Skip to main content
SpringerLink
Log in

Core–shell Particles for the Dispersion of Small Polar Drugs and Biomolecules in Hydrofluoroalkane Propellants

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

Abstract

Purpose

Demonstrate the applicability of a novel particle-based technology for the development of suspensions of small polar drugs and biomolecules in hydrofluoroalkane (HFA) propellants for pressurized metered-dose inhalers (pMDIs).

Materials and Methods

Emulsification diffusion was used to prepare core–shell particles. The shell consisted of oligo(lactide) grafts attached onto a short chitosan backbone. The active drug was arrested within the particle core. Colloidal Probe Microscopy (CPM) was used to determine the cohesive forces between particles in a model HFA propellant. The aerosol characteristics of the formulations were determined using an Anderson Cascade Impactor (ACI). Cytotoxicity studies were performed on lung epithelial and alveolar type II cells.

Results

CPM results indicate that particle cohesive forces in liquid HFA are significantly screened in the presence of the polymeric shell and correlate well with the physical stability of suspensions in propellant HFA. The proposed formulation showed little or no cytotoxic effects on both Calu-3 and A549 cells.

Conclusions

Core–shell particles with a shell containing the lactide moiety as the HFA-phile showed excellent dispersion stability and aerosol characteristics in HFA-based pMDIs. This is a general strategy that can be used for developing novel suspension pMDIs of both small polar drugs and large therapeutic molecules.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. R. U. Agu, M. I. Ugwoke, M. Armand, R. Kinget, and N. Verbeke. The lung as a route for systemic delivery of therapeutic proteins and peptides. Respir. Res. 2:198–209 (2001).

    Article  PubMed  CAS  Google Scholar 

  2. M. Bivas-Benita, T. H. M. Ottenhoff, H. E. Junginger, and G. Borchard. Pulmonary DNA vaccination: concepts, possibilities and perspectives. J. Control. Release 107:1–29 (2005).

    Article  PubMed  CAS  Google Scholar 

  3. L. R. Brown. Commercial challenges of protein drug delivery. Expert. Opin. Drug Delivery 2:29–42 (2005).

    Article  Google Scholar 

  4. S. A. Cryan. Carrier-based strategies for targeting protein and peptide drugs to the lungs. AAPS J. 7:20–41 (2005).

    Article  Google Scholar 

  5. B. L. Laube. The expanding role of aerosols in systemic drug delivery, gene therapy, and vaccination. Respir. Care. 50:1161–1176 (2005).

    PubMed  Google Scholar 

  6. D. T. O’Hagan, and R. Rappuoli. Novel approaches to vaccine delivery. Pharm. Res. 21:1519–1530 (2004).

    Article  PubMed  CAS  Google Scholar 

  7. J. S. Patton. Mechanisms of macromolecule absorption by the lungs. Adv. Drug Delivery Rev. 19:3–36 (1996).

    Article  CAS  Google Scholar 

  8. H. M. Courrier, N. Butz, and T. F. Vandamme. Pulmonary drug delivery system: recent developments and prospects. Crit. Rev. Ther. Drug Carrier Syst. 19:425–498 (2002).

    Article  PubMed  CAS  Google Scholar 

  9. D. K. Malik, S. Baboota, A. Ahuja, S. Hasan, and J. Ali. Recent advances in protein and peptide drug delivery systems. Current Drug Delivery 4:141–151 (2007).

    Article  PubMed  CAS  Google Scholar 

  10. D. R. Owens, B. Zinman, and G. Bolli. Alternative routes of insulin delivery. Diabetic Med. 20:886–898 (2003).

    Article  PubMed  CAS  Google Scholar 

  11. Y. Berthiaume, K. H. Albertine, M. Grody, G. Fick, and M. A. Matthay. Protein clearance from the air spaces and lungs of unanesthetized sheep over 144 h. J. Appl. Physiol. 67:1887–1897 (1989).

