Skip to main content
Log in

Chitosan-Modified Dry Powder Formulations for Pulmonary Gene Delivery

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Purpose

Spray-drying is an effective process for preparing micron-dimensioned particles for pulmonary delivery. Previously, we have demonstrated enhanced dispersibility and fine particle fraction of spray-dried nonviral gene delivery formulations using amino acids or absorption enhancers as dispersibility-enhancing excipients. In this study, we investigate the use of the cationic polymer chitosan as a readily available and biocompatible dispersibility enhancer.

Methods

Lactose-lipid:polycation:pDNA (LPD) powders were prepared by spray-drying and post-mixed with chitosan or spray-dried chitosan. In addition, the water-soluble chitosan derivative, trimethyl chitosan, was added to the lactose-LPD formulation before spray-drying.

Results

Spray-dried chitosan particles, displaying an irregular surface morphology and diameter of less than 2 μm, readily adsorbed to lactose-LPD particles following mixing. In contrast with the smooth spherical surface of lactose-LPD particles, spray-dried trimethyl chitosan-lactose-LPD particles demonstrated increased surface roughness and a unimodal particle size distribution (mean diameter 3.4 μm), compared with the multimodal distribution for unmodified lactose-LPD powders (mean diameter 23.7 μm). The emitted dose and in vitro deposition of chitosan-modified powders was significantly greater than that of unmodified powders. Moreover, the inclusion of chitosan mediated an enhanced level of reporter gene expression.

Conclusions

In summary, chitosan enhances the dispersibility and in vitro pulmonary deposition performance of spray-dried powders.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

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

Similar content being viewed by others

References

  1. B. L. Laube (2005) ArticleTitleThe expanding role of aerosols in systemic drug delivery, gene therapy, and vaccination Respir. Care 50 1161–1176 Occurrence Handle16122400

    PubMed  Google Scholar 

  2. H. Y. Li H. Neill R. Innocent P. C. Seville I. Williamson J. C. Birchall (2003) ArticleTitleEnhanced dispersibility and deposition of spray-dried powders for pulmonary gene therapy J. Drug Target. 11 425–432 Occurrence Handle15203931 Occurrence Handle1:CAS:528:DC%2BD2cXjtFOjs7s%3D Occurrence Handle10.1080/10611860410001659786

    Article  PubMed  CAS  Google Scholar 

  3. H. Y. Li P. C. Seville I. J. Williamson J. C. Birchall (2005) ArticleTitleThe use of amino acids to enhance the aerosolisation of spray-dried powders for pulmonary gene therapy J. Gene Med. 7 343–353 Occurrence Handle15515142 Occurrence Handle1:CAS:528:DC%2BD2MXjtlamu7c%3D Occurrence Handle10.1002/jgm.654

    Article  PubMed  CAS  Google Scholar 

  4. H. Y. Li P. C. Seville I. J. Williamson J. C. Birchall (2005) ArticleTitleThe use of absorption enhancers to enhance the aerosolisation of spray-dried powders for pulmonary gene therapy J. Gene Med. 7 1035–1043 Occurrence Handle15756712 Occurrence Handle1:CAS:528:DC%2BD2MXhtVCksLbL Occurrence Handle10.1002/jgm.749

    Article  PubMed  CAS  Google Scholar 

  5. P. C. Seville I. W. Kellaway J. C. Birchall (2002) ArticleTitlePreparation of dry powder dispersions for non-viral gene delivery by freeze-drying and spray-drying J. Gene Med. 4 428–437 Occurrence Handle12124985 Occurrence Handle1:CAS:528:DC%2BD38XmsVKksrg%3D Occurrence Handle10.1002/jgm.282

    Article  PubMed  CAS  Google Scholar 

  6. J. H. Kuo R. Hwang (2004) ArticleTitlePreparation of DNA dry powder for non-viral gene delivery by spray-freeze drying: effect of protective agents (polyethyleneimine and sugars) on the stability of DNA J. Pharm. Pharmacol. 56 27–33 Occurrence Handle14979998 Occurrence Handle1:CAS:528:DC%2BD2cXhvVCksL4%3D Occurrence Handle10.1211/0022357022494

    Article  PubMed  CAS  Google Scholar 

  7. F. L. Sorgi S. Bhattacharya L. Huang (1997) ArticleTitleProtamine sulfate enhances lipid-mediated gene transfer Gene Ther. 4 961–968 Occurrence Handle9349433 Occurrence Handle1:CAS:528:DyaK2sXmtVWjsLg%3D Occurrence Handle10.1038/sj.gt.3300484

