-emulsifying drug delivery system from pharmacokinetic point of view. Drug Deliv. 2016;23(9):3639–52.

    CAS  PubMed  Google Scholar 

  13. Karamanidou T, Karidi K, Kammona O, et al. Effective incorporation of insulin in mucus permeating self-nanoemulsifying drug delivery systems. Eur J Pharm Biopharm. 2015;97(Pt A):223–9.

    CAS  PubMed  Google Scholar 

  14. Friedl H, Dünnhaupt S, Hintzen F, Waldner C, Parikh S, Pearson JP, et al. Development and evaluation of a novel mucus diffusion test system approved by self-nanoemulsifying drug delivery systems. J Pharm Sci. 2013;102(12):4406–13.

    CAS  PubMed  Google Scholar 

  15. Date AA, Desai N, Dixit R, Nagarsenker M. Self-nanoemulsifying drug delivery systems: formulation insights, applications and advances. Nanomedicine. 2010;5(10):1595–616.

    CAS  PubMed  Google Scholar 

  16. Qi X, Qin J, Ma N, Chou X, Wu Z. Solid self-microemulsifying dispersible tablets of celastrol: formulation development, characterization and bioavailability evaluation. Int J Pharm. 2014;472(1–2):40–7.

    CAS  PubMed  Google Scholar 

  17. Nan Z, Lijun G, Tao W, Dongqin Q. Evaluation of carbamazepine (CBZ) supersaturatable self- microemulsifying (S-SMEDDS) formulation in-vitro and in-vivo. Iran J Pharm Res. 2012;11(1):257–64.

    PubMed  PubMed Central  Google Scholar 

  18. Knaub K, Sartorius T, Dharsono T, Wacker R, Wilhelm M, Schön C. A novel self-emulsifying drug delivery system (SEDDS) based on VESIsorb® formulation technology improving the oral bioavailability of cannabidiol in healthy subjects. Molecules. 2019;24(16):2967.

    CAS  PubMed Central  Google Scholar 

  19. Agrawal AG, Kumar A, Gide PS. Self emulsifying drug delivery system for enhanced solubility and dissolution of glipizide. Colloids Surf B Biointerfaces. 2015;126:553–60.

    CAS  PubMed  Google Scholar 

  20. Zhu Y, Xu W, Zhang J, Liao Y, Firempong CK, Adu-Frimpong M, et al. Self-microemulsifying drug delivery system for improved oral delivery of limonene: preparation, characterization, in vitro and in vivo evaluation. AAPS PharmSciTech. 2019;20(4):153–64.

    PubMed  Google Scholar 

  21. Balakrishnan P, Lee BJ, Oh DH, Kim JO, Lee YI, Kim DD, et al. Enhanced oral bioavailability of coenzyme Q10 by self-emulsifying drug delivery systems. Int J Pharm. 2009;374(1–2):66–72.

    CAS  PubMed  Google Scholar 

  22. Kim DW, Kang JH, Oh DH, Yong CS, Choi HG. Development of novel flurbiprofen-loaded solid self-microemulsifying drug delivery system using gelatin as solid carrier. J Microencapsul. 2012;29(4):323–30.

    CAS  PubMed  Google Scholar 

  23. Zidan AS, Sammour OA, Hammad MA, Megrab NA, Habib MJ, Khan MA. Quality by design: understanding the product variability of a self-nanoemulsified drug delivery system of cyclosporine A. J Pharm Sci. 2007;96(9):2409–23.

    CAS  PubMed  Google Scholar 

  24. Huang Z, Xia J, Li J, et al. Optimization and bioavailability evaluation of self-microemulsifying drug delivery system of the daidzein-nicotinamide complex. RSC Adv. 2016;10:1–10.

    Google Scholar 

  25. Tong Y, Wang Y, Yang M, Yang J, Chen L, Chu X, et al. Systematic development of self-nanoemulsifying liquisolid tablets to improve the dissolution and oral bioavailability of an oily drug, vitamin K1. Pharmaceutics. 2018;10(3):96.

