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Excipient selection and aerodynamic characterization of nebulized lipid-based nanoemulsion loaded with docetaxel for lung cancer treatment

Abstract

Docetaxel has demonstrated extraordinary anticancer effects on lung cancer. However, lack of optimal bioavailability due to poor solubility and high toxicity at its therapeutic dose has hampered the clinical use of this anticancer drug. Development of nanoemulsion formulation along with biocompatible excipients aimed for pulmonary delivery is a potential strategy to deliver this poorly aqueous soluble drug with improved bioavailability and biocompatibility. In this work, screening and selection of pharmaceutically acceptable excipients at their minimal optimal concentration have been conducted. The selected nanoemulsion formulations were prepared using high-energy emulsification technique and subjected to physicochemical and aerodynamic characterizations. The formulated nanoemulsion had mean particle size and ζ-potential in the range of 90 to 110 nm and − 30 to − 40 mV respectively, indicating high colloidal stability. The pH, osmolality, and viscosity of the systems met the ideal requirement for pulmonary application. The DNE4 formulation exhibited slow drug release and excellent stability even under the influence of extreme environmental conditions. This was further confirmed by transmission electron microscopy as uniform spherical droplets in nanometer range were observed after storage at 45 ± 1 °C for 3 months indicating high thermal stability. The nebulized DNE4 exhibited desirable aerosolization properties for pulmonary delivery application and found to be more selective on human lung carcinoma cell (A549) than normal cell (MRC-5). Hence, these characteristics make the formulation a great candidate for the potential use as a carrier system for docetaxel in targeting lung cancer via pulmonary delivery.

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References

  1. Kan CS, Chan KMJA. Review of lung cancer research in Malaysia. Med J Malaysia. 2016;71:70–8.

    CAS  PubMed  Google Scholar 

  2. Liu TT, Mu LQ, Dai W, Wang CB, Liu XY, Xiang DX. Preparation, characterization, and evaluation of antitumor effect of Brucea javanica oil cationic nanoemulsions. Int J Nanomedicine. 2016;11:2515–29.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Lee WH, Loo CY, Traini D, Young PM. Inhalation of nanoparticle-based drug for lung cancer treatment: advantages and challenges. Asian J Pharm Sci. 2015;10:481–9.

    Article  Google Scholar 

  4. Baltali E, Ozişik Y, Güler N, Firat D, Altundağ K. Combination of docetaxel and doxorubicin as first-line chemotherapy in metastatic breast cancer. Tumori. 2016;87:18–9.

    Article  Google Scholar 

  5. Gubens MA, Wakelee HA. Docetaxel in the treatment of non-small cell lung carcinoma: an update and analysis. Int J Nanomedicine. 2010;1:63–76.

    CAS  Google Scholar 

  6. Hong JM, Park CS, Nam-goong IS, Kim YS, Lee JC, Han MW, et al. Curcumin enhances docetaxel-induced apoptosis of 8505C anaplastic thyroid carcinoma cells. Endocrinol Metab. 2014;29:54–61.

    Article  Google Scholar 

  7. Ganta S, Singh A, Rawal Y, Cacaccio J, Patel NR, Kulkarni P, et al. Formulation development of a novel targeted theranostic nanoemulsion of docetaxel to overcome multidrug resistance in ovarian cancer. Drug Deliv. 2014;23:1–13.

    Google Scholar 

  8. Afzal SM, Shareef MZ, Dinesh T, Kishan V. Folate-PEG-decorated docetaxel lipid nanoemulsion for improved antitumor activity. Nanomedicine. 2016;11:1–14.

    Article  CAS  Google Scholar 

  9. Ngan CL, Fard Masoumi HR, Basri M, Abdul Rahman MB. Development of nano-colloidal system for fullerene by ultrasonic-assisted emulsification techniques based on artificial neural network. Arab J Chem. 2016. https://doi.org/10.1016/j.arabjc.2016.04.011.

  10. Musa SH, Basri M, Reza H, Masoumi F, Shamsudin N, Salim N. Enhancement of physicochemical properties of nanocolloidal carrier loaded with cyclosporine for topical treatment of psoriasis: in vitro diffusion and in vivo hydrating action. Int J Nanomedicine. 2017;Volume 12:2427–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Gupta S, Kesarla R, Omri A. Formulation strategies to improve the bioavailability of poorly absorbed drugs with special emphasis on self-emulsifying systems. ISRN Pharm. 2013;2013:1–16.

