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A review on multivesicular liposomes for pharmaceutical applications: preparation, characterization, and translational challenges

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Abstract

Multivesicular liposomes (MVLs) are non-concentric, lipid-based micron-sized spherical particles. The usage of MVL for sustained drug delivery has seen progression over the last decade due to successful clinical and commercial applications. It provides attractive characteristics, such as high encapsulation efficiency, variety of sizes, structural stability, and different choices for the route of administration. Drug molecules are encapsulated in internal aqueous compartments of MVL, separated by lipid bilayer septa to form polyhedral structures. The integrity of these entrapped small molecules, peptides, or proteins is maintained throughout the therapy, thus providing sustained drug release on non-vascular administration. Despite the frequent use of unilamellar liposomes, characterization of MVLs is critical due to different puzzling problems, such as real-time size evaluation, initial burst, and in vivo performance. Moreover, available regulatory guidelines on liposomal drug product development are insufficient to assure ample in vitro-in vivo behavior of MVL. This review hereby highlights the innovations pertaining to development and manufacturing procedures, drug release mechanisms, and characterization techniques. The review also summarizes the applications, challenges, and future perspectives for successfully translating the research concept to a clinically accepted delivery system. Despite the intricacies involved in the development of MVL, establishing steadfast characterization techniques and regulatory paths could pave the way to its extensive clinical use.

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Abbreviations

13C NMR:

Carbon-13 nuclear magnetic resonance

Cryo-SEM:

Cryo-scanning electron microscopy

DEPC:

1,2-Dierucoyl-sn-glycero-3-phosphocholine

DNPC:

1,2-Dinervonoyl-sn-glycero-3-phospho-choline

DOPC:

1,2-Dioleoyl-sn-glycero-3-phosphocholine

DPPG:

1,2-Dipalmitoyl-sn-glycero-3-phosphoglycerol

EPC:

Egg phosphatidylcholine

GIT:

Gastrointestinal tract

MVLs:

Multivesicular liposomes

PC:

Phosphatidyl choline

RP-HPLC:

Reversed phase high-performance liquid chromatography

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

Tg:

Glass transition temperature

TG:

Triglycerides

TLC:

Thin-layer chromatography

USFDA:

US Food and Drug Administration

References

  1. Li N, Shi A, Wang Q, et al. Multivesicular liposomes for the sustained release of angiotensin I-converting enzyme (ACE) inhibitory peptides from peanuts: design, characterization, and in vitro evaluation. Molecules. 2019;24:1746. https://doi.org/10.3390/molecules24091746.

    Article  CAS  PubMed Central  Google Scholar 

  2. He S, Zhu J, Xie F. Preparation and characterization of tramadol PEG-coated multivesicular liposomes for sustained release. Pharmazie. 2010;65:467–70.

    CAS  PubMed  Google Scholar 

  3. Pacira Biosciences, Inc. How Depofoam Works. https://www.pacira.com/products/depofoam. Accessed 05 Jul 2021.

  4. Mu H, Wang Y, Chu Y, et al. Multivesicular liposomes for sustained release of bevacizumab in treating laser-induced choroidal neovascularization. Drug Deliv. 2018;25:1372–83. https://doi.org/10.1080/10717544.2018.1474967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mantripragada BS, Sinil K. Multivesicular liposomes with controlled release of encapsulated biologically active substances. (U.S. Patent No. US6132766A). U.S. Patent and Trademark Office. 2000. https://patents.google.com/patent/US6132766A/en. Accessed 05 Jul 2021.

  6. Bulbake U, Doppalapudi S, Kommineni N, et al. Liposomal formulations in clinical use: an updated review. Pharmaceutics. 2017;9:12. https://doi.org/10.3390/pharmaceutics9020012.

    Article  CAS  PubMed Central  Google Scholar 

  7. Katre NV, Asherman J, Schaefer H, et al. Multivesicular liposome (DepoFoam) technology for the sustained delivery of insulin-like growth factor-I (IGF-I). J Pharm Sci. 1998;87:1341–6. https://doi.org/10.1021/js980080t.

    Article  CAS  PubMed  Google Scholar 

  8. Philippot JR, Schuber F. Liposomes as tools in basic research and industry. CRC Press; 1994.

  9. Shen Y, Ji Y, Xu S, et al. Multivesicular liposome formulations for the sustained delivery of ropivacaine hydrochloride: preparation, characterization, and pharmacokinetics. Drug Deliv. 2011;18:361–6. https://doi.org/10.3109/10717544.2011.557788.