    CAS  PubMed Central  Google Scholar 

  26. Takahashi R, Imai K, Yamamoto Y, Takahashi Y, Hamano SI, Yoshida H. Determination of stiripentol in plasma by high-performance liquid chromatography with fluorescence detection. Jpn J Pharm Health Care Sci. 2015;41(9):643–50.

    Google Scholar 

  27. Seo YG, Kim DW, Yousaf AM, Park JH, Chang PS, Baek HH, et al. Solid self-nanoemulsifying drug delivery system (SNEDDS) for enhanced oral bioavailability of poorly water-soluble tacrolimus: physicochemical characterisation and pharmacokinetics. J Microencapsul. 2015;32(5):503–10.

    CAS  PubMed  Google Scholar 

  28. Rao SVR, Shao J. Self-nanoemulsifying drug delivery systems (SNEDDS) for oral delivery of protein drugs: I. formulation development. Int J Pharm. 2008;362(1–2):2–9.

    CAS  PubMed  Google Scholar 

  29. Omari-Siaw E, Zhu Y, Wang H, Peng W, Firempong CK, Wang YW, et al. Hypolipidemic potential of perillaldehyde-loaded self-nanoemulsifying delivery system in high-fat diet induced hyperlipidemic mice: formulation, in vitro and in vivo evaluation. Eur J Pharm Sci. 2016;85:112–22.

    CAS  PubMed  Google Scholar 

  30. U.S. FDA. Inactive Ingredients Database of the FDA https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm.

  31. Cheng G, Hu R, Ye L, Wang B, Gui Y, Gao S, et al. Preparation and in vitro/in vivo evaluation of puerarin solid self-microemulsifying drug delivery system by spherical crystallization technique. AAPS PharmSciTech. 2016;17(6):1336–46.

    CAS  PubMed  Google Scholar 

  32. Cui SX, Nie SF, Li L, Wang CG, Pan WS, Sun JP. Preparation and evaluation of self-microemulsifying drug delivery system containing vinpocetine. Drug Dev Ind Pharm. 2009;35(5):603–11.

    CAS  PubMed  Google Scholar 

  33. Man N, Wang Q, Li H, Adu-Frimpong M, Sun C, Zhang K, et al. Improved oral bioavailability of myricitrin by liquid self-microemulsifying drug delivery systems. J Drug Deliv Sci Tec. 2019;52:597–606.

    CAS  Google Scholar 

  34. Bookstaff RC, PaiBir S, Bharaj SS, Kelm GR, Kulick RM, Balm TK, et al. The safety of the use of ethyl oleate in food is supported by metabolism data in rats and clinical safety data in humans. Regul Toxicol Pharmacol. 2003;37(1):133–48.

    CAS  PubMed  Google Scholar 

  35. Bier M, De Graaf J, Zwanikken J, et al. Curvature dependence of the electrolytic liquid-liquid interfacial tension. J Chem Phys. 2009;130(2):024703.

    PubMed  Google Scholar 

  36. Onoue S, Uchida A, Kuriyama K, Nakamura T, Seto Y, Kato M, et al. Novel solid self-emulsifying drug delivery system of coenzyme Q10 with improved photochemical and pharmacokinetic behaviors. Eur J Pharm Sci. 2012;46(5):492–9.

  37. Nazzal S, Smalyukh II, Lavrentovich OD, Khan MA. Preparation and in vitro characterization of a eutectic based semisolid self-nanoemulsified drug delivery system (SNEDDS) of ubiquinone: mechanism and progress of emulsion formation. Int J Pharm. 2002;235(1–2):247–65.

    CAS  PubMed  Google Scholar 

  38. Spernath A, Yaghmur A, Aserin A, Hoffman RE, Garti N. Food-grade microemulsions based on nonionic emulsifiers: media to enhance lycopene solubilization. J Agric Food Chem. 2002;50(23):6917–22.

    CAS  PubMed  Google Scholar 

  39. Niu B, Yin Z, Qiu N, Yu Y, Huang Q, Zhu Q, et al. Effective management of acute postoperative pain using intravenous emulsions of novel ketorolac prodrugs: in vitro and in vivo evaluations. Eur J Pharm Sci. 2020;149:105344.

    CAS  PubMed  Google Scholar 

  40. Shen Q, Li X, Yuan D, Jia W. Enhanced oral bioavailability of daidzein by self-microemulsifying drug delivery system. Chem Pharm Bull. 2010;58(5):639–43.

