Skip to main content
SpringerLink
Log in

Prediction of Free Drug Absorption in Cyclodextrin Formulation by a Modified Physiologically Based Pharmacokinetic Model and Phase Solubility 3-D Surface Graph

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Cyclodextrin (CD) is commonly used to enhance the solubility of oral drugs. However, with the increase of CD concentrations, the fraction of free drug molecules decreases, which may potentially impede drug absorption. This study aims to predict the optimal ratio between drug and CD to achieve the best absorption efficiency by computational simulation.

Methods

First, a physiologically based pharmacokinetic (PBPK) model was developed. This model can continuously adjust absorption according to free drug fraction and was validated against two model drugs, progesterone (PG) and andrographolide (AG). The further analysis involves 3-D surface graphs to investigate the relationship between free drug amount, theoretically absorbable concentration, and contents of drug and CD in the formulation.

Results

The PBPK model predicted the PK behavior of two drugs well. The concentration ratio of drug to CD, leading to maximal free drug amount and the best absorption efficiency, is nearly the same as the slope determined in the phase solubility test. The new modified PBPK model and 3-D surface graph can easily predict the absorption difference of formulations with various drug/CD ratios.

Conclusion

This PBPK model and 3-D surface graph can predict the absorption and determine the optimal concentration ratio of CD formulation, which could accelerate the R&D of CD formulation.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Di Maio S, Carrier RL. Gastrointestinal contents in fasted state and post-lipid ingestion: in vivo measurements and in vitro models for studying oral drug delivery. J Control Release. 2011;151(2):110–22. https://doi.org/10.1016/j.jconrel.2010.11.034.

    Article  CAS  PubMed  Google Scholar 

  2. Williams HD, Trevaskis NL, Charman SA, Shanker RM, Charman WN, Pouton CW, et al. Strategies to address low drug solubility in discovery and development. Pharmacol Rev. 2013;65(1):315–499. https://doi.org/10.1124/pr.112.005660.

    Article  CAS  PubMed  Google Scholar 

  3. Challa R, Ahuja A, Ali J, Khar RK. Cyclodextrins in drug delivery: an updated review. AAPS PharmSciTech. 2005;6(2):E329–57. https://doi.org/10.1208/pt060243.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Rong WT, Lu YP, Tao Q, Guo M, Lu Y, Ren Y, et al. Hydroxypropyl-sulfobutyl-beta-cyclodextrin improves the oral bioavailability of edaravone by modulating drug efflux pump of enterocytes. J Pharm Sci. 2014;103(2):730–42. https://doi.org/10.1002/jps.23807.

    Article  CAS  PubMed  Google Scholar 

  5. Dahan A, Miller JM, Hoffman A, Amidon GE, Amidon GL. The solubility-permeability interplay in using Cyclodextrins as pharmaceutical Solubilizers: mechanistic modeling and application to progesterone. J Pharm Sci. 2010;99(6):2739–49. https://doi.org/10.1002/jps.22033.

    Article  CAS  PubMed  Google Scholar 

  6. Beig A, Agbaria R, Dahan A. Oral delivery of lipophilic drugs: the tradeoff between solubility increase and permeability decrease when using cyclodextrin-based formulations. PLoS One. 2013;8(7):e68237. https://doi.org/10.1371/journal.pone.0068237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Beig A, Agbaria R, Dahan A. The use of captisol (SBE7-beta-CD) in oral solubility-enabling formulations: comparison to HP beta CD and the solubility-permeability interplay. Eur J Pharm Sci. 2015;77:73–8. https://doi.org/10.1016/j.ejps.2015.05.024.

    Article  CAS  PubMed  Google Scholar 

  8. Fine-Shamir N, Beig A, Zur M, Lindley D, Miller JM, Dahan A. Toward successful Cyclodextrin based solubility-enabling formulations for Oral delivery of lipophilic drugs: solubility-permeability trade-off, biorelevant dissolution, and the unstirred water layer. Mol Pharm. 2017;14(6):2138–46. https://doi.org/10.1021/acs.molpharmaceut.7b00275.

    Article  CAS  PubMed  Google Scholar 

  9. Sun L, Zhang B, Sun J. The solubility-permeability trade-off of progesterone with Cyclodextrins under physiological conditions: experimental observations and computer simulations. J Pharm Sci. 2018;107(1):488–94. https://doi.org/10.1016/j.xphs.2017.09.032.

    Article  CAS  PubMed  Google Scholar 

  10. Yu LX, Amidon G, Khan MA, Hoag SW, Polli J, Raju GK, et al. Understanding pharmaceutical quality by design. AAPS J. 2014;16(4):771–83. https://doi.org/10.1208/s12248-014-9598-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhao L, Kim MJ, Zhang L, Lionberger R. Generating model integrated evidence for generic drug development and assessment. Clin Pharmacol Ther. 2019;105(2):338–49. https://doi.org/10.1002/cpt.1282.

