Skip to main content

Advertisement

SpringerLink
Log in

Dynamic intervention to enhance the stability of PEGylated Ibrutinib loaded lipidic nano-vesicular systems: transitioning from colloidal dispersion to lyophilized product

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Liposomes being a promising colloidal system facilitates delivery of drugs with limited pharmacokinetic properties to achieve desirable clinical applications. However, development of a stable liposomal system is always challenging due to multiple complexities involved. Aqueous instability of liposomes and impact of various process and formulation parameters can lead to serious alteration of its therapeutic performance. In the proposed work, the authors aim to develop stable Ibrutinib-loaded liposomes using lyophilization and Quality-by-Design and assess their long-term stability. Ibrutinib-loaded liposomes were developed and optimized using Quality-by-Design technique and were further PEGylated and characterized for the same. Effect of cryoprotectants during lyophilization and other parameters are evaluated to obtain a robust formulation. The stability studies were conducted upto 6 months at various storage conditions to evaluate the effect of lyophilization. The impact of formulation, processing and lyophilization parameters on physicochemical properties of developed liposomal systems were evaluated and are critically discussed. Liquid dispersion exhibited a %degradation of 16–36% at 25 °C/60% RH which was reduced for less than 1% in lyophilized formulation for 6 months. Critical analysis and assessment of various parameters lead to identification of optimum conditions to manufacture this drug product and also opens way forward for further evaluation and translational possibilities.

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

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on request.

Abbreviations

% EE:

Percent Entrapment Efficiency

CMA:

Critical Material Attributes

CPP:

Critical Process Parameters

CQA:

Critical Quality Attributes

DoE:

Design of Experiments

DSC:

Differential Scanning Calorimetry

DSPG-Na:

1,2-Distearoyl-sn-glycero-3-phospho-rac-glycerol, sodium salt

FALT:

Fixed Aqueous Layer Thickness

HSPC:

Hydrogenated Soybean Phosphatidylcholine

IBR-LIP:

Ibrutinib Liposomes

IBR-LIP-PEG:

Ibrutinib Liposomes PEGylated

mPEG-2000-DSPE:

N-(Carbonyl-methoxypolyethylenglycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine

PS:

Particle Size

QbD:

Quality-by-Design

QTPP:

Quality Target Product Profile

ZP:

Zeta Potential

References

  1. Maja L, Željko K, Mateja P. Sustainable technologies for liposome preparation. J Supercrit Fluids. 2020;165:104984. https://doi.org/10.1016/j.supflu.2020.104984.

    Article  CAS  Google Scholar 

  2. Immordino ML, Dosio F, Cattel L. Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomed. 2006;1:297–315.

    CAS  Google Scholar 

  3. Mishima K. Biodegradable particle formation for drug and gene delivery using supercritical fluid and dense gas. Adv Drug Deliv Rev. 2008;60:411–32. https://doi.org/10.1016/j.addr.2007.02.003.

    Article  CAS  PubMed  Google Scholar 

  4. Wang Y, Grainger DW. Lyophilized liposome-based parenteral drug development: reviewing complex product design strategies and current regulatory environments. Adv Drug Deliv Rev. 2019;151–152:56–71. https://doi.org/10.1016/j.addr.2019.03.003.

    Article  CAS  PubMed  Google Scholar 

  5. Chen C, Han D, Cai C, Tang X. An overview of liposome lyophilization and its future potential. J Controlled Release. 2010;142:299–311. https://doi.org/10.1016/j.jconrel.2009.10.024.

    Article  CAS  Google Scholar 

  6. Cacela C, Hincha DK. Low amounts of sucrose are sufficient to depress the phase transition temperature of Dry Phosphatidylcholine, but not for Lyoprotection of liposomes. Biophys J. 2006;90:2831–42. https://doi.org/10.1529/biophysj.105.074427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fonteyne M, Vercruysse J, Díaz DC, Gildemyn D, Vervaet C, Remon JP, Beer TD. Real-time assessment of critical quality attributes of a continuous granulation process. Pharm Dev Technol. 2013;18:85–97. https://doi.org/10.3109/10837450.2011.627869.

    Article  CAS  PubMed  Google Scholar 

  8. Hunter P. The fourth pillar: despite some setbacks in the clinic, immunotherapy has made notable progress toward becoming an additional therapeutic option against cancer. EMBO Rep. 2017;18:1889–92. https://doi.org/10.15252/embr.201745172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Panchal K, Sahoo RK, Gupta U, Chaurasiya A. Role of targeted immunotherapy for pancreatic ductal adenocarcinoma (PDAC) treatment: an overview. Int Immunopharmacol. 2021;95:107508. https://doi.org/10.1016/j.intimp.2021.107508.