    Google Scholar 

  12. Ganta S, Amiji M. Coadministration of paclitaxel and curcumin in nanoemulsion formulations to overcome multidrug resistance in tumor cells. Mol Pharm. 2009;6:928–39.

    Article  CAS  PubMed  Google Scholar 

  13. Agrawal N, Maddikeri GL, Pandit AB. Sustained release formulations of citronella oil nanoemulsion using cavitational techniques. Ultrason Sonochem. 2017;36:367–74.

    Article  CAS  PubMed  Google Scholar 

  14. Hughes BGM, Stuart-Harris R. Docetaxel-induced myositis: report of a novel side-effect. Clinical-scientific Notes. Intern Med J. 2005;35:369–70.

    Article  CAS  PubMed  Google Scholar 

  15. Ho MY, Mackey JR. Presentation and management of docetaxel-related adverse effects in patients with breast cancer. Cancer Manag Res. 2014;6:253–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Perel-Winkler A, Belokovskaya R, Amigues I, Larusso M, Hussain N. A case of docetaxel induced myositis and review of the literature. Case Rep Rheumatol. 2015;2015:1–8.

    Article  Google Scholar 

  17. Nesamony J, Shah IS, Kalra A, Jung R. Nebulized oil-in-water nanoemulsion mists for pulmonary delivery: development, physico-chemical characterization and in vitro evaluation. Drug Dev Ind Pharm. 2014;40:1253–63.

    Article  CAS  PubMed  Google Scholar 

  18. Keng PS, Basri M, Zakaria MRS, Rahman MBA, Ariff AB, Rahman RNZA, et al. Newly synthesized palm esters for cosmetics industry. Ind Crop Prod. 2009;29:37–44.

    Article  CAS  Google Scholar 

  19. Verma P, Meher JG, Asthana S, Pawar VK, Chaurasia M, Chourasia MK. Perspectives of nanoemulsion assisted oral delivery of docetaxel for improved chemotherapy of cancer. Drug Deliv. 2016;23:479–88.

    Article  CAS  PubMed  Google Scholar 

  20. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46:3–26.

    Article  CAS  Google Scholar 

  21. Bajerski L, Michels LR, Colomé LM, Bender EA, Freddo RJ, Bruxel F, et al. The use of Brazilian vegetable oils in nanoemulsions: an update on preparation and biological applications. Braz J Pharm Sci. 2016;52:347–63.

    Article  CAS  Google Scholar 

  22. Komaiko JS, McClements DJ. Formation of food-grade nanoemulsions using low-energy preparation methods: a review of available methods. Compr Rev Food Sci. 2016;15:331–52.

    Article  CAS  Google Scholar 

  23. Mahdi ES, Sattar M, Sakeena MHF, Abdulkarim M, Noor AM, Abdullah G. Effect of surfactant and surfactant blends on pseudoternary phase diagram behavior of newly synthesized palm kernel oil esters. Drug Des Devel Ther. 2011;5:311.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Li Y, Zhang Z, Yuan Q, Liang H, Vriesekoop F. Process optimization and stability of d-limonene nanoemulsions prepared by catastrophic phase inversion method. J Food Eng. 2013;119:419–24.

    Article  CAS  Google Scholar 

  25. Han X, Cheng L, Zhang R, Bi J. Extraction of safflower seed oil by supercritical CO2. J Food Eng. 2009;92:370–6.

    Article  CAS  Google Scholar 

  26. Floyd AG. Top ten considerations in the development of parenteral emulsions. Pharm Sci Technol Today. 1999;2(4):134–43.

    Article  CAS  Google Scholar 

  27. Saberi AH, Fang Y, McClements DJ. Fabrication of vitamin E-enriched nanoemulsions: factors affecting particle size using spontaneous emulsification. J Colloid Interface Sci. 2013;391:95–102.

    Article  CAS  PubMed  Google Scholar 

  28. Musa SH, Basri M, Fard Masoumi HR, Karjiban RA, Malek EA, Basri H, et al. Formulation optimization of palm kernel oil esters nanoemulsion-loaded with chloramphenicol suitable for meningitis treatment. Colloids Surf B Biointerfaces. 2013;112:113–9.

    Article  CAS  PubMed  Google Scholar 

  29. Davies MJ, Brindley A, Chen X, Doughty SW, Marlow M, Roberts CJ. A quantitative assessment of inhaled drug particle-pulmonary surfactant interaction by atomic force microscopy. Colloids Surf B Biointerfaces. 2009;73:97–102.

    Article  CAS  PubMed  Google Scholar 

  30. Ruge C, CA KJ, Lehr C-M. Pulmonary drug delivery: from generating aerosols to overcoming biological barriers—therapeutic possibilities and technological challenges. Lancet Respir Med. 2013;1:402–13.