    PubMed  CAS  Google Scholar 

  12. R. H. Hastings, M. Grady, T. Sakuma, and M. A. Matthay. Clearance of different-sized proteins from the alveolar space in humans and rabbits. J. Appl. Physiol. 73:1310–1316 (1992).

    PubMed  CAS  Google Scholar 

  13. S. S. Davis. Delivery of peptide and non-peptide drugs through the respiratory tract. Pharm Sci Technol To. 2:450–456 (1999).

    Article  CAS  Google Scholar 

  14. P. Rogueda. Novel hydrofluoroalkane suspension formulations for respiratory drug delivery. Expert. Opin. Drug Delivery. 2:625–638 (2005).

    Article  CAS  Google Scholar 

  15. M. J. Telko, and A. J. Hickey. Dry powder inhaler formulation. Respir. Care 50:1209–1227 (2005).

    PubMed  Google Scholar 

  16. K. J. McDonald, and G. P. Martin. Transition to CFC-free metered dose inhalers—into the new millennium. Int. J. Pharm. 201:89–107 (2000).

    Article  PubMed  CAS  Google Scholar 

  17. H. D. C. Smyth. Propellant-driven metered-dose inhalers for pulmonary drug delivery. Expert. Opin. Drug Delivery. 2:53–74 (2005).

    Article  Google Scholar 

  18. D. Traini, P. M. Young, P. Rogueda, and R. Price. In vitro investigation of drug particulates interactions and aerosol performance of pressurized metered dose inhalers. Pharm. Res. 24:125–135 (2007).

    Article  PubMed  CAS  Google Scholar 

  19. C. Vervaet, and P. R. Byron. Drug-surfactant-propellant interactions in HFA-formulations. Int. J. Pharm. 186:13–30 (1999).

    Article  PubMed  CAS  Google Scholar 

  20. L. A. Dellamary, T. E. Tarara, D. J. Smith, C. H. Woelk, A. Adractas, M. L. Costello, H. Gill, and J. G. Weers. Hollow porous particles in metered dose inhalers. Pharm. Res. 17:168–174 (2000).

    Article  PubMed  CAS  Google Scholar 

  21. D. A. Edwards, J. Hanes, G. Caponetti, J. Hrkach, A. Ben-Jebria, M. L. Eskew, J. Mintzes, D. Deaver, N. Lotan, and R. Langer. Large porous particles for pulmonary drug delivery. Science. 276:1868–1871 (1997).

    Article  PubMed  CAS  Google Scholar 

  22. S. A. Jones, G. P. Martin, and M. B. Brown. Stabilization of deoxyribonuclease in hydrofluoroalkanes using miscible vinyl polymers. J. Control. Release 115:1–8 (2006).

    Article  PubMed  CAS  Google Scholar 

  23. Y.-H. Liao, M. B. Brown, S. A. Jones, T. Nazir, and G. P. Martin. The effects of polyvinyl alcohol on the in vitro stability and delivery of spray-dried protein particles from surfactant-free HFA 134a-based pressurised metered dose inhalers. Int. J. Pharm. 304:29–39 (2005).

    Article  PubMed  CAS  Google Scholar 

  24. T. E. Tarara, M. S. Hartman, H. Gill, A. A. Kennedy, and J. G. Weers. Characterization of suspension-based metered dose inhaler formulations composed of spray-dried budesonide microcrystals dispersed in HFA-134a. Pharm. Res. 21:1607–1614 (2004).

    Article  PubMed  CAS  Google Scholar 

  25. D. A. Edwards, A. Ben-Jebria, and R. Langer. Recent advances in pulmonary drug delivery using large, porous inhaled particles. J. Appl. Physiol. 85:379–385 (1998).

    PubMed  CAS  Google Scholar 

  26. D. H. Napper. Polymeric Stabilization of Colloidal Dispersions. Academic Press, Orlando, 1983.

    Google Scholar 

  27. L. Wu, R. P. S. Peguin, and S. R. P. da Rocha. Understanding solvation in hydrofluoroalkanes: ab initio calculations and chemical force microscopy. J Phys Chem B 111:8096–8104 (2007).

