Skip to main content

Advertisement

SpringerLink
Log in

Assessment of Biopharmaceutical Performance of Supersaturating Formulations of Carbamazepine in Rats Using Physiologically Based Pharmacokinetic Modeling

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

Abstract

There is an overgrowing emphasis on supersaturating drug delivery systems (SDDS) with increase in number of poorly water-soluble compounds. However, biopharmaceutical performance from these formulations is limited by phase transformation to stable crystalline form due to their high-energy physical form. In the present study, in vitro kinetic solubility in water and dissolution in biorelevant medium integrated with in silico physiologically based pharmacokinetic (PBPK) modeling was used to predict biopharmaceutical performance of SDDS of poorly water-soluble compound, carbamazepine (CBZ). GastroPlus™ with advanced compartmental absorption and transit model was used as a simulation tool for the study. Wherein, the model was developed using physicochemical properties of CBZ and disposition parameters obtained after intravenous administration of CBZ (20 mg/kg) into Sprague-Dawley (SD) rats. Biorelevant medium was selected by screening different dissolution media for their capability to predict oral plasma concentration-time profile of marketed formulation of CBZ. In vivo performance of SDDS was predicted with the developed model and compared to observed plasma concentration-time profile obtained after oral administration of SDDS into SD rats (20 mg/kg). The predictions, with strategy of using kinetic solubility and dissolution in the selected biorelevant medium, were consistent with observed biopharmaceutical performance of SDDS. Additionally, phase transformation of CBZ during gastrointestinal transit of formulations was evaluated and correlated with in vivo dissolution deconvoluted by Loo-Reigelman analysis.

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

Abbreviations

CBZ:

Carbamazepine

BCS:

Biopharmaceutics Classification System

CBZ-DH:

Carbamazepine dihydrate

GIT:

Gastrointestinal tract

SDDS:

Supersaturating drug delivery systems

CoC:

Cocrystal

ASD:

Amorphous solid dispersion

G+:

GastroPlusTM

PBPK:

Physiologically based pharmacokinetic modeling

ACAT:

Advanced compartmental absorption and transit

LR:

Loo-Reigelman

SAC:

Saccharin

HPMCAS:

Hydroxypropyl methylcellulose acetate succinate

DSC:

Differential scanning calorimetry

PXRD:

Powder X-ray diffraction

CPCSEA:

Committee for the Purpose of Control and Supervision of Experiments on Animals

%PE:

% prediction error

EHC:

Enterohepatic circulation

SEM:

Scanning electron microscopy

References

  1. Jones HM, Gardner IB, Watson KJ. Modelling and PBPK simulation in drug discovery. AAPS J. 2009;11(1):155–66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Kesisoglou F, Chung J, van Asperen J, Heimbach T. Physiologically based absorption modeling to impact biopharmaceutics and formulation strategies in drug development—industry case studies. J Pharm Sci. 2016;105(9):2723–34.

    Article  CAS  PubMed  Google Scholar 

  3. Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm Sci. 2009;98(8):2549–72.

    Article  CAS  PubMed  Google Scholar 

  4. Raw AS, Furness MS, Gill DS, Adams RC, Holcombe FO, Lawrence XY. Regulatory considerations of pharmaceutical solid polymorphism in abbreviated new drug applications (ANDAs). Adv Drug Deliv Rev. 2004;56(3):397–414.

    Article  CAS  PubMed  Google Scholar 

  5. Bertilsson L. Clinical pharmacokinetics of carbamazepine. Clin Pharmacokinet. 1978;3(2):128–43.

    Article  CAS  PubMed  Google Scholar 

  6. Wilding I, Davis S, Hardy J, Robertson C, John V, Powell M, et al. Relationship between systemic drug absorption and gastrointestinal transit after the simultaneous oral administration of carbamazepine as a controlled-release system and as a suspension of 15N-labelled drug to healthy volunteers. Br J Clin Pharmacol. 1991;32(5):573–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Riad LE, Sawchuk RJ. Absorptive clearance of carbamazepine and selected metabolites in rabbit intestine. Pharm Res. 1991;8(8):1050–5.

    Article  CAS  PubMed  Google Scholar 

  8. Kahela P, Aaltonen R, Lewing E, Anttila M, Kristoffersson E. Pharmacokinetics and dissolution of two crystalline forms of carbamazepine. Int J Pharm. 1983;14(1):103–12.

