Skip to main content
SpringerLink
Log in

Liposomal Formulation for Oral Delivery of Cyclosporine A: Usefulness as a Semisolid-Dispersion System

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

A Correction to this article was published on 10 June 2022

This article has been updated

Abstract

Purpose

This study aims to understand the process and mechanism of oral drug absorption from liposomes and to verify the usefulness of liposomal formulation for poorly soluble drugs.

Methods

Cyclosporine A (CsA) was used as a model drug and entrapped into Dipalmitoylphosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC) liposomes. Molecular state of CsA in the liposomes was analyzed using powder X-ray diffraction (PXRD) and polarized light microscopy (PLM). Release profiles of CsA from liposomes were observed in fasted state simulated intestinal fluid (FaSSIF). Oral absorption of CsA from liposomal formulations were investigated in rats.

Results

PXRD and PLM analyses suggested that CsA exists in the lipid layer of liposomes as a molecular dispersed state. Although both liposomes retained CsA stably in the simple buffer, DPPC liposomes quickly released CsA within 10 min in FaSSIF due to the interaction with bile acid. In contrast, effect of bile acid was negligible in DSPC, indicating a high resistivity to membrane perturbation. Oral bioavailability of CsA from liposomal formulations were almost comparable with that from a marketed product (Neoral). However, the absorption profiles were clearly different. CsA was absorbed quickly from DPPC liposomes and Neoral, while sustained absorption profile was observed from DSPC liposomes. Further study in which ritonavir was co-entrapped in the liposomes with CsA showed the higher efficacy of ritonavir to increase oral bioavailability of CsA.

Conclusion

Liposomes allows the appropriate formulation design for oral delivery of poorly soluble drugs, not only to increase the extent but also to control the rate of absorption.

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

Change history

References

  1. Sawyer T K, Partridge A W, Kaan H Y K, Juang Y C, Lim S, Johannes C, Yuen, et al. Macrocyclic α helical peptide therapeutic modality: A perspective of learnings and challenges. Bioorg Med Chem. 2018;26(10):2807–15.

  2. Josephson K, Ricardo A, Szostak JW. mRNA display: from basic principles to macrocycle drug discovery. Drug Discov Today. 2014;19(4):388–99.

    Article  CAS  Google Scholar 

  3. Di Gioia ML, Leggio A, Malagrinò F, Romio E, Siciliano C, Liguori A. N-Methylated α-Amino acids and peptides: synthesis and biological activity. Mini Rev Med Chem. 2016;16(9):683–90.

    Article  Google Scholar 

  4. A. Williams HD, Sassene P, Kleberg K, Bakala-N'Goma JC, Calderone M, Jannin V, et al. Toward the establishment of standardized in vitro tests for lipid-based formulations, part 1: method parameterization and comparison of in vitro digestion profiles across a range of representative formulations. J Pharm Sci. 2012;101(9):3360–80.

  5. Vithani K, Hawley A, Jannin V, Pouton C, Boyd BJ. Solubilisation behaviour of poorly water-soluble drugs during digestion of solid SMEDDS. Eur J Pharm Biopharm. 2018;130:236–46.

    Article  CAS  Google Scholar 

  6. Goddeeris C, Coacci J, Van den Mooter G. Correlation between digestion of the lipid phase of smedds and release of the anti-HIV drug UC 781 and the anti-mycotic drug enilconazole from smedds. Eur J Pharm Biopharm. 2007;66(2):173–81.

    Article  CAS  Google Scholar 

  7. Neoral, Interview Form.

  8. Ross C, Taylor M, Fullwood N, Allsop D. Liposome delivery systems for the treatment of Alzheimer’s disease. Int J Nanomedicine. 2018;13:8507–22.

    Article  CAS  Google Scholar 

  9. Riaz MK, Riaz MA, Zhang X, Lin C, Wong KH, Chen X, et al. Surface functionalization and targeting strategies of liposomes in solid tumor therapy: a review. Int J Mol Sci. 2018;19(1):195.

    Article  Google Scholar 

  10. Khadke S, Roces CB, Cameron A, Devitt A, Perrie Y. Formulation and manufacturing of lymphatic targeting liposomes using microfluidics. J Control Release. 2019;307:211–20.