    Article  PubMed  CAS  Google Scholar 

  28. R. P. S. Peguin, L. Wu, and S. R. P. da Rocha. The Ester Group: how hydrofluoroalkane-philic is it. Langmuir. 23:8291–8194 (2007).

    Article  PubMed  CAS  Google Scholar 

  29. R. Ashayer, P. F. Luckham, S. Manimaaran, and P. Rogueda. Investigation of the molecular interactions in a pMDI formulation by atomic force microscopy. Colloids Surf, A 21:533–543 (2004).

    CAS  Google Scholar 

  30. D. Traini, P. Rogueda, P. M. Young, and R. Price. Surface energy and interparticle forces correlations in model pMDI formulations. Pharm. Res. 22:816–825 (2005).

    Article  PubMed  CAS  Google Scholar 

  31. D. Traini, P. M. Young, P. Rogueda, and R. Price. Investigation into the influence of polymeric stabilizing excipients on inter-particulate forces in pressurised metered dose inhalers. Int. J. Pharm. 320:58–63 (2006).

    Article  PubMed  CAS  Google Scholar 

  32. P. M. Young, R. Price, D. Lewis, S. Edge, and D. Traini. Under pressure: predicting pressurized metered dose inhaler interactions using the atomic force microscope. J Colloid Interface Sci 261:298–302 (2003).

    Article  Google Scholar 

  33. F. Tian, Y. Liu, K. Hu, and B. Zhao. The depolymerization mechanism of chitosan by hydrogen peroxide. J. Mater Sci. 38:4709–4712 (2003).

    Article  CAS  Google Scholar 

  34. Y. Liu, F. Tian, and K. A. Hu. Synthesis and characterization of a brush-like copolymer of polylactide grafted onto chitosan. Carbohydr. Res. 339:845–851 (2004).

    Article  PubMed  CAS  Google Scholar 

  35. H.-J. Butt, B. Cappella, and M. Kappl. Force measurements with the atomic force microscope: Technique, interpretation and applications. Surf. Sci. Rep. 59:1–152 (2005).

    Article  CAS  Google Scholar 

  36. P. G. A. Rogueda. HPFP, a model propellant for pMDIs. Drug Dev. Ind. Pharm. 29:39–49 (2003).

    Article  PubMed  CAS  Google Scholar 

  37. P. Selvam, R. P. S. Peguin, U. Chokshi, and S. R. P. da Rocha. Surfactant design for the 1,1,1,2-tetrafluoroethane-water interface: ab initio calculations and in situ high-pressure tensiometry. Langmuir. 22:8675–8683 (2006).

    Article  PubMed  CAS  Google Scholar 

  38. T. L. Riss, and R. A. Moravec. Comparison of MTT, XTT and a novel tetrazolium compound MTS form in vitro proliferation and chemosensitivity assays. Mol. Biol. Cell (Suppl). 3:184a(1992).

    Google Scholar 

  39. M. Amidi, S. Romeijn, G. Borchard, H. E. Junginger, W. E. Hennink, and W. Jiskoot. Preparation and characterization of protein-loaded N-trimethyl chitosan nanoparticles as nasal delivery system. J. Controlled Release 111:107–116 (2006).

    Article  CAS  Google Scholar 

  40. L. Illum, I. Jabbal-Gill, M. Hinchcliffe, A. N. Fisher, and S. S. Davis. Chitosan as a novel nasal delivery system for vaccines. Adv. Drug Delivery Rev. 51:81–96 (2001).

    Article  CAS  Google Scholar 

  41. R. O. Williams III, M. K. Barron, M. Jose Alonso, and C. Remunan-Lopez. Investigation of a pMDI system containing chitosan microspheres and P134a. Int. J. Pharm. 174:209–222 (1998).

