Novel Inhalable Ciprofloxacin Dry Powders for Bronchiectasis Therapy: Mannitol–Silk Fibroin Binary Microparticles with High-Payload and Improved Aerosolized Properties

Abstract

Non-cystic fibrosis bronchiectasis (NCFB) is a chronic respiratory disease associated with the high morbidity and mortality. Long-term intermittent therapy by inhalable antibiotics has recently emerged as an effective approach for NCFB treatment. However, the effective delivery of antibiotics to the lung requires administering a high dose to the site of infection. Herein, we investigated the novel inhalable silk-based microparticles as a promising approach to deliver high-payload ciprofloxacin (CIP) for NCFB therapy. Silk fibroin (SF) was applied to improve drug-payload and deposit efficiency of the dry powder particles. Mannitol was added as a mucokinetic agent. The dry powder inhaler (DPI) formulations of CIP microparticles were evaluated in vitro in terms of the aerodynamic performance, particle size distribution, drug loading, morphology, and their solid state. The optimal formulation (highest drug loading, 80%) exhibited superior aerosolization performance in terms of fine particle fraction (45.04 ± 0.84%), emitted dose (98.10 ± 1.27%), mass median aerodynamic diameter (3.75 ± 0.03 μm), and geometric standard deviation (1.66 ± 0.10). The improved drug loading was due to the electrostatic interactions between the SF and CIP by adsorption, and the superior aerosolization efficiency would be largely attributed to the fluffy and porous cotton-like property and low-density structure of SF. The presented results indicated the novel inhalable silk-based DPI microparticles of CIP could provide a promising strategy for the treatment of NCFB.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

References

  1. 1.

    Polverino E, Dimakou K, Hurst J, Angel Martinez-Garcia M, Miravitlles M, Paggiaro P, et al. The overlap between bronchiectasis and chronic airways diseases: state of the art and future directions. Eur Respir J. 2018;52:1800328. https://doi.org/10.1183/13993003.00328-2018.

    Article  PubMed  Google Scholar 

  2. 2.

    Athanazio R, da Costa JC, de la Rosa Carrillo D, Martinez-Garcia MA. Current and future pharmacotherapy options for non-cystic fibrosis bronchiectasis. Expert Rev Respir Med. 2018;12:569–84.

    CAS  PubMed  Google Scholar 

  3. 3.

    Amaro R, Panagiotaraka M, Alcaraz V, Torres A. The efficacy of inhaled antibiotics in non-cystic fibrosis bronchiectasis. Expert Rev Respir Med. 2018;12:683–91.

    CAS  PubMed  Google Scholar 

  4. 4.

    Chalmers JD, Smith MP, McHugh BJ, Doherty C, Govan JR, Hill AT. Short- and long-term antibiotic treatment reduces airway and systemic inflammation in non-cystic fibrosis bronchiectasis. Am J Resp Crit Care. 2012;186:657–65.

    CAS  Google Scholar 

  5. 5.

    Zhou Q, Leung SSY, Tang P, Parumasivam T, Loh ZH, Chan H-K. Inhaled formulations and pulmonary drug delivery systems for respiratory infections. Adv Drug Deliv Rev. 2015;85:83–99.

    CAS  PubMed  Google Scholar 

  6. 6.

    Ungaro F, d’Angelo I, Coletta C, d’Emmanuele di Villa Bianca R, Sorrentino R, Perfetto B, et al. Dry powders based on PLGA nanoparticles for pulmonary delivery of antibiotics: modulation of encapsulation efficiency, release rate and lung deposition pattern by hydrophilic polymers. J Control Release. 2012;157:149–59.

    CAS  PubMed  Google Scholar 

  7. 7.

    Quon BS, Goss CH, Ramsey BW. Inhaled antibiotics for lower airway infections. Ann Am Thorac Soc. 2014;11:425–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Barker AF, O’Donnell AE, Flume P, Thompson PJ, Ruzi JD, de Gracia J, et al. Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebo-controlled phase 3 trials. Lancet Respir Med. 2014;2:738–49.

    CAS  PubMed  Google Scholar 

  9. 9.

    Justo JA, Danziger LH, Gotfried MH. Efficacy of inhaled ciprofloxacin in the management of non-cystic fibrosis bronchiectasis. Ther Adv Respir Dis. 2013;7:272–87.

    PubMed  Google Scholar 

  10. 10.

    Cartlidge MK, Hill AT. Inhaled or nebulised ciprofloxacin for the maintenance treatment of bronchiectasis. Expert Opin Investig Drugs. 2017;26:1091–7.

    CAS  PubMed  Google Scholar 

  11. 11.