    Article  CAS  PubMed  Google Scholar 

  10. Sun L, Wang T, Gao L, et al. Multivesicular liposomes for sustained release of naltrexone hydrochloride: design, characterization and in vitro/in vivo evaluation. Pharm Dev Technol. 2013;18:828–33. https://doi.org/10.3109/10837450.2012.700934.

    Article  CAS  PubMed  Google Scholar 

  11. Jain SK, Gupta Y, Jain A, et al. Multivesicular liposomes bearing celecoxib-beta-cyclodextrin complex for transdermal delivery. Drug Deliv. 2007;14:327–35. https://doi.org/10.1080/10717540601098740.

    Article  CAS  PubMed  Google Scholar 

  12. Kim S, Turker MS, Chi EY, et al. Preparation of multivesicular liposomes. Biochim Biophys Acta. 1983;728:339–48. https://doi.org/10.1016/0005-2736(83)90504-7.

    Article  CAS  PubMed  Google Scholar 

  13. Spector MS, Zasadzinski JA, Sankaram MB. Topology of multivesicular liposomes, a model biliquid foam. Langmuir. 1996;12:4704–8. https://doi.org/10.1021/la960218s.

    Article  CAS  Google Scholar 

  14. Schneider M. Process for the preparation of liposomes in aqueous solution (U.S. Patent No. US4224179A). U.S. Patent and Trademark Office. 1980. https://patents.google.com/patent/US4224179A/en. Accessed 24 August 2021.

  15. Ellena JF, Michelle L, Cafiso DS, et al. Distribution of phospholipids and triglycerides in multivesicular lipid particles. Drug Deliv. 1999;6:97–106. https://doi.org/10.1080/107175499267011.

    Article  CAS  Google Scholar 

  16. Mantripragada S. A lipid based depot (DepoFoam technology) for sustained release drug delivery. Prog Lipid Res. 2002;41:392–406. https://doi.org/10.1016/s0163-7827(02)00004-8.

    Article  CAS  PubMed  Google Scholar 

  17. Zuo J, Gong T, Sun X, et al. Multivesicular liposomes for the sustained release of thymopentin: stability, pharmacokinetics and pharmacodynamics. Pharmazie. 2012;67:507–12.

    CAS  PubMed  Google Scholar 

  18. Mantripragada BS, Sinil K. Preparation of multivesicular liposomes for controlled release of active agents. (WIPO Patent No. WO1996008235A1). PCT. 1996. https://patentscope.wipo.int/search/en/detail.jsf?docId=WO1996008235&_cid=P10-KTK1IE-06419-1. Accessed on 14 Sept 2021.

  19. Briuglia ML, Rotella C, McFarlane A, et al. Influence of cholesterol on liposome stability and on in vitro drug release. Drug Deliv Transl Res. 2015;5:231–42. https://doi.org/10.1007/s13346-015-0220-8.

    Article  CAS  PubMed  Google Scholar 

  20. Miñones J Jr, Dynarowicz-Łatka P, Miñones J, et al. Orientational changes in dipalmitoyl phosphatidyl glycerol Langmuir monolayers. J Colloid Interface Sci. 2003;265:380–5. https://doi.org/10.1016/s0021-9797(03)00479-x.

    Article  PubMed  Google Scholar 

  21. Maltseva E, Shapovalov VL, Möhwald H, et al. Ionization state and structure of l-1,2-dipalmitoylphosphatidylglycerol monolayers at the liquid/air interface. J Phys Chem B. 2006;110:919–26. https://doi.org/10.1021/jp0555697.

    Article  CAS  PubMed  Google Scholar 

  22. Hartounian H, Meissner D, Pepper CB. Production of multivesicular liposomes (U.S. Patent No. US9585838B2). U.S. Patent and Trademark Office. 2017. https://patents.google.com/patent/US9585838B2/en. Accessed 24 August 2021.

  23. Mantripragada BS. Biodegradable compositions for the controlled release of encapsulated substances. (European Patent No. EP1098610B1). European Patent Office. 2009. https://patents.google.com/patent/EP1098610B1/en. Accessed 24 August 2021.

  24. Schutt EG, McGuire RW, Walters PA, et al. Method for formulating large diameter synthetic membrane vesicles. (U.S. Patent No. US20110250264A1). U.S. Patent and Trademark Office. 2019. https://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=15&f=G&l=50&co1=AND&d=PTXT&s1=Pacira.ASNM.&OS=AN/Pacira&RS=AN/Pacira. Accessed 24 August 2021.