    Article  PubMed  CAS  Google Scholar 

  8. Y. Kato H. Onishi Y. Machida (2003) ArticleTitleApplication of chitin and chitosan derivatives in the pharmaceutical field Curr. Pharm. Biotechnol. 4 303–309 Occurrence Handle14529420 Occurrence Handle1:CAS:528:DC%2BD3sXnvVyju7o%3D Occurrence Handle10.2174/1389201033489748

    Article  PubMed  CAS  Google Scholar 

  9. S. Hirano (1996) ArticleTitleChitin biotechnology applications Biotechnol. Annu. Rev. 2 237–258 Occurrence Handle9704098 Occurrence Handle1:CAS:528:DyaK28XlvFWhtbY%3D Occurrence Handle10.1016/S1387-2656(08)70012-7

    Article  PubMed  CAS  Google Scholar 

  10. J. H. Hamman C. M. Schultz A. F. Kotze (2003) ArticleTitleN-trimethyl chitosan chloride: optimum degree of quaternization for drug absorption enhancement across epithelial cells Drug Dev. Ind. Pharm. 29 161–172 Occurrence Handle12648013 Occurrence Handle1:CAS:528:DC%2BD3sXhvF2isrs%3D Occurrence Handle10.1081/DDC-120016724

    Article  PubMed  CAS  Google Scholar 

  11. P. Artursson T. Lindmark S. S. Davis L. Illum (1994) ArticleTitleEffect of chitosan on the permeability of monolayers of intestinal epithelial cells (Caco-2) Pharm. Res. 11 1358–1361 Occurrence Handle7816770 Occurrence Handle1:CAS:528:DyaK2cXls12ltbg%3D Occurrence Handle10.1023/A:1018967116988

    Article  PubMed  CAS  Google Scholar 

  12. A. Portero C. Remunan-Lopez H. M. Nielsen (2002) ArticleTitleThe potential of chitosan in enhancing peptide and protein absorption across the TR146 cell culture model—an in vitro model of the buccal epithelium Pharm. Res. 19 169–174 Occurrence Handle11883644 Occurrence Handle1:CAS:528:DC%2BD38XitVSlsr8%3D Occurrence Handle10.1023/A:1014220832384

    Article  PubMed  CAS  Google Scholar 

  13. L. Illum N. F. Farraj S. S. Davis (1994) ArticleTitleChitosan as a novel nasal delivery system for peptide drugs Pharm. Res. 11 1186–1189 Occurrence Handle7971722 Occurrence Handle1:CAS:528:DyaK2cXltFOmtLg%3D Occurrence Handle10.1023/A:1018901302450

    Article  PubMed  CAS  Google Scholar 

  14. M. Thanou J. C. Verhoef H. E. Junginger (2001) ArticleTitleChitosan and its derivatives as intestinal absorption enhancers Adv. Drug Deliv. Rev. 50 S91–S101 Occurrence Handle11576697 Occurrence Handle1:CAS:528:DC%2BD3MXntVWku7w%3D Occurrence Handle10.1016/S0169-409X(01)00180-6

    Article  PubMed  CAS  Google Scholar 

  15. I. Grabnar M. Bogataj A. Mrhar (2003) ArticleTitleInfluence of chitosan and polycarbophil on permeation of a model hydrophilic drug into the urinary bladder wall Int. J. Pharm. 256 167–173 Occurrence Handle12695023 Occurrence Handle1:CAS:528:DC%2BD3sXivVGjtrg%3D Occurrence Handle10.1016/S0378-5173(03)00074-7

    Article  PubMed  CAS  Google Scholar 

  16. S. S. Davis (1999) ArticleTitleDelivery of peptide and non-peptide drugs through the respiratory tract Pharm. Sci. Technol. Today 2 450–456 Occurrence Handle10542391 Occurrence Handle1:CAS:528:DyaK1MXotVSnsL4%3D Occurrence Handle10.1016/S1461-5347(99)00199-6

    Article  PubMed  CAS  Google Scholar 

  17. G. Colo ParticleDi Y. Zambito S. Burgalassi I. Nardini M. F. Saettone (2004) ArticleTitleEffect of chitosan and of N-carboxymethylchitosan on intraocular penetration of topically applied ofloxacin Int. J. Pharm. 273 37–44 Occurrence Handle15010128 Occurrence Handle10.1016/j.ijpharm.2003.12.018 Occurrence Handle1:CAS:528:DC%2BD2cXhvVGqs74%3D

    Article  PubMed  CAS  Google Scholar 

  18. S. Senel M. J. Kremer S. Kas P. W. Wertz A. A. Hincal C. A. Squier (2000) ArticleTitleEnhancing effect of chitosan on peptide drug delivery across buccal mucosa Biomaterials 21 2067–2071 Occurrence Handle10966016 Occurrence Handle1:CAS:528:DC%2BD3cXlt1Kisbw%3D Occurrence Handle10.1016/S0142-9612(00)00134-4