    CAS  PubMed  Google Scholar 

  41. Kaasalainen M, Aseyev V, von Haartman E, Karaman DŞ, Mäkilä E, Tenhu H, et al. Size, stability, and porosity of mesoporous nanoparticles characterized with light scattering. Nanoscale Res Lett. 2017;12(1):74.

    PubMed  PubMed Central  Google Scholar 

  42. Moulik SP, Paul BK. Structure, dynamics and transport properties of microemulsions. Adv Colloid Interf Sci. 1998;78(2):99–195.

    CAS  Google Scholar 

  43. Hellmig S, Schöning FV, Gadow C, et al. Gastric emptying time of fluids and solids in healthy subjects determined by 13C breath tests: influence of age, sex and body mass index. J Gastroenterol Hepatol. 2006;21(12):1832–8.

    PubMed  Google Scholar 

  44. Darwish HW, Abdelhameed AS, Attia MI, et al. A stability-indicating HPLC-DAD method for determination of stiripentol: development, validation, kinetics, structure elucidation and application to commercial dosage form. J Anal Methods Chem. 2014;2014:638951.

    PubMed  PubMed Central  Google Scholar 

  45. Qureshi MJ, Mallikarjun C, Kian WG. Enhancement of solubility and therapeutic potential of poorly soluble lovastatin by SMEDDS formulation adsorbed on directly compressed spray dried magnesium aluminometasilicate liquid loadable tablets: a study in diet induced hyperlipidemic rabbits. Asi J Pharm Sci. 2015;10(1):40–56.

    Google Scholar 

  46. Nazzal S, Nutan M, Palamakula A, Shah R, Zaghloul AA, Khan MA. Optimization of a self-nanoemulsified tablet dosage form of ubiquinone using response surface methodology: effect of formulation ingredients. Int J Pharm. 2002;240(1–2):103–14.

    CAS  PubMed  Google Scholar 

  47. Huang J, Gong W, Chen Z, Huang J, Chen Q, Huang H, et al. Emodin self-emulsifying platform ameliorates the expression of FN, ICAM-1 and TGF-β1 in AGEs-induced glomerular mesangial cells by promoting absorption. Eur J Pharm Sci. 2017;99:128–36.

    CAS  PubMed  Google Scholar 

  48. Shen DD, Levy RH, Moor MJ, Savitch JL. Efficacy of stiripentol in the intravenous pentylenetetrazol infusion seizure model in the rat. Epilepsy Res. 1990;7(1):40–8.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We acknowledge the valuable help from Dr. Changlai Zhu at Jiangsu Key Laboratory of Nerve Regeneration of Nantong University for the acquisition of the TEM images.

Funding

We thank the financial supports from the China National Natural Science Foundation (81603044), the China Postdoctoral Science Foundation (2017 M611886), the Innovation and Entrepreneurship Training Program for College Students in Jiangsu Province (201710304080Y, 201810304040Z), the Large Instruments Open Foundation of Nantong University (KFJN1852), and the Nantong University Cooperative Innovation Program of Small Molecular Compound R&D-NTU2016–1.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu Province, China

    Qiuyang Dai, Peiyan Zhang, Yilan Jin, Mi Tang, Mengling Shen, Shujun Xu, Susu Huang & Yong Chen

Authors
  1. Qiuyang Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peiyan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yilan Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mi Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mengling Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shujun Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Susu Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yong Chen.

Ethics declarations

This study was approved by the Laboratory Animal Ethics Committee of Nantong University. All the animal experiments were performed according to the NIH (National Institutes of Health USA) (2011) Guide for the Care and Use of Laboratory Animals.

Conflict of Interest

The authors declare that they have no conflict of interest.

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

Dai, Q., Zhang, P., Jin, Y. et al. Using Self-Nanoemulsifying System to Improve Oral Bioavailability of a Pediatric Antiepileptic Agent Stiripentol: Formulation and Pharmacokinetics Studies. AAPS PharmSciTech 21, 192 (2020). https://doi.org/10.1208/s12249-020-01730-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-020-01730-z

KEY WORDS

Search

Navigation