    Article  PubMed  Google Scholar 

  12. Hartmanshenn C, Scherholz M, Androulakis IP. Physiologically-based pharmacokinetic models: approaches for enabling personalized medicine. J Pharmacokinet Pharmacodyn. 2016;43(5):481–504. https://doi.org/10.1007/s10928-016-9492-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Christodoulou E, Kechagia IA, Balafas E, Kostomitsopoulos N, Archontaki H, Dokoumetzidis A, et al. Serum and tissue pharmacokinetics of silibinin after per os and i.v. administration to mice as a HP-β-CD lyophilized product. Int J Pharm. 2015;493(1–2):366–73. https://doi.org/10.1016/j.ijpharm.2015.07.060.

    Article  CAS  PubMed  Google Scholar 

  14. Taupitz T, Dressman JB, Buchanan CM, Klein S. Cyclodextrin-water soluble polymer ternary complexes enhance the solubility and dissolution behaviour of poorly soluble drugs. Case example: Itraconazole. Eur J Pharm Biopharm. 2013;83(3):378–87. https://doi.org/10.1016/j.ejpb.2012.11.003.

    Article  CAS  PubMed  Google Scholar 

  15. Gao H, Su Y, Wang W, Xiong W, Sun X, Ji Y, et al. Integrated computer-aided formulation design: A case study of andrographolide/ cyclodextrin/ TPGS ternary formulation. Asian J Pharm Sci. 2021 (Accepted).

  16. Yu LX, Crison JR, Amidon GL. Compartmental transit and dispersion model analysis of small intestinal transit flow in humans. International Journal of Pharmaceutics. 1996;140(1):111–8. https://doi.org/10.1016/0378-5173(96)04592-9.

    Article  CAS  Google Scholar 

  17. Peters SA. Physiologically-based pharmacokinetic (PBPK) modeling and simulations: principles, methods, and applications in the pharmaceutical industry. John Wiley & Sons 2012.

  18. Yang T, Xu C, Wang ZT, Wang CH. Comparative pharmacokinetic studies of andrographolide and its metabolite of 14-deoxy-12-hydroxy-andrographolide in rat by ultra-performance liquid chromatography-mass spectrometry. Biomed Chromatogr. 2013;27(7):931–7. https://doi.org/10.1002/bmc.2884.

    Article  CAS  PubMed  Google Scholar 

  19. Panossian A, Hovhannisyan A, Mamikonyan G, Abrahamian H, Hambardzumyan E, Gabrielian E, et al. Pharmacokinetic and oral bioavailability of andrographolide from Andrographis paniculata fixed combination Kan Jang in rats and human. Phytomedicine. 2000;7(5):351–64. https://doi.org/10.1016/s0944-7113(00)80054-9.

    Article  CAS  PubMed  Google Scholar 

  20. Du H, Yang X, Li H, Han L, Li X, Dong X, et al. Preparation and evaluation of andrographolide-loaded microemulsion. J Microencapsul. 2012;29(7):657–65. https://doi.org/10.3109/02652048.2012.680508.

    Article  CAS  PubMed  Google Scholar 

  21. Ye L, Wang T, Tang L, Liu W, Yang Z, Zhou J, et al. Poor oral bioavailability of a promising anticancer agent andrographolide is due to extensive metabolism and efflux by P-glycoprotein. J Pharm Sci. 2011;100(11):5007–17. https://doi.org/10.1002/jps.22693.

    Article  CAS  PubMed  Google Scholar 

  22. Kuemmel C, Yang Y, Zhang X, Florian J, Zhu H, Tegenge M, et al. Consideration of a credibility assessment framework in model-informed drug development: potential application to physiologically-based pharmacokinetic modeling and simulation. CPT Pharmacometrics Syst Pharmacol. 2020;9(1):21–8. https://doi.org/10.1002/psp4.12479.

    Article  CAS  PubMed  Google Scholar 

  23. Jambhekar SS, Breen P. Cyclodextrins in pharmaceutical formulations I: structure and physicochemical properties, formation of complexes, and types of complex. Drug Discov Today. 2016;21(2):356–62. https://doi.org/10.1016/j.drudis.2015.11.017.

    Article  CAS  PubMed  Google Scholar 

  24. Zhao Q, Ye Z, Su Y, Ouyang D. Predicting complexation performance between cyclodextrins and guest molecules by integrated machine learning and molecular modeling techniques. Acta Pharm Sin B. 2019;9(6):1241–52. https://doi.org/10.1016/j.apsb.2019.04.004.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Chinese Medical Sciences, University of Macau, Macau, China

    Wei Wang & Defang Ouyang

Authors
  1. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Defang Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Defang Ouyang.

Additional information

Publisher’s Note

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

Supplementary Information

ESM 1

(DOCX 502 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, W., Ouyang, D. Prediction of Free Drug Absorption in Cyclodextrin Formulation by a Modified Physiologically Based Pharmacokinetic Model and Phase Solubility 3-D Surface Graph. Pharm Res 38, 1157–1168 (2021). https://doi.org/10.1007/s11095-021-03071-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-021-03071-3

Key Words

Search

Navigation