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Freeze-drying of bupivacaine lipospheres: preparation, characterization, and evaluation of anti-microbial properties

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Abstract

Purpose

To prepare freeze-dried bupivacaine lipospheres intended for topical application in burn injuries. The aim was improving the storage stability and developing a prolonged release pattern to tackle the adverse reactions resulting from the frequent administration of bupivacaine.

Methods

The lipospheres were prepared by hot-melt dispersion method employing bupivacaine base at 1.5 and 3%w/w, tristearin 6% w/w as the core while dipalmitoyl phosphatidylcholine (DPPC) and soy phosphatidylcholine (SPC) as the coat at 0.75, 1.5 and 3% w/w. The lotion was then freeze-dried and cryoprotected by sucrose 3% w/w. Evaluation was carried out through loading and release analysis, storage study, particle characterization including morphology, zeta potential and particle size as well as anti-microbial assessment.

Results

The highest loading, (87.6 ± 0.1%), was achieved using bupivacaine 3% and SPC 0.75%. After 6 months of storage at 4 ͦC, the loading in the lotion and the freeze-dried samples were 17.4 ± 0.2 and 87.2 ± 0.3%, respectively. In vitro dissolution test demonstrated 94.5% and 95% of bupivacaine release from lotion and freeze-dried samples, after 24 h. The respective zeta potential of -1.30 and 26 mV was recorded for lotion and solid-state bupivacaine. Micromeritic evaluation of freeze-dried powder exhibited particle size of 35.23 ± 2.02 μm and highly-wrinkled-irregular morphology without detectable needle structures related to drug free crystals. The powder had rapid reconstitution property and antibacterial activity.

Conclusion

Freeze- drying holds a promising potential to improve the storage stability of bupivacaine lipospheres with well- preserved release pattern and particle properties for further topical application.

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References

  1. Myers R, et al. Sedation and Analgesia for Dressing Change: a survey of American Burn Association Burn Centers. J Burn Care Res. 2017;38(1):e48–54.

    Article  PubMed  Google Scholar 

  2. Hernandez JL, et al. Use of continuous local anesthetic infusion in the management of postoperative split-thickness skin graft donor site pain. J Burn Care Res. 2013;34(4):e257-262.

    Article  PubMed  Google Scholar 

  3. Jellish WS, et al. Effect of topical local anesthetic application to skin harvest sites for pain management in burn patients undergoing skin-grafting procedures. Ann Surg. 1999;229(1):115–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Desai C, et al. Effectiveness of a topical local anaesthetic spray as analgesia for dressing changes: a double-blinded randomised pilot trial comparing an emulsion with an aqueous lidocaine formulation. Burns. 2014;40(1):106–12.

    Article  PubMed  Google Scholar 

  5. Toongsuwan S, et al. Formulation and characterization of bupivacaine lipospheres. Int J Pharm. 2004;280(1):57–65.

    Article  CAS  PubMed  Google Scholar 

  6. Malinovsky JM, et al. Motor and blood pressure effects of epidural sustained-release bupivacaine from Polymer microspheres: a dose-response study in rabbits. Anesth Analg. 1995;81(3):519–24.

    CAS  PubMed  Google Scholar 

  7. Kopacz DJ et al. A model to evaluate the pharmacokinetic and pharmacodynamic variables of extended-release products using in vivo tissue microdialysis in humans: bupivacaine-loaded microcapsules. Anesth Analg. 2003;97(1):124 − 31. table of contents.

  8. Masters DB, Domb AJ. Liposphere local anesthetic timed-release for perineural site application. Pharm Res. 1998;15(7):1038–45.

    Article  CAS  PubMed  Google Scholar 

  9. Chime SA, et al. Sustained-release diclofenac potassium-loaded solid lipid microparticle based on solidified reverse micellar solution: in vitro and in vivo evaluation. J Microencapsul. 2013;30(4):335–45.