    Article  CAS  PubMed  Google Scholar 

  10. Paydas S. Management of adverse effects/toxicity of ibrutinib. Crit Rev Oncol Hematol. 2019;136:56–63. https://doi.org/10.1016/j.critrevonc.2019.02.001.

    Article  PubMed  Google Scholar 

  11. Profitt RT, Adler-Moore J, Chiang. S-M Amphotericin B liposome preparation.

  12. Zhai B, Wu Q, Wang W, Zhang M, Han X, Li Q, Chen P, Chen X, Huang X, Li G, Zhang Q, Zhang R, Xiang Y, Liu S, Duan T, Lou J, Xie T, Sui X. Preparation, characterization, pharmacokinetics and anticancer effects of PEGylated β-elemene liposomes. Cancer Biol Med. 2020;17:60–75. https://doi.org/10.20892/j.issn.2095-3941.2019.0156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Park S-J, Choo G-H, Hwang S-J, Kim M-S. Quality by design: screening of critical variables and formulation optimization of Eudragit E nanoparticles containing dutasteride. Arch Pharm Res. 2013;36:593–601. https://doi.org/10.1007/s12272-013-0064-z.

    Article  CAS  PubMed  Google Scholar 

  14. Panigrahi KC, Patra CN, Rao MEB. Quality by design enabled development of oral self-nanoemulsifying drug delivery system of a Novel Calcimimetic Cinacalcet HCl using a porous carrier: in vitro and in vivo characterisation. AAPS PharmSciTech. 2019;20:216. https://doi.org/10.1208/s12249-019-1411-2.

    Article  CAS  PubMed  Google Scholar 

  15. Lim J, Yeap SP, Che HX, Low SC. Characterization of magnetic nanoparticle by dynamic light scattering. Nanoscale Res Lett. 2013;8:381. https://doi.org/10.1186/1556-276X-8-381.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  16. Corbett JCW, McNeil-Watson F, Jack RO, Howarth M. Measuring surface zeta potential using phase analysis light scattering in a simple dip cell arrangement. Colloids Surf Physicochem Eng Asp. 2012;396:169–76. https://doi.org/10.1016/j.colsurfa.2011.12.065.

    Article  CAS  Google Scholar 

  17. Shimada K, Miyagishima A, Sadzuka Y, Nozawa Y, Mochizuki Y, Ohshima H, Hirota S. Determination of the thickness of the fixed aqueous layer around polyethyleneglycol-coated liposomes. J Drug Target. 1995;3:283–9. https://doi.org/10.3109/10611869509015957.

    Article  CAS  PubMed  Google Scholar 

  18. Danhier F, Lecouturier N, Vroman B, Jérôme C, Marchand-Brynaert J, Feron O, Préat V. Paclitaxel-loaded PEGylated PLGA-based nanoparticles: in vitro and in vivo evaluation. J Controlled Release. 2009;133:11–7. https://doi.org/10.1016/j.jconrel.2008.09.086.

    Article  CAS  Google Scholar 

  19. Taylor-Vine G, Mead H, Paraskevopoulou V, Mann J. Evaluation of NanoDis as an automated sampling technology for in vitro release testing of nanomedicines. Dissolution Technol. 2023;30:126–32. https://doi.org/10.14227/DT300323P126.

    Article  Google Scholar 

  20. Lambert WJ. Considerations in developing a Target Product Profile for Parenteral Pharmaceutical products. AAPS PharmSciTech. 2010;11:1476–81. https://doi.org/10.1208/s12249-010-9521-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. USFDA. (2018) Liposome Drug Products: Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/liposome-drug-products-chemistry-manufacturing-and-controls-human-pharmacokinetics-and.

  22. ICH PHARMACEUTICAL DEVELOPMENT Q8(R2.). https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf.

  23. Bonde GV, Ajmal G, Yadav SK, Mittal P, Singh J, Bakde BV, Mishra B. Assessing the viability of Soluplus® self-assembled nanocolloids for sustained delivery of highly hydrophobic lapatinib (anticancer agent): optimisation and in-vitro characterisation. Colloids Surf B Biointerfaces. 2020;185:110611. https://doi.org/10.1016/j.colsurfb.2019.110611.

    Article  CAS  PubMed  Google Scholar 

  24. Lujan H, Griffin WC, Taube JH, Sayes CM. Synthesis and characterization of nanometer-sized liposomes for encapsulation and microRNA transfer to breast cancer cells. Int J Nanomed Volume. 2019;14:5159–73. https://doi.org/10.2147/IJN.S203330.