  25. Ye Q, Katre N, Mantripragada S. Modulation of drug loading in multivesicular liposomes. (WIPO Patent No. WO1999012523A1). PCT. 1999. https://patents.google.com/patent/WO1999012523A1/en. Accessed 24 August 2021.

  26. Ramprasad MP, Anantharamaiah GM, Garber DW, et al. Sustained-delivery of an apolipoprotein E-peptidomimetic using multivesicular liposomes lowers serum cholesterol levels. J Control Release : Official J Control Release Society. 2002;79:207–18. https://doi.org/10.1016/s0168-3659(01)00552-1.

    Article  CAS  Google Scholar 

  27. Abuzar SM, Park EJ, Seo Y, et al. Preparation and evaluation of intraperitoneal long-acting oxaliplatin-loaded multi-vesicular liposomal depot for colorectal cancer treatment. Pharmaceutics. 2020;12:736. https://doi.org/10.3390/pharmaceutics12080736.

    Article  CAS  PubMed Central  Google Scholar 

  28. Vyas SP, Rawat M, Rawat A, et al. Pegylated protein encapsulated multivesicular liposomes: a novel approach for sustained release of interferon alpha. Drug Dev Ind Pharm. 2006;32:699–707. https://doi.org/10.1080/03639040500528954.

    Article  CAS  PubMed  Google Scholar 

  29. Manna S, Wu Y, Wang Y, et al. Probing the mechanism of bupivacaine drug release from multivesicular liposomes. J Control Release: Official J Control Release Society. 2019;294:279–87. https://doi.org/10.1016/j.jconrel.2018.12.029.

    Article  CAS  Google Scholar 

  30. Lu B, Ma Q, Zhang J, et al. Preparation and characterization of bupivacaine multivesicular liposome: a QbD study about the effects of formulation and process on critical quality attributes. Int J Pharm. 2021;598: 120335. https://doi.org/10.1016/j.ijpharm.2021.120335.

    Article  CAS  PubMed  Google Scholar 

  31. Zheng N, Jiang W, Lionberger RA, et al. Bioequivalence for liposomal drug products. FDA Bioequivalence Standards. 2014;275–296. https://doi.org/10.1007/978-1-4939-1252-0_11.

  32. FDA. Liposome Drug Products - Guidance for Industry. CDER. 2018. https://www.fda.gov/media/70837/download. Accessed 24 August 2021.

  33. Manna S, Wu Y, Koo B, et al. Significance of cryo-scanning electron microscopy (Cryo-SEM) in evaluating the morphology of multivesicular liposomes. Microsc Microanal. 2019;25:1272–3. https://doi.org/10.1017/S1431927619007098.

    Article  Google Scholar 

  34. Manna S, Wu Y, Petrochenko P, et al. Developing physicochemical characterization and in vitro release test methods to probe drug release mechanism from multivesicular liposomes. microscopy and microanalysis. 2018;24:1426–1427. doi:https://doi.org/10.1017/S1431927618007614.

  35. Patel M, Bae J, Manna S, et al. Confocal laser scanning microscopy to study the effect of manufacturing process on the critical quality attributes of multivesicular liposomes. Microsc Microanal. 2020;26:1–3. https://doi.org/10.1017/s1431927620021066.

    Article  Google Scholar 

  36. Garcia LD, Zhu L, Lambert WJ, et al. A sustained release formulation of a non-steroidal anti-inflammatory drug. (WIPO Patent No. WO/2012/058483). PCT. 2012. https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012058483. Accessed 24 August 2021.

  37. Ye Q, Asherman J, Stevenson M, et al. DepoFoam™ technology: a vehicle for controlled delivery of protein and peptide drugs. J Control Release 2000;64:155–166. https://doi.org/10.1016/S0168-3659(99)00146-7.

  38. Vafaei SY, Dinarvand R, Esmaeili M, et al. Controlled-release drug delivery system based on fluocinolone acetonide-cyclodextrin inclusion complex incorporated in multivesicular liposomes. Pharm Dev Technol. 2015;20:775–81. https://doi.org/10.3109/10837450.2014.920358.

    Article  CAS  PubMed  Google Scholar 

  39. Zhao Y, Liu J, Sun X, et al. Sustained release of hydroxycamptothecin after subcutaneous administration using a novel phospholipid complex—DepoFoam™ technology Drug. Dev Ind Pharm 2010;36:823–831. https://doi.org/10.3109/03639040903520975.