    De Soyza A, Aksamit T, Bandel T-J, Criollo M, Elborn JS, Operschall E, et al. RESPIRE 1: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis. Eur Respir J. 2018;51:1702052. https://doi.org/10.1183/13993003.02052-2017.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Aksamit T, De Soyza A, Bandel T-J, Criollo M, Elborn JS, Operschall E, et al. RESPIRE 2: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis. Eur Respir J. 2018;51:1702053. https://doi.org/10.1183/13993003.02053-2017.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Haworth C, Wanner A, Froehlich J, O’Neal T, Davis A, Gonda I, et al. Inhaled liposomal ciprofloxacin in patients with non-cystic fibrosis bronchiectasis and chronic Pseudomonas aeruginosa infection. J Aerosol Med Pulm Drug Deliv. 2017;30:29.

    Google Scholar 

  14. 14.

    De Soyza A, Aksamit T. Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis. Expert Opin Orphan Drugs. 2016;4:875–84.

    Google Scholar 

  15. 15.

    Chalmers JD, Aliberti S, Blasi F. Management of bronchiectasis in adults. Eur Respir J. 2015;45:1446–62.

    PubMed  Google Scholar 

  16. 16.

    Polverino E, Goeminne PC, McDonnell MJ, Aliberti S, Marshall SE, Loebinger MR, et al. European Respiratory Society guidelines for the management of adult bronchiectasis. Eur Respir J. 2017;50:1–23.

    Google Scholar 

  17. 17.

    Martínez-García MÁ, Máiz L, Olveira C, Girón RM, de la Rosa D, Blanco M, et al. Spanish guidelines on treatment of bronchiectasis in adults. Archivos de Bronconeumología (English Edition). 2018;54:88–98.

    Google Scholar 

  18. 18.

    Claus S, Weiler C, Schiewe J, Friess W. How can we bring high drug doses to the lung? Eur J Pharm Biopharm. 2014;86:1–6.

    CAS  PubMed  Google Scholar 

  19. 19.

    Traini D, Young PM. Delivery of antibiotics to the respiratory tract: an update. Expert Opin Drug Deliv. 2009;6:897–905.

    CAS  PubMed  Google Scholar 

  20. 20.

    Lai SK, Wang Y-Y, Wirtz D, Hanes J. Micro- and macrorheology of mucus. Adv Drug Deliv Rev. 2009;61:86–100.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    d’Angelo I, Conte C, La Rotonda MI, Miro A, Quaglia F, Ungaro F. Improving the efficacy of inhaled drugs in cystic fibrosis: challenges and emerging drug delivery strategies. Adv Drug Deliv Rev. 2014;75:92–111.

    PubMed  Google Scholar 

  22. 22.

    Wenk E, Merkle HP, Meinel L. Silk fibroin as a vehicle for drug delivery applications. J Control Release. 2011;150:128–41.

    CAS  PubMed  Google Scholar 

  23. 23.

    Mottaghitalab F, Farokhi M, Shokrgozar MA, Atyabi F, Hosseinkhani H. Silk fibroin nanoparticle as a novel drug delivery system. J Control Release. 2015;206:161–76.

    CAS  PubMed  Google Scholar 

  24. 24.

    Kim SY, Wong AH, Abou Neel EA, Chrzanowski W, Chan HK. The future perspectives of natural materials for pulmonary drug delivery and lung tissue engineering. Expert Opin Drug Deliv. 2015;12:869–87.

    CAS  PubMed  Google Scholar 

  25. 25.

    Schultz I, Vollmers F, Lühmann T, Rybak J-C, Wittmann R, Stank K, et al. Pulmonary insulin-like growth factor I delivery from trehalose and silk-fibroin microparticles. ACS Biomater Sci Eng. 2015;1:119–29.

    CAS  Google Scholar 

  26. 26.

    Ong HX, Traini D, Salama R, Anderson SD, Daviskas E, Young PM. The effects of mannitol on the transport of ciprofloxacin across respiratory epithelia. Mol Pharm. 2013;10:2915–24.

    CAS  PubMed  Google Scholar 

  27. 27.

    Yang Y, Tsifansky MD, Shin S, Lin Q, Yeo Y. Mannitol-guided delivery of ciprofloxacin in artificial cystic fibrosis mucus model. Biotechnol Bioeng. 2011;108:1441–9.

    CAS  PubMed  Google Scholar 

  28. 28.

    Wilson R, Aksamit T, Aliberti S, De Soyza A, Elborn JS, Goeminne P, et al. Challenges in managing Pseudomonas aeruginosa in non-cystic fibrosis bronchiectasis. Respir Med. 2016;117:179–89.

    PubMed  Google Scholar 

  29. 29.

    Dhand R. The rationale and evidence for use of inhaled antibiotics to control Pseudomonas aeruginosa infection in non-cystic fibrosis bronchiectasis. J Aerosol Med Pulm Drug Deliv. 2018;31:121–38.

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Hofmann S, Wong Po Foo CT, Rossetti F, Textor M, Vunjak-Novakovic G, Kaplan DL, et al. Silk fibroin as an organic polymer for controlled drug delivery. J Control Release. 2006;111:219–27.

    CAS  PubMed  Google Scholar 

  31. 31.

    Bayraktar O, Malay Ö, Özgarip Y, Batıgün A. Silk fibroin as a novel coating material for controlled release of theophylline. Eur J Pharm Biopharm. 2005;60:373–81.