    Article  CAS  Google Scholar 

  25. Chen H, Fang Z, Song M, Liu K. Mitochondrial targeted hierarchical drug delivery system based on HA-modified liposomes for cancer therapy. Eur J Med Chem. 2022;241:114648. https://doi.org/10.1016/j.ejmech.2022.114648.

    Article  CAS  PubMed  Google Scholar 

  26. Kong G, Braun RD, Dewhirst MW. Hyperthermia enables tumor-specific nanoparticle delivery: effect of particle size. Cancer Res. 2000;60:4440–5.

    CAS  PubMed  Google Scholar 

  27. Kirby C, Gregoriadis G. Dehydration-rehydration vesicles: a simple method for High Yield Drug Entrapment in liposomes. Nat Biotechnol. 1984;2:979–84. https://doi.org/10.1038/nbt1184-979.

    Article  CAS  Google Scholar 

  28. Sabeti B, Noordin MI, Mohd S, Hashim R, Dahlan A, Akbari Javar H. Development and characterization of liposomal doxorubicin hydrochloride with Palm Oil. BioMed Res Int. 2014;2014:1–6. https://doi.org/10.1155/2014/765426.

    Article  Google Scholar 

  29. Smith MC, Crist RM, Clogston JD, McNeil SE. Zeta potential: a case study of cationic, anionic, and neutral liposomes. Anal Bioanal Chem. 2017;409:5779–87. https://doi.org/10.1007/s00216-017-0527-z.

    Article  CAS  PubMed  Google Scholar 

  30. Joseph E, Singhvi G. Multifunctional nanocrystals for cancer therapy: a potential nanocarrier. Nanomaterials for drug delivery and therapy. Elsevier; 2019. pp. 91–116.

  31. StatEase Randomized Factorial Designs. https://www.statease.com/docs/v12/designs/factorial-randomized/#:~:text=Minimum%20Run%2 C%20Resolution%20IV%20Factorial,extremely%20sensitive%20to%20missing%20data.

  32. Hu X, Wang H, Liu Y. Statistical analysis of Main and Interaction effects on Cu(II) and cr(VI) decontamination by Nitrogen–Doped magnetic graphene oxide. Sci Rep. 2016;6:34378. https://doi.org/10.1038/srep34378.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  33. Shaker S, Gardouh A, Ghorab M. Factors affecting liposomes particle size prepared by ethanol injection method. Res Pharm Sci. 2017;12:346. https://doi.org/10.4103/1735-5362.213979.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Mukherjee S, Ray S, Thakur R. Solid lipid nanoparticles: a modern formulation approach in drug delivery system. Indian J Pharm Sci. 2009;71:349. https://doi.org/10.4103/0250-474X.57282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. He Y, Luo L, Liang S, Long M, Xu H. Influence of probe-sonication process on drug entrapment efficiency of liposomes loaded with a hydrophobic drug. Int J Polym Mater Polym Biomater. 2019;68:193–7. https://doi.org/10.1080/00914037.2018.1434651.

    Article  CAS  Google Scholar 

  36. Shi L, Zhang J, Zhao M, Tang S, Cheng X, Zhang W, Li W, Liu X, Peng H, Wang Q. Effects of polyethylene glycol on the surface of nanoparticles for targeted drug delivery. Nanoscale. 2021;13:10748–64. https://doi.org/10.1039/D1NR02065J.

    Article  CAS  PubMed  Google Scholar 

  37. Pan Z, Fang D, Song N, Song Y, Ding M, Li J, Luo F, Tan H, Fu Q. Surface distribution and Biophysicochemical properties of Polymeric micelles Bearing Gemini Cationic and hydrophilic groups. ACS Appl Mater Interfaces. 2017;9:2138–49. https://doi.org/10.1021/acsami.6b14339.

    Article  CAS  PubMed  Google Scholar 

  38. Xu J, Gattacceca F, Amiji M. Biodistribution and Pharmacokinetics of EGFR-Targeted thiolated gelatin nanoparticles following systemic administration in pancreatic tumor-bearing mice. Mol Pharm. 2013;10:2031–44. https://doi.org/10.1021/mp400054e.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kowalska M, Broniatowski M, Mach M, Płachta Ł, Wydro P. The effect of the polyethylene glycol chain length of a lipopolymer (DSPE-PEGn) on the properties of DPPC monolayers and bilayers. J Mol Liq. 2021;335:116529. https://doi.org/10.1016/j.molliq.2021.116529.

    Article  CAS  Google Scholar 

  40. Ohtake S, Schebor C, Palecek SP, De Pablo JJ. Phase behavior of freeze-dried phospholipid–cholesterol mixtures stabilized with trehalose. Biochim Biophys Acta BBA - Biomembr. 2005;1713:57–64. https://doi.org/10.1016/j.bbamem.2005.05.001.