    Article  CAS  Google Scholar 

  42. S. Lu, X. Song, D. Cao, Y. Chen, and K. Yao. Preparation of water-soluble chitosan. J. Appl. Polym. Sci. 91:3497–3503 (2004).

    Article  CAS  Google Scholar 

  43. A. Grenha, C. I. Grainger, L. A. Dailey, B. Seijo, G. P. Martin, C. Remunan-Lopez, and B. Forbes. Chitosan nanoparticles are compatible with respiratory epithelial cells in vitro. Eur. J. Pharm. Sci. 31:73–84 (2007).

    Article  PubMed  CAS  Google Scholar 

  44. 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).

    Article  PubMed  CAS  Google Scholar 

  45. M. Huang, E. Khor, and L.-Y. Lim. Uptake and cytotoxicity of chitosan molecules and nanoparticles: effects of molecular weight and degree of deacetylation. Pharm. Res. 21:344–353 (2004).

    Article  PubMed  CAS  Google Scholar 

  46. M. F. Zambaux, F. G. Bonneaux, R. E. Dellacherie, and C. Vigneron. Preparation and characterization of protein C-loaded PLA nanoparticles. J. Controlled Release. 60:179–188 (1999).

    Article  CAS  Google Scholar 

  47. S. A. Hagan, S. E. Dunn, M. C. Garnett, M. C. Davies, L. Illum, and S. S. Davis. PLA-PEG micelles—a novel drug delivery system. Proc. Intern. Symp. Controlled Release Bioact. Mater. 22nd:194–195 (1995).

    CAS  Google Scholar 

  48. M. A. Vandelli, B. Ruozi, and F. Forni. PLA microparticles for the prolonged release of nimesulide: effect of preparative variables. STP Pharma Sci. 9:567–572 (1999).

    CAS  Google Scholar 

  49. A. Vila, A. Sanchez, C. Evora, I. Soriano, J. L. Vila Jato, and M. J. Alonso. PEG-PLA nanoparticles as carriers for nasal vaccine delivery. J. Aerosol. Med. 17:174–185 (2004).

    Article  PubMed  CAS  Google Scholar 

  50. J. S. Stefely, D. C. Duan, P. B. Myrdal, D. L. Ross, D. W. Schultz, and C. L. Leach. Desing and utility of a novel class of biocompatible excipients for HFA-based MDIs. Respir. Drug Delivery VII:83–90 (2000).

    Google Scholar 

  51. G. E. Luckachan, and C. K. S. Pillai. Chitosan/oligo l-lactide graft copolymers: effect of hydrophobic side chains on the physico-chemical properties and biodegradability. Carbohydr. Polym. 64:254–266 (2006).

    Article  CAS  Google Scholar 

  52. M. H. Boskabady, and M. Saadatinejad. Airway responsiveness to beta-adrenergic agonist (Salbutamol) in asthma. J. Asthma 40:917–925 (2003).

    Article  PubMed  CAS  Google Scholar 

  53. J. C. Leroux, E. Alleman, E. Doelker, and R. Gurny. New approach for the preparation of nanoparticles by an emulsification-diffusion method. Eur. J. Pharm. Biopharm. 41:14–18 (1995).

    CAS  Google Scholar 

  54. D. Quintanar-Guerrero, H. Fessi, E. Allemann, and E. Doelker. Influence of stabilizing agents and preparative variables on the formation of poly(d,l-lactic acid) nanoparticles by an emulsification–diffusion technique. Int. J. Pharm. 143:133–141 (1996).

    Article  CAS  Google Scholar 

  55. S. Galindo-Rodriguez, E. Allemann, H. Fessi, and E. Doelker. Physicochemical parameters associated with nanoparticle formation in the salting-out, emulsification–diffusion, and nanoprecipitation methods. Pharm. Res. 21:1428–1439 (2004).