    Article  CAS  Google Scholar 

  9. Murphy D, Rodrıguez-Cintrón F, Langevin B, Kelly R, Rodrıguez-Hornedo N. Solution-mediated phase transformation of anhydrous to dihydrate carbamazepine and the effect of lattice disorder. Int J Pharm. 2002;246(1):121–34.

    Article  CAS  PubMed  Google Scholar 

  10. Yates I, Bi V, Farzana I, Deal S, Durig T. Selection of polymeric carriers for carbamazepine amorphous solid dispersions 2014. Available from: http://www.ashland.com/Ashland/Static/Documents/ASI/Pharmaceutical/aaps2014/2014AAPS_Carbamazepine.pdf.

  11. Alshahrani SM, Lu W, Park J-B, Morott JT, Alsulays BB, Majumdar S, et al. Stability-enhanced hot-melt extruded amorphous solid dispersions via combinations of Soluplus® and HPMCAS-HF. AAPS PharmSciTech. 2015;16(4):824–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hickey MB, Peterson ML, Scoppettuolo LA, Morrisette SL, Vetter A, Guzmán H, et al. Performance comparison of a co-crystal of carbamazepine with marketed product. Eur J Pharm Biopharm. 2007;67(1):112–9.

    Article  CAS  PubMed  Google Scholar 

  13. Friščić T, Fábián L, Burley JC, Jones W, Motherwell WS. Exploring cocrystal–cocrystal reactivity via liquid-assisted grinding: the assembling of racemic and dismantling of enantiomeric cocrystals. ChCom. 2006;(48):5009–11.

  14. Vasconcelos T, Sarmento B, Costa P. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discov Today. 2007;12(23):1068–75.

    Article  CAS  PubMed  Google Scholar 

  15. Patil SR, Kumar L, Kohli G, Bansal AK. Validated HPLC method for concurrent determination of antipyrine, carbamazepine, furosemide and phenytoin and its application in assessment of drug permeability through Caco-2 cell monolayers. Sci Pharm. 2012;80(1):89–100.

    Article  CAS  PubMed  Google Scholar 

  16. Otsuka K, Shono Y, Dressman J. Coupling biorelevant dissolution methods with physiologically based pharmacokinetic modelling to forecast in-vivo performance of solid oral dosage forms. J Pharm Pharmacol. 2013;65(7):937–52.

    Article  CAS  PubMed  Google Scholar 

  17. Avdeef A. Solubility of sparingly-soluble ionizable drugs. Adv Drug Deliv Rev. 2007;59(7):568–90.

    Article  CAS  PubMed  Google Scholar 

  18. Lee H, Park S-A, Sah H. Surfactant effects upon dissolution patterns of carbamazepine immediate release tablet. Arch Pharm Res. 2005;28(1):120–6.

    Article  CAS  PubMed  Google Scholar 

  19. Kovacevic I, Parojcic J, Homšek I, Tubic-Grozdanis M, Langguth P. Justification of biowaiver for carbamazepine, a low soluble high permeable compound, in solid dosage forms based on IVIVC and gastrointestinal simulation. Mol Pharm. 2008;6(1):40–7.

    Article  CAS  Google Scholar 

  20. Madden S, Maggs JL, Park BK. Bioactivation of carbamazepine in the rat in vivo. Evidence for the formation of reactive arene oxide (s). Drug Metab Dispos. 1996;24(4):469–79.

    CAS  PubMed  Google Scholar 

  21. Šehić S, Betz G, Hadžidedić Š, El-Arini SK, Leuenberger H. Investigation of intrinsic dissolution behavior of different carbamazepine samples. Int J Pharm. 2010;386(1):77–90.

    Article  PubMed  CAS  Google Scholar 

  22. Remmel RP, Sinz MW, Cloyd JC. Dose-dependent pharmacokinetics of carbamazepine in rats: determination of the formation clearance of carbamazepine-10, 11-epoxide. Pharm Res. 1990;7(5):513–7.

    Article  CAS  PubMed  Google Scholar 

  23. Wagner C, Jantratid E, Kesisoglou F, Vertzoni M, Reppas C, Dressman JB. Predicting the oral absorption of a poorly soluble, poorly permeable weak base using biorelevant dissolution and transfer model tests coupled with a physiologically based pharmacokinetic model. Eur J Pharm Biopharm. 2012;82(1):127–38.

    Article  CAS  PubMed  Google Scholar 

  24. Loo J, Riegelman S. New method for calculating the intrinsic absorption rate of drugs. J Pharm Sci. 1968;57(6):918–28.