    Article  CAS  Google Scholar 

  41. Koster KL, Lei YP, Anderson M, Martin S, Bryant G. Effects of Vitrified and Nonvitrified sugars on Phosphatidylcholine Fluid-to-gel phase transitions. Biophys J. 2000;78:1932–46. https://doi.org/10.1016/S0006-3495(00)76741-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Leslie SB, Israeli E, Lighthart B, Crowe JH, Crowe LM. Trehalose and sucrose protect both membranes and proteins in intact bacteria during drying. Appl Environ Microbiol. 1995;61:3592–7. https://doi.org/10.1128/aem.61.10.3592-3597.1995.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ohtake S, Schebor C, De Pablo JJ. Effects of trehalose on the phase behavior of DPPC–cholesterol unilamellar vesicles. Biochim Biophys Acta BBA - Biomembr. 2006;1758:65–73. https://doi.org/10.1016/j.bbamem.2006.01.002.

    Article  CAS  Google Scholar 

  44. Yoshida K, Ono F, Chouno T, Perocho BR, Ikegami Y, Shirakigawa N, Ijima H. Cryoprotective enhancing effect of very low concentration of trehalose on the functions of primary rat hepatocytes. Regen Ther. 2020;15:173–9. https://doi.org/10.1016/j.reth.2020.08.003.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Franzé S, Selmin F, Samaritani E, Minghetti P, Cilurzo F. Lyophilization of liposomal formulations: still necessary, still challenging. Pharmaceutics. 2018;10:139. https://doi.org/10.3390/pharmaceutics10030139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Degobert G, Aydin D. Lyophilization of Nanocapsules: instability sources, formulation and process parameters. Pharmaceutics. 2021;13:1112. https://doi.org/10.3390/pharmaceutics13081112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Field C. Developing a Method for Suitable Loss on Drying by TGA.

  48. Zhang M, Suo Z, Peng X, Gan N, Zhao L, Tang P, Wei X, Li H. Microcrystalline cellulose as an effective crystal growth inhibitor for the ternary Ibrutinib formulation. Carbohydr Polym. 2020;229:115476. https://doi.org/10.1016/j.carbpol.2019.115476.

    Article  CAS  PubMed  Google Scholar 

  49. Brophy MR, Deasy PB. Application of the Higuchi model for drug release from dispersed matrices to particles of general shape. Int J Pharm. 1987;37:41–7. https://doi.org/10.1016/0378-5173(87)90008-1.

    Article  CAS  Google Scholar 

  50. USFDA Onivyde PIL. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207793lbl.pdf.

  51. Karmakar S. Particle size distribution and Zeta potential based on dynamic light scattering: techniques to Characterise Stability and Surface distribution of Charged colloids. In: Recent Trends in Materials Physics and Chemistry; 2019.

  52. Izutsu K-I, Yomota C, Kawanishi T. Stabilization of liposomes in Frozen Solutions through Control of Osmotic Flow and Internal Solution freezing by Trehalose. J Pharm Sci. 2011;100:2935–44. https://doi.org/10.1002/jps.22518.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would also like to extend their gratitude to Central Analytical Laboratory, BITS Pilani, Hyderabad Campus for providing the necessary support.

Funding

This work was supported by the Parenteral Drug Association, India Chapter.

Author information

Authors and Affiliations

  1. Translational Pharmaceutics Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, 500078, Hyderabad, Telangana, India

    Kanan Panchal, Akhila Reddy & Akash Chaurasiya

  2. Nanomedicine and Bioengineering Research Laboratory, Department of Pharmacy, Indira Gandhi National Tribal University, Amarkantak, India

    Rishi Paliwal

Authors
  1. Kanan Panchal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akhila Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rishi Paliwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akash Chaurasiya
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Kanan Panchal: conceptualization, data curation, formal analysis, investigation, methodology, visualization, writing– original draft; Akhila Reddy: investigation, methodology, writing– original draft; Rishi Paliwal: data curation, formal analysis, writing– review & editing; Akash Chaurasiya: conceptualization, funding acquisition, project administration, supervision, visualization, writing - review & editing.

Corresponding author

Correspondence to Akash Chaurasiya.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Author declares that they have provided their consent for publishing this manuscript.

Conflict of interest

The authors have filed a patent; Indian Patent Authority, Application No. 202211003679.

Additional information

Publisher’s Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Panchal, K., Reddy, A., Paliwal, R. et al. Dynamic intervention to enhance the stability of PEGylated Ibrutinib loaded lipidic nano-vesicular systems: transitioning from colloidal dispersion to lyophilized product. Drug Deliv. and Transl. Res. (2024). https://doi.org/10.1007/s13346-024-01555-4

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s13346-024-01555-4

Keywords

Search

Navigation