    Article  CAS  PubMed  Google Scholar 

  10. Audu M, Achile PA, Amaechi AA. Phospholipon 90G based SLMs loaded with ibuprofen: an oral antiinflammatory and gastrointestinal sparing evaluation in rats. Pakistan J Zool. 2012;44:1657–64.

    CAS  Google Scholar 

  11. Vase H, Nemattalab M, Rohani M, Hesari Z. Comparison of chitosan and SLN nano-delivery systems for antibacterial effect of tea tree (Melaleuca alternifolia) oil against P. aeruginosa and S. aureus. Lett Appl Microbiol. 2023;76(11). https://doi.org/10.1093/lambio/ovad130.

  12. Souto EB, et al. Development of a controlled release formulation based on SLN and NLC for topical clotrimazole delivery. Int J Pharm. 2004;278(1):71–7.

    Article  CAS  PubMed  Google Scholar 

  13. Nasr M, et al. Lipospheres as carriers for topical delivery of aceclofenac: preparation, characterization and in vivo evaluation. AAPS PharmSciTech. 2008;9(1):154–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. El-Nesr OH, Yahiya SA, El-Gazayerly ON. Effect of formulation design and freeze-drying on properties of fluconazole multilamellar liposomes. Saudi Pharm J. 2010;18(4):217–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Varshosaz J, Eskandari S, Tabbakhian M. Freeze-drying of nanostructure lipid carriers by different carbohydrate polymers used as cryoprotectants. Carbohydr Polym. 2012;88(4):1157–63.

    Article  CAS  Google Scholar 

  16. Chime SA, Gugu TH. Effect of lyophilization on the physicochemical and physicotechnical properties of aspirin-loaded lipospheres. Innovare J Sci. 2014;2(3):4–8.

    Google Scholar 

  17. Lee MK, et al. Cryoprotectants for freeze drying of drug nano-suspensions: effect of freezing rate. J Pharm Sci. 2009;98(12):4808–17.

    Article  CAS  PubMed  Google Scholar 

  18. Leng D, et al. Formulating inhalable dry powders using two-fluid and three-fluid nozzle spray drying. Pharm Res. 2018;35(12):247.

    Article  PubMed  Google Scholar 

  19. Faghihi H, et al. The effect of freeze-dried antibody concentrations on its stability in the presence of trehalose and hydroxypropyl-β-cyclodextrin: a box–behnken statistical design. Pharm Dev Technol. 2017;22(6):724–32.

    Article  CAS  PubMed  Google Scholar 

  20. Prajapati L, et al. Lipospheres: recent advances in various drug delivery system. Int J Pharm Technol. 2013;5:2446–64.

    CAS  Google Scholar 

  21. Tomar Y, Maheshwari S, Gorantla S, Singhvi G. Curcumin loaded liquid crystalline nanoparticles for enhanced topical application: Design, characterization, ex vivo and dermatokinetic evaluation. J Drug Deliv Sci Technol. 2024;92:105391. https://www.sciencedirect.com/science/article/pii/S1773224724000595. https://doi.org/10.1016/j.jddst.2024.105391.

  22. Rohani M, Nemattalab M, Hedayati M, Ghasemi S, Hesari Z. Comparison of chitosan and SLN nano-delivery systems for antibacterial effect of cinnamon (Cinnamomum verum) oil against MDR K pneumoniae and E coli. Phys Scr. 2023;98(10):105002. https://doi.org/10.1088/1402-4896/acf3a5.

    Article  Google Scholar 

  23. Ghanbarzadeh S, Valizadeh H, Zakeri-Milani P. The effects of lyophilization on the physico-chemical stability of sirolimus liposomes. Adv Pharm Bull. 2013;3(1):25–9.

    PubMed  PubMed Central  Google Scholar 

  24. Valjakka-Koskela R, et al. Enhancement of percutaneous absorption of naproxen by phospholipids. Int J Pharm. 1998;175(2):225–30.

    Article  CAS  Google Scholar 

  25. Li J, et al. A review on phospholipids and their main applications in drug delivery systems. Asian J Pharm Sci. 2015;10(2):81–98.