  40. Jain SK, Jain RK, Chourasia MK, et al. Design and development of multivesicular liposomal depot delivery system for controlled systemic delivery of acyclovir sodium. AAPS PharmSciTech. 2005;6:E35–41. https://doi.org/10.1208/pt060108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Los KDA, Garcia LD, Kurz S et al. Multivesicular liposome formulations of tranexamic acid. (WIPO Patent No. WO2016118652A1). PCT. 2016. https://patents.google.com/patent/WO2016118652A1/en. Accessed 24 August 2021.

  42. Assessment report. Exparel liposomal. European Medicine Agency. 2020. https://www.ema.europa.eu/en/documents/assessment-report/exparel-liposomal-epar-public-assessment-report_en.pdf. Accessed 24 August 2021.

  43. FDA. Exparel briefing document. FDA Advisory Committee Meeting. 2018. https://www.fda.gov/files/advisory%20committees/published/FDA-Briefing-Information-for-the-February-14-15--2018-Meeting-of-the-Anesthetic-and-Analgesic-Drug-Products-Advisory-Committee.pdf. Accessed 24 August 2021.

  44. USFDA. Exparel® USFDA Product Label. 1972. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022496s030lbl.pdf. Accessed 24 August 2021.

  45. USFDA. DepoCyt® USFDA Product Label. 1999. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021041s031lbl.pdf. Accessed 24 August 2021.

  46. WCG FDA News. Pacira shutters DepoCyt operations after years of manufacturing problems. 2017. https://www.fdanews.com/articles/182667-pacira-shutters-depcyt-operations-after-years-of-manufacturing-problems. Accessed 24 August 2021.

  47. Nagle PC, Gerancher J. DepoDur® (extended-release epidural morphine): a review of an old drug in a new vehicle. Tech Reg Anesth Pain Manag. 2007;11:9–18. https://doi.org/10.1053/J.TRAP.2007.02.011.

    Article  Google Scholar 

  48. Pacira Pharmaceuticals, Inc. Form 10-K annual report submitted to United States securities and exchange commission. 2015. https://www.sec.gov/Archives/edgar/data/1396814/000162828016011728/pcrx-12312015x10k.htm. Accessed 24 August 2021.

  49. Pacira Pharmaceuticals, Inc. Study of local administration of DepoTXA for reduced postsurgical bleeding in subjects undergoing TKA. Clinical trials.gov: NCT number: NCT02922582. 2020. https://clinicaltrials.gov/ct2/show/results/NCT02922582?term=NCT02922582&view=results. Accessed 24 August 2021.

  50. Langston MV, Ramprasad MP, Kararli TT, et al. Modulation of the sustained delivery of myelopoietin (Leridistim) encapsulated in multivesicular liposomes (DepoFoam). J Control Release : Official J Control Release Society. 2003;89:87–99. https://doi.org/10.1016/s0168-3659(03)00073-7.

    Article  CAS  Google Scholar 

  51. Grayson LS, Hansbrough JF, Zapata-Sirvent RL, et al. Pharmacokinetics of DepoFoam gentamicin delivery system and effect on soft tissue infection. J Surg Res. 1993;55:559–64. https://doi.org/10.1006/jsre.1993.1184.

    Article  CAS  PubMed  Google Scholar 

  52. Los KDA, Garcia LD, Kurz S, et al. Zinc meloxicam complex microparticle multivesicular liposome formulations and processes for making the same (U.S. Patent No. US20180161275A1). U.S. Patent and Trademark Office. 2020. https://patents.google.com/patent/US20180161275A1/en. Last Accessed 14 Sept 2021.

  53. Zhong H, Deng Y, Wang X, et al. Multivesicular liposome formulation for the sustained delivery of breviscapine. Int J Pharm. 2005;14:15–24. https://doi.org/10.1016/j.ijpharm.2005.04.001.

    Article  CAS  Google Scholar 

  54. Roehrborn AA, Hansbrough JF, Gualdoni B, et al. Lipid-based slow-release formulation of amikacin sulfate reduces foreign body-associated infections in mice. Antimicrob Agents Chemother. 1995;39:1752–5. https://doi.org/10.1128/AAC.39.8.1752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Assil KK, Weinreb RN. Multivesicular liposomes. Sustained release of the antimetabolite cytarabine in the eye. Arch Ophthalmol. 1987;105(3):400–403. https://doi.org/10.1001/archopht.1987.01060030120040

  56. Kim S, Scheerer S, Geyer MA, et al. Direct cerebrospinal fluid delivery of an antiretroviral agent using multivesicular liposomes. J Infect Dis. 1990;162:750–2. https://doi.org/10.1093/infdis/162.3.750.