    Article  CAS  PubMed  Google Scholar 

  25. Rodríguez-Hornedo N, Murphy D. Surfactant-facilitated crystallization of dihydrate carbamazepine during dissolution of anhydrous polymorph. J Pharm Sci. 2004;93(2):449–60.

    Article  PubMed  CAS  Google Scholar 

  26. Tian F, Zeitler J, Strachan C, Saville D, Gordon K, Rades T. Characterizing the conversion kinetics of carbamazepine polymorphs to the dihydrate in aqueous suspension using Raman spectroscopy. J Pharm Biomed Anal. 2006;40(2):271–80.

    Article  CAS  PubMed  Google Scholar 

  27. Grzesiak AL, Lang M, Kim K, Matzger AJ. Comparison of the four anhydrous polymorphs of carbamazepine and the crystal structure of form I. J Pharm Sci. 2003;92(11):2260–71.

    Article  CAS  PubMed  Google Scholar 

  28. Alhalaweh A, Roy L, Rodríguez-Hornedo N, Velaga SP. pH-dependent solubility of indomethacin–saccharin and carbamazepine–saccharin cocrystals in aqueous media. Mol Pharm. 2012;9(9):2605–12.

    Article  CAS  PubMed  Google Scholar 

  29. Porter Iii WW, Elie SC, Matzger AJ. Polymorphism in carbamazepine cocrystals. Cryst Growth Des. 2008;8(1):14–6.

    Article  CAS  Google Scholar 

  30. Sigma-Aldrich. Product comparision guide: Sodium dodecyl sulfate 2016. Available from: http://www.sigmaaldrich.com/catalog/substance/sodiumdodecylsulfate2883815121311?lang=en&region=IN&attrlist=Critical micelle concentration.

  31. Gabrielsson J, Weiner D. Non-compartmental analysis. Computational toxicology: Springer; 2012. p. 377–89.

    Google Scholar 

  32. Qureshi SA. Developing discriminatory drug dissolution tests and profiles: some thoughts for consideration on the concept and its interpretation. Dissolut Technol. 2006;13(4):18–23.

    Article  CAS  Google Scholar 

  33. Ueda K, Higashi K, Yamamoto K, Moribe K. The effect of HPMCAS functional groups on drug crystallization from the supersaturated state and dissolution improvement. Int J Pharm. 2014;464(1–2):205–13.

    Article  CAS  PubMed  Google Scholar 

  34. AquaSolve™ hypromellose acetate succinate 2015. Available from: https://www.ashland.com/industries/pharmaceutical/oral-solid-dose/aquasolve-hypromellose-acetate-succinate.

  35. Tajarobi F, Larsson A, Matic H, Abrahmsén-Alami S. The influence of crystallization inhibition of HPMC and HPMCAS on model substance dissolution and release in swellable matrix tablets. Eur J Pharm Biopharm. 2011;78(1):125–33.

    Article  CAS  PubMed  Google Scholar 

  36. Homayouni A, Sadeghi F, Varshosaz J, Garekani HA, Nokhodchi A. Promising dissolution enhancement effect of soluplus on crystallized celecoxib obtained through antisolvent precipitation and high pressure homogenization techniques. Colloids Surf B: Biointerfaces. 2014;122:591–600.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Mohali, Punjab, 160062, India

    Samarth D. Thakore, Poonam Singh Thakur, Ganesh Shete, Abhay T. Sangamwar & Arvind Kumar Bansal

  2. Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Mohali, Punjab, 160062, India

    Rahul Gangwal

  3. Small Molecule Pharmaceutical Sciences, Genentech, Inc., One DNA Way, South San Francisco, California, 94080, USA

    Ajit S. Narang

Authors
  1. Samarth D. Thakore
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Poonam Singh Thakur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ganesh Shete
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rahul Gangwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ajit S. Narang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Abhay T. Sangamwar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Arvind Kumar Bansal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Arvind Kumar Bansal.

Additional information

Publisher’s Note

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

Electronic Supplementary Material

ESM 1

(DOC 1315 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Thakore, S.D., Thakur, P.S., Shete, G. et al. Assessment of Biopharmaceutical Performance of Supersaturating Formulations of Carbamazepine in Rats Using Physiologically Based Pharmacokinetic Modeling. AAPS PharmSciTech 20, 179 (2019). https://doi.org/10.1208/s12249-019-1386-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-019-1386-z

KEY WORDS

Search

Navigation