    Article  Google Scholar 

  26. Momoh MA, Kenechukwu FC, Attama AA. Formulation and evaluation of novel solid lipid microparticles as a sustained release system for the delivery of metformin hydrochloride. Drug Deliv. 2013;20(3–4):102–11.

    Article  CAS  PubMed  Google Scholar 

  27. Kim B-D, Na K, Choi H-K. Preparation and characterization of solid lipid nanoparticles (SLN) made of cacao butter and curdlan. Eur J Pharm Sci: Official J Eur Federation Pharm Sci. 2005;24:2–3.

    Article  Google Scholar 

  28. Taylor KMG, Morris RM. Thermal analysis of phase transition behaviour in liposomes. Thermochim Acta. 1995;248:289–301.

    Article  CAS  Google Scholar 

  29. Iscan Y, et al. DEET-loaded solid lipid particles for skin delivery: in vitro release and skin permeation characteristics in different vehicles. J Microencapsul. 2006;23(3):315–27.

    Article  CAS  PubMed  Google Scholar 

  30. Vighi E, et al. Re-dispersible cationic solid lipid nanoparticles (SLNs) freeze-dried without cryoprotectors: characterization and ability to bind the pEGFP-plasmid. Eur J Pharm Biopharm. 2007;67(2):320–8.

    Article  CAS  PubMed  Google Scholar 

  31. Schreier H, Levy M, Mihalko P. Sustained release of liposome-encapsulated gentamicin and fate of phospholipid following intramuscular injection in mice. J Controlled Release. 1987;5(2):187–92.

    Article  CAS  Google Scholar 

  32. Adler DMT, Damborg P, Verwilghen DR. The antimicrobial activity of bupivacaine, lidocaine and mepivacaine against equine pathogens: an investigation of 40 bacterial isolates. Vet J. 2017;223:27–31.

    Article  CAS  PubMed  Google Scholar 

  33. Johnson SM, Saint John BE, Dine AP. Local anesthetics as antimicrobial agents: a review. Surg Infect (Larchmt). 2008;9(2):205–13.

    Article  PubMed  Google Scholar 

  34. Kesici S, Demırci M, Kesici U. Antimicrobial effects of fentanyl and bupivacaine]. Braz J Anesthesiol. 2020;70(4):357–63.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Casillas-Vargas G, et al. Antibacterial fatty acids: an update of possible mechanisms of action and implications in the development of the next-generation of antibacterial agents. Prog Lipid Res. 2021;82: 101093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yoon BK, Jackman JA, Valle-González ER, Cho NJ. Antibacterial free fatty acids and monoglycerides: biological activities, experimental testing, and therapeutic applications. Int J Mol Sci. 2018;19(4). https://doi.org/10.3390/ijms19041114.

  37. Nemati S, et al. Formulation of neem oil-loaded solid lipid nanoparticles and evaluation of its anti-toxoplasma activity. BMC Complement Med Ther. 2022;22(1):122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutics and Pharmaceutical Nanotechnology, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran

    Sepehr Labanian & Homa Faghihi

  2. Department of Pharmacognosy and Pharmaceutical Biotechnology, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran

    Hamed Montazeri

  3. Department of Anesthesiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Aliakbar Jafarian

Authors
  1. Sepehr Labanian
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  2. Homa Faghihi
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  3. Hamed Montazeri
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  4. Aliakbar Jafarian
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Contributions

This study was a part of a Pharm D thesis of SL who did all the practical experiments and drafted the article. Authors (HF, AJ, and HM) contributed to editing the manuscript. HM was the supervisor of anti-microbial examination. HF supervised all the steps of the thesis. All authors read and approved the final copy of the text.

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Correspondence to Homa Faghihi.

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Labanian, S., Faghihi, H., Montazeri, H. et al. Freeze-drying of bupivacaine lipospheres: preparation, characterization, and evaluation of anti-microbial properties. DARU J Pharm Sci 32, 207–214 (2024). https://doi.org/10.1007/s40199-024-00506-1

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