    Article  CAS  Google Scholar 

  11. Kawakami S, Hashida M. Glycosylation-mediated targeting of carriers. J Control Release. 2014;190:542–55.

    Article  CAS  Google Scholar 

  12. Agrawal M, Ajazuddin, Tripathi D. K, Saraf S, Saraf S, Antimisiaris S. G, et al. Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer's disease. J Control Release. 2017;260:61–77.

  13. Wong CY, Al-Salami H, Dass CR. Recent advancements in oral administration of insulin-loaded liposomal drug delivery systems for diabetes mellitus. Int J Pharm. 2018;549(1–2):201–17.

    Article  CAS  Google Scholar 

  14. Ismail R, Csóka I. Novel strategies in the oral delivery of antidiabetic peptide drugs - Insulin, GLP 1 and its analogs. Eur J Pharm Biopharm. 2017;115:257–67.

    Article  CAS  Google Scholar 

  15. Chen Y, Lu Y, Chen J, Lai J, Sun J, Hu F, et al. Enhanced bioavailability of the poorly water-soluble drug fenofibrate by using liposomes containing a bile salt. Int J Pharm. 2009;376(1–2):153–60.

    Article  CAS  Google Scholar 

  16. Zhou Y, Ning Q, Yu DN, Li WG, Deng J. Improved oral bioavailability of breviscapine via a Pluronic P85-modified liposomal delivery system. J Pharm Pharmacol. 2014;66(7):903–11.

    Article  CAS  Google Scholar 

  17. Guan P, Lu Y, Qi J, Niu M, Lian R, Hu F, et al. Enhanced oral bioavailability of cyclosporine A by liposomes containing a bile salt. Int J Nanomedicine. 2011;6:965–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Deng J, Zhang Z, Liu C, Yin L, Zhou J, Lv H. The studies of N-Octyl-N-Arginine-Chitosan coated liposome as an oral delivery system of Cyclosporine A. J Pharm Pharmacol. 2015;67(10):1363–70.

    Article  CAS  Google Scholar 

  19. Tanaka Y, Hara T, Waki R, Nagata S. Regional differences in the components of luminal water from rat gastrointestinal tract and comparison with other species. J Pharm Pharm Sci. 2012;15(4):510–8.

    Article  CAS  Google Scholar 

  20. Minami K, Higashino H, Kataoka M, Yamashita S. Species differences in the drug-drug interaction between atorvastatin and cyclosporine: In vivo study using a stable isotope-IV method in rats and dogs. Eur J Pharm Sci. 2020;152: 105409.

    Article  CAS  Google Scholar 

  21. Anby MU, Williams HD, McIntosh M, Benameur H, Edwards GA, Pouton CW, . Lipid digestion as a trigger for supersaturation: evaluation of the impact of supersaturation stabilization on the in vitro and in vivo performance of self-emulsifying drug delivery systems. Mol Pharm. 2012;9(7):2063–79.

    Article  CAS  Google Scholar 

  22. Baghel S, Cathcart H, O’Reilly NJ. Polymeric amorphous solid dispersions: a review of amorphization, crystallization, stabilization, solid-state characterization, and aqueous solubilization of biopharmaceutical classification system class II drugs. J Pharm Sci. 2016;105(9):2527–44.

    Article  CAS  Google Scholar 

  23. Kapourani A, Vardaka E, Katopodis K, Kachrimanis K, Barmpalexis P. Rivaroxaban polymeric amorphous solid dispersions: Moisture-induced thermodynamic phase behavior and intermolecular interactions. Eur J Pharm Biopharm. 2019;145:98–112.

    Article  CAS  Google Scholar 

  24. Ji Y, Paus R, Prudic A, Lübbert C, Sadowski G. A novel approach for analyzing the dissolution mechanism of solid dispersions. Pharm Res. 2015;32(8):2559–78.

    CAS  PubMed  Google Scholar 

  25. Nagata M, Yotsuyanagi T, Ikeda K. A two-step model of disintegration kinetics of liposomes in bile salts. Chem Pharm Bull. 1988;36(4):1508–13.

    Article  CAS  Google Scholar 

  26. Rowland RN, Woodley JF. The stability of liposomes in vitro to pH, bile salts and pancreatic lipase. Biochim Biophys Acta. 1980;620(3):400–9.