    CAS  PubMed  Google Scholar 

  32. 32.

    Razuc M, Piña J, Ramírez-Rigo MV. Optimization of ciprofloxacin hydrochloride spray-dried microparticles for pulmonary delivery using design of experiments. AAPS PharmSciTech. 2018;19:3085–96. https://doi.org/10.1208/s12249-018-1137-6.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Weers J. Inhaled antimicrobial therapy—barriers to effective treatment. Adv Drug Deliv Rev. 2015;85:24–43.

    CAS  PubMed  Google Scholar 

  34. 34.

    Chew NYK, Chan HK. Use of solid corrugated particles to enhance powder aerosol performance. Pharm Res. 2001;18:1570–7.

    CAS  PubMed  Google Scholar 

  35. 35.

    Sahoo S, Chakraborti CK, Mishra SC, Nanda UN, Naik S. FTIR and XRD investigations of some fluoroquinolones. Int J Pharm Pharm Sci. 2011;3:165–70.

    CAS  Google Scholar 

  36. 36.

    Bhardwaj A, Mehta S, Yadav S, Singh SK, Grobler A, Goyal AK, et al. Pulmonary delivery of antitubercular drugs using spray-dried lipid-polymer hybrid nanoparticles. Artif Cell Nanomed B. 2016;44:1544–55.

    CAS  Google Scholar 

  37. 37.

    Wang Q, Dong ZF, Du YM, Kennedy JF. Controlled release of ciprofloxacin hydrochloride from chitosan/polyethylene glycol blend films. Carbohydr Polym. 2007;69:336–43.

    CAS  Google Scholar 

  38. 38.

    Anderson JP. Morphology and crystal structure of a recombinant silk-like molecule, SLP4. Biopolymers. 1998;45:307–21.

    CAS  Google Scholar 

  39. 39.

    Lammel AS, Hu X, Park SH, Kaplan DL, Scheibel TR. Controlling silk fibroin particle features for drug delivery. Biomaterials. 2010;31:4583–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Pritchard EM, Kaplan DL. Silk fibroin biomaterials for controlled release drug delivery. Expert Opin Drug Deliv. 2011;8:797–811.

    CAS  PubMed  Google Scholar 

  41. 41.

    Kaialy W, Hussain T, Alhalaweh A, Nokhodchi A. Towards a more desirable dry powder inhaler formulation: large spray-dried mannitol microspheres outperform small microspheres. Pharm Res. 2014;31:60–76.

    CAS  PubMed  Google Scholar 

  42. 42.

    Yucel T, Lovett ML, Keplan DL. Silk-based biomaterials for sustained drug delivery. J Control Release. 2014;190:381–97.

    CAS  PubMed  Google Scholar 

  43. 43.

    Kim EHJ, Chen XD, Pearce D. Surface composition of industrial spray-dried milk powders. 2. Effects of spray drying conditions on the surface composition. J Food Eng. 2009;94:169–81.

    CAS  Google Scholar 

  44. 44.

    Meerdink G, Riet KVT. Modeling segregation of solute material during drying of liquid foods. AICHE J. 1995;41:732–6.

    CAS  Google Scholar 

  45. 45.

    Chen XD, Sidhu H, Nelson M. Theoretical probing of the phenomenon of the formation of the outermost surface layer of a multi-component particle, and the surface chemical composition after the rapid removal of water in spray drying. Chem Eng Sci. 2011;66:6375–84.

    CAS  Google Scholar 

  46. 46.

    Zhao ZY, Huang ZW, Zhang XJ, Huang Y, Cui YT, Ma C, et al. Low density, good flowability cyclodextrin-raffinose binary carrier for dry powder inhaler: anti-hygroscopicity and aerosolization performance enhancement. Expert Opin Drug Deliv. 2018;15:443–57.

    CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by National Natural Science Foundation of China (Grant No. 81503001), Guangdong Natural Science Foundation (Grant No. 2016A030313330), Guangdong Province Science and Technology Plan Project Public Welfare Fund and Ability Construction Project (Grant No. 2017A020215081, Grant No. 2016A020215069, Grant No. 2016A020215063), the Science and Technology Foundation of Guangzhou (Grant No.201707010103), and Yixian Scientific Research Project Set Sail (Grant No. YXQH201706).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Guilan Quan or Guocheng Li.

Additional information

Publisher’s Note

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

Electronic supplementary material

ESM 1

(DOCX 15 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Liu, C., Lin, L., Huang, Z. et al. Novel Inhalable Ciprofloxacin Dry Powders for Bronchiectasis Therapy: Mannitol–Silk Fibroin Binary Microparticles with High-Payload and Improved Aerosolized Properties. AAPS PharmSciTech 20, 85 (2019). https://doi.org/10.1208/s12249-019-1291-5

Download citation

KEY WORDS

  • dry powder inhaler
  • silk fibroin
  • bronchiectasis
  • antibiotic
  • ciprofloxacin