    Article  CAS  PubMed  Google Scholar 

  31. Porras M, Solans C, González C, Gutiérrez JM. Properties of water-in-oil (W/O) nano-emulsions prepared by a low-energy emulsification method. Colloids Surf A Physicochem Eng Asp. 2008;324:181–8.

    Article  CAS  Google Scholar 

  32. Gullapalli RP, Sheth BB. Influence of an optimized non-ionic emulsifier blend on properties of oil-in-water emulsions. Eur J Pharm Biopharm. 1999;48:233–8.

    Article  CAS  PubMed  Google Scholar 

  33. Wang L, Dong J, Chen J, Eastoe J, Li X. Design and optimization of a new self-nanoemulsifying drug delivery system. J Colloid Interface Sci. 2009;330:443–8.

    Article  CAS  PubMed  Google Scholar 

  34. Chen G, Tao D. An experimental study of stability of oil–water emulsion. Fuel Process Technol. 2005;86:499–508.

    Article  CAS  Google Scholar 

  35. Guttoff M, Saberi AH, McClements DJ. Formation of vitamin D nanoemulsion-based delivery systems by spontaneous emulsification: factors affecting particle size and stability. Food Chem. 2015;171:117–22.

    Article  CAS  PubMed  Google Scholar 

  36. Siekmeier R, Scheuch G. Systemic treatment by inhalation of macromolecules—principles, problems, and examples. J Physiol Pharmacol. 2008;59(Suppl 6):53–79.

    PubMed  Google Scholar 

  37. Li M, Zhu L, Liu B, Du L, Jia X, Han L, et al. Tea tree oil nanoemulsions for inhalation therapies of bacterial and fungal pneumonia. Colloids Surf B Biointerfaces. 2016;141:408–16.

    Article  CAS  PubMed  Google Scholar 

  38. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part II: The role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 2003;56:600–12.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Klement W, Arndt JO. Pain on I.V. injection of some anaesthetic agents is evoked by the unphysiological osmolality or pH of their formulations. Br J Anaesth. 1991;66:189–95.

    Article  CAS  PubMed  Google Scholar 

  40. Krumschnabel G, Gstir R, Manzl C, Prem C, Pafundo D, Schwarzbaum PJ. Metabolic and ionic responses of trout hepatocytes to anisosmotic exposure. J Exp Biol. 2003;206:1799–808.

    Article  CAS  PubMed  Google Scholar 

  41. Lee W-H, Loo C-Y, Young PM, Traini D, Mason RS, Rohanizadeh R. Recent advances in curcumin nanoformulation for cancer therapy. Expert Opin Drug Deliv. 2014;11:1183–201.

    Article  CAS  PubMed  Google Scholar 

  42. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 2003;56:588–99.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Mason TG, Graves SM, Wilking JN, Lin MY. Extreme emulsification: formation and structure of nanoemulsions. Condens Matter Phys. 2006;9:193–9.

    Article  Google Scholar 

  44. Zhang L, Tan L, Chen L, Chen X, Long C, Peng J, et al. A simple method to improve the stability of docetaxel micelles. Sci Rep. 2016;6:36957.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Fang G, Tang B, Chao Y, Zhang Y, Xu H, Tang X. Improved oral bioavailability of docetaxel by nanostructured lipid carriers: in vitro characteristics, in vivo evaluation and intestinal transport studies. RSC Adv. 2015;5:96437–47.

    Article  CAS  Google Scholar 

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Acknowledgements

Sincere appreciation to Universiti Putra Malaysia (UPM) for the facilities provided throughout this research.

Funding

This project is funded by Malaysian Institute for Innovative Nanotechnology (NanoMITe) (Vote. No. 5526306) and AAA is financially supported by the Ministry of Higher Education Malaysia (MoHE) under MyBrain15 scholarship programme.

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Correspondence to Mohd Basyaruddin Abdul Rahman.

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Asmawi, A.A., Salim, N., Ngan, C.L. et al. Excipient selection and aerodynamic characterization of nebulized lipid-based nanoemulsion loaded with docetaxel for lung cancer treatment. Drug Deliv. and Transl. Res. 9, 543–554 (2019). https://doi.org/10.1007/s13346-018-0526-4

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  • DOI: https://doi.org/10.1007/s13346-018-0526-4

Keywords

  • Docetaxel
  • Lung cancer
  • Nanoemulsion
  • Pulmonary delivery
  • Sustained release