    Article  CAS  PubMed  Google Scholar 

  57. Angst MS, Drover DR. Pharmacology of drugs formulated with DepoFoam: a sustained release drug delivery system for parenteral administration using multivesicular liposome technology. Clin Pharmacokinet. 2006;45(12):1153–76. https://doi.org/10.2165/00003088-200645120-00002.

    Article  CAS  PubMed  Google Scholar 

  58. Roy R, Kim S. Multivesicular liposomes containing bleomycin for subcutaneous administration. Cancer Chemother Pharmacol. 1991;28(2):105–8. https://doi.org/10.1007/BF00689697.

    Article  CAS  PubMed  Google Scholar 

  59. Ali MF. Topical delivery and photodynamic evaluation of a multivesicular liposomal rose bengal. Lasers Med Sci. 2011;26:267–75. https://doi.org/10.1007/s10103-010-0859-9.

    Article  PubMed  Google Scholar 

  60. Li H, An JH, Park JS, et al. Multivesicular liposomes for oral delivery of recombinant human epidermal growth factor. Arch Pharm Res. 2005;28:988–94. https://doi.org/10.1007/BF02973888.

    Article  CAS  PubMed  Google Scholar 

  61. Kapoor M, Lee SL, Tyner KM. Liposomal drug product development and quality: current US experience and perspective. AAPS J. 2017;19(3):632–41. https://doi.org/10.1208/s12248-017-0049-9.

    Article  CAS  PubMed  Google Scholar 

  62. Hua S, de Matos MBC, Metselaar JM, et al. Current trends and challenges in the clinical translation of nanoparticulate nanomedicines: pathways for translational development and commercialization. Front Pharmacol. 2018; https://doi.org/10.3389/fphar.2018.00790

  63. Product specific guidance for Bupivacaine: https://www.accessdata.fda.gov/drugsatfda_docs/psg/Bupivacaine_%20liposomal%20injectable%20injection_NDA%20022496_RC11-17.pdf. Accessed 24 August 2021.

  64. Giuliano CB, Cvjetan N, Ayache J, et al. Multivesicular vesicles: preparations and applications. Chem Systems Chem. 2020. https://doi.org/10.1002/syst.202000049.

    Article  Google Scholar 

  65. Ryan RO, Oda MN. Lipophilic drug delivery vehicle and methods of use thereof. (Canadian Patent No. CA2515892C). Canadian Intellectual Property Office. 2004. https://patents.google.com/patent/CA2515892C/en?q=(multivesicular+liposomes)&scholar. Accessed 16 Jul 2021.

  66. Leadiant Biosciences, Inc. DepoCyt notification. 2017. https://leadiant.com/wp-content/uploads/2017/08/DepoCyt-HCP-Notification-Ltr-8-7-17-PDF.pdf. Accessed 02 Jul 2021.

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Funding

This study was funded by ICMR-DHR under grant-in-aid for ad hoc research scheme.

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Authors and Affiliations

  1. Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Hyderabad Campus, Medchal District, Jawahar Nagar, Kapra Mandal, 500078, Telangana, India

    Akash Chaurasiya, Kanan Panchal & Sumeet Katke

  2. R&D - Injectables, Amneal Pharmaceuticals, Ahmedabad, India

    Amruta Gorajiya

  3. R&D, Intas Pharmaceuticals, Ahmedabad, India

    Ajeet Kumar Singh

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  1. Akash Chaurasiya
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The idea for the articles was created by Akash Chaurasiya. The literature searches and data analysis were done by Amruta Gorajiya, Akash Chaurasiya, and Kanan Panchal. The article was drafted by Amruta Gorajiya, Kanan Panchal, Sumeet Katke, and Akash Chaurasiya. The article is critically reviewed and revised by Ajeet K Singh and Akash Chaurasiya.

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Chaurasiya, A., Gorajiya, A., Panchal, K. et al. A review on multivesicular liposomes for pharmaceutical applications: preparation, characterization, and translational challenges. Drug Deliv. and Transl. Res. 12, 1569–1587 (2022). https://doi.org/10.1007/s13346-021-01060-y

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