    Article  PubMed  CAS  Google Scholar 

  56. S.-W. Choi, H.-Y. Kwon, W.-S. Kim, and J.-H. Kim. Thermodynamic parameters on poly(d,l-lactide-co-glycolide) particle size in emulsification–diffusion process. Colloids Surf, A 201:283–289 (2002).

    Article  CAS  Google Scholar 

  57. M. Trotta, D. Chirio, R. Cavalli, and E. Peira. Hydrophilic microspheres from water-in-oil emulsions by the water diffusion technique. Pharm. Res. 21:1445–1449 (2004).

    Article  PubMed  CAS  Google Scholar 

  58. H.-Y. Kwon, J.-Y. Lee, S.-W. Choi, Y. Jang, and J.-H. Kim. Preparation of PLGA nanoparticles containing estrogen by emulsification-diffusion method. Colloids Surf, A 182:123–130 (2001).

    Article  CAS  Google Scholar 

  59. S. Galindo-Rodriguez, E. Allemann, E. Doelker, and H. Fessi. Versatility of three techniques for preparing ibuprofen-loaded methacrylic acid copolymer nanoparticles of controlled sizes. J. Drug Delivery Sci. Tech. 15:347–354 (2005).

    CAS  Google Scholar 

  60. M. Liu, J. Dong, Y. Yang, X. Yang, and H. Xu. Characterization and release of triptolide-loaded poly(d,l-lactic acid) nanoparticles. Euro. Polym. J. 41:375–382 (2005).

    Article  CAS  Google Scholar 

  61. P. Begat, D. A. V. Morton, J. N. Staniforth, and R. Price. The cohesive-adhesive balances in dry powder inhaler formulations I: direct quantification by atomic force microscopy. Pharm. Res. 21:1591–1597 (2004).

    Article  PubMed  CAS  Google Scholar 

  62. H. D. C. Smyth, V. P. Beck, D. Williams, and A. J. Hickey. The influence of formulation and spacer device on the in vitro performance of solution chlorofluorocarbon-free propellant-driven metered dose inhalers. AAPS PharmSciTech. 5:1–7 (2004).

    Article  Google Scholar 

  63. R. O. Williams III, A. M. Patel, M. K. Barron, and T. L. Rogers. Investigation of some commercially available spacer devices for the delivery of glucocorticoid steroids from a pMDI. Drug Dev. Ind. Pharm. 27:401–412 (2001).

    Article  PubMed  CAS  Google Scholar 

  64. B. Forbes, and C. Ernhardt. Human respiratory epithelial cell culture for drug delivery applications. Eur. J. Pharm. Biopharm. 60:193–205 (2005).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

L.W. acknowledges Wayne State University (WSU) for a Ph.D. assistantship. The authors would also like to acknowledge Solvay Fluor und Derivate GmbH & Co., Hannover—Germany, for the propellant HFAs; West Pharmaceuticals and 3M, for the glass vials and metering valves, respectively; Dr. Verani’s group (Department of Chemistry at WSU), Dr. Oupicky’s group (College of Pharmacy at WSU), and Dr. Sujatha Kannan’s group (Med School at WSU) for providing access to the FTIR, GPC and plate reader, and the A549 cell line, respectively; and financial support from the Office of the VP for Research at Wayne State University, through a Nano@Wayne grant, and from the National Science Foundation through an NSF-CBET grant no. 0553537.

Author information

Authors and Affiliations

  1. Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, Michigan, USA

    Libo Wu, Balaji Bharatwaj & Sandro R. P. da Rocha

  2. Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan, USA

    Jayanth Panyam

Authors
  1. Libo Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Balaji Bharatwaj
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jayanth Panyam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sandro R. P. da Rocha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sandro R. P. da Rocha.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, L., Bharatwaj, B., Panyam, J. et al. Core–shell Particles for the Dispersion of Small Polar Drugs and Biomolecules in Hydrofluoroalkane Propellants. Pharm Res 25, 289–301 (2008). https://doi.org/10.1007/s11095-007-9466-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-007-9466-2

Key words

Search

Navigation