    Article  PubMed  CAS  Google Scholar 

  19. W. Guang Liu K. Yao ParticleDe (2002) ArticleTitleChitosan and its derivatives—a promising non-viral vector for gene transfection J. Control. Release 83 1–11 Occurrence Handle12220833 Occurrence Handle10.1016/S0168-3659(02)00144-X

    Article  PubMed  Google Scholar 

  20. M. Thanou B. I. Florea M. Geldof H. E. Junginger G. Borchard (2002) ArticleTitleQuaternized chitosan oligomers as novel gene delivery vectors in epithelial cell lines Biomaterials 23 153–159 Occurrence Handle11762833 Occurrence Handle1:CAS:528:DC%2BD3MXosFKnt74%3D Occurrence Handle10.1016/S0142-9612(01)00090-4

    Article  PubMed  CAS  Google Scholar 

  21. W. Liu S. Sun Z. Cao X. Zhang K. Yao W. Lu K. D. Luk (2005) ArticleTitleAn investigation on the physicochemical properties of chitosan/DNA polyelectrolyte complexes Biomaterials 26 2705–2711 Occurrence Handle15585274 Occurrence Handle1:CAS:528:DC%2BD2cXhtVChsrvN Occurrence Handle10.1016/j.biomaterials.2004.07.038

    Article  PubMed  CAS  Google Scholar 

  22. M. Lee J. W. Nah Y. Kwon J. J. Koh K. S. Ko S. W. Kim (2001) ArticleTitleWater-soluble and low molecular weight chitosan-based plasmid DNA delivery Pharm. Res. 18 427–431 Occurrence Handle11451027 Occurrence Handle1:CAS:528:DC%2BD3MXkvFCgu7g%3D Occurrence Handle10.1023/A:1011037807261

    Article  PubMed  CAS  Google Scholar 

  23. B. I. Florea, M. Thanou, H. E. Junginger, and G. Borchard. Enhancement of bronchial octreotide absorption by chitosan and N-trimethyl chitosan shows linear in vitro/in vivo correlation. J. Control. Release 110:353–361 (2006). DOI 10.1016/j.jconrel.2005.10.001

    Google Scholar 

  24. J. C. Birchall I. W. Kellaway S. N. Mills (1999) ArticleTitlePhysico-chemical characterisation and transfection efficiency of cationic lipid-plasmid DNA gene delivery complexes Int. J. Pharm. 183 195–207 Occurrence Handle10361170 Occurrence Handle1:CAS:528:DyaK1MXjsFKltrw%3D Occurrence Handle10.1016/S0378-5173(99)00117-9

    Article  PubMed  CAS  Google Scholar 

  25. Preparations for inhalation: aerodynamic assessment of fine particles. In European Pharmacopoeia, Vol. 5.9.1, European Pharmacopoeia Convention, 1997, pp. 143–150.

  26. J. Smith E. Wood M. Dornish (2004) ArticleTitleEffect of chitosan on epithelial cell tight junctions Pharm. Res. 21 43–49 Occurrence Handle14984256 Occurrence Handle1:CAS:528:DC%2BD2cXkt1Onuw%3D%3D Occurrence Handle10.1023/B:PHAM.0000012150.60180.e3

    Article  PubMed  CAS  Google Scholar 

  27. T. Kean S. Roth M. Thanou (2005) ArticleTitleTrimethylated chitosans as non-viral gene delivery vectors: cytotoxicity and transfection efficiency J. Control. Release 103 643–653 Occurrence Handle15820411 Occurrence Handle1:CAS:528:DC%2BD2MXjt1aht7k%3D Occurrence Handle10.1016/j.jconrel.2005.01.001

    Article  PubMed  CAS  Google Scholar 

  28. M. M. Thanou J. C. Verhoef S. G. Romeijn J. F. Nagelkerke F. W. Merkus H. E. Junginger (1999) ArticleTitleEffects of N-trimethyl chitosan chloride, a novel absorption enhancer, on caco-2 intestinal epithelia and the ciliary beat frequency of chicken embryo trachea Int. J. Pharm. 185 73–82 Occurrence Handle10425367 Occurrence Handle1:CAS:528:DyaK1MXks1Cqurc%3D Occurrence Handle10.1016/S0378-5173(99)00126-X

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors are grateful for financial support from The Cardiff Young Researcher Initiative. Many thanks are also given to Dr. Maya Thanou for her kind donation of chitosan derivatives.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to James Birchall.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, HY., Birchall, J. Chitosan-Modified Dry Powder Formulations for Pulmonary Gene Delivery. Pharm Res 23, 941–950 (2006). https://doi.org/10.1007/s11095-006-0027-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-006-0027-x

Key Words

Navigation