    Article  CAS  Google Scholar 

  27. Andrieux K, Forte L, Lesieur S, Paternostre M, Ollivon M, Grabielle-Madelmont C. Solubilisation of dipalmitoylphosphatidylcholine bilayers by sodium taurocholate: a model to study the stability of liposomes in the gastrointestinal tract and their mechanism of interaction with a model bile salt. Eur J Pharm Biopharm. 2009;71(2):346–55.

    Article  CAS  Google Scholar 

  28. Hildebrand A, Beyer K, Neubert R, Garidel P, Blume A. Solubilization of negatively charged DPPC/DPPG liposomes by bile salts. J Colloid Interface Sci. 2004;279(2):559–71.

    Article  CAS  Google Scholar 

  29. Hermida LG, Sabés-Xamaní M, Barnadas-Rodríguez R. Characteristics and behaviour of liposomes when incubated with natural bile salt extract: implications for their use as oral drug delivery systems. Soft Matter. 2014;10(35):6677–85.

    Article  CAS  Google Scholar 

  30. Sugano K, Kataoka M, Mathews Cda. C, Yamashita S. Prediction of food effect by bile micelles on oral drug absorption considering free fraction in intestinal fluid. Eur J Pharm Sci. 2010;40(2):118–24.

  31. Cho Y, Ha ES, Baek IH, Kim MS, Cho CW, Hwang SJ. Enhanced supersaturation and oral absorption of sirolimus using an amorphous solid dispersion based on Eudragit® e. Molecules. 2015;20(6):9496–509.

    Article  CAS  Google Scholar 

  32. Suzuki K, Kawakami K, Fukiage M, Oikawa M, Nishida Y, Matsuda M, Fujita T. Relevance of liquid-liquid phase separation of supersaturated solution in oral absorption of albendazole from amorphous solid dispersions. Pharmaceutics. 2021;13(2):220.

    Article  CAS  Google Scholar 

  33. Minami K, Takazawa A, Taniguchi Y, Higashino H, Kataoka M, Asai T, et al. Challenge for oral delivery of middle-molecular drugs: Use of osmolarity-sensitive liposome as a drug carrier in the GI tract. J Drug Deliv Sci Technol. 2020;56 Part B:101041.

  34. Kokkona M, Kallinteri P, Fatouros D, Antimisiaris SG. Stability of SUV liposomes in the presence of cholate salts and pancreatic lipases: effect of lipid composition. Eur J Pharm Sci. 2000;9(3):245–52.

    Article  CAS  Google Scholar 

  35. Porter CJ, Charman WN. In vitro assessment of oral lipid based formulations. Adv Drug Deliv Rev. 2001;50(Suppl 1):S127–47.

    Article  CAS  Google Scholar 

  36. Lee MK. Liposomes for enhanced bioavailability of water-insoluble drugs: in vivo evidence and recent approaches. Pharmaceutics. 2020;12(3):264.

  37. Harjinder S, Aiqian Y. Structural and biochemical factors affecting the digestion of protein-stabilized emulsions. Curr Opin Colloid Interface Sci. 2013;18(4):360–70.

    Article  Google Scholar 

  38. Seelig A, Seelig J. The dynamic structure of fatty acyl chains in a phospholipid bilayer measured by deuterium magnetic resonance. Biochemistry. 1974;13(23):4839–45.

    Article  CAS  Google Scholar 

  39. Inoue K. Permeability properties of liposomes prepared from dipalmitoyllecithin, dimyristoyllecithin, egg lecithin, rat liver lecithin and beef brain sphingomyelin. Biochim Biophys Acta. 1974;339(3):390–402.

    Article  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to acknowledge Dr. Satomi Onoue and Dr. Kohei Yamada for the experimental support of PXRD and PLM. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Author information

Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka, 573-0101, Japan

    Keiko Minami, Makoto Kataoka, Toshihide Takagi & Shinji Yamashita

  2. School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan

    Tomohiro Asai

  3. Faculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan

    Naoto Oku

Authors
  1. Keiko Minami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Makoto Kataoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshihide Takagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomohiro Asai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Naoto Oku
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shinji Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shinji Yamashita.

Additional information

Publisher's Note

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

This article was updated to correct the name of author Toshihide Takagi.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Minami, K., Kataoka, M., Takagi, T. et al. Liposomal Formulation for Oral Delivery of Cyclosporine A: Usefulness as a Semisolid-Dispersion System. Pharm Res 39, 977–987 (2022). https://doi.org/10.1007/s11095-022-03276-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-022-03276-0

KEY WORDS

Search

Navigation