Skip to main content
SpringerLink
Log in

Phospholipid-stabilized nanoparticles of cyclosporine a by rapid expansion from supercritical to aqueous solution

  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The purpose of this research was to form stable suspensions of submicron particles of cyclosporine A, a water-insoluble drug, by rapid expansion from supercritical to aqueous solution (RESAS). A solution of cyclosporine A in CO2 was expanded into an aqueous solution containing phospholipid vesicles mixed with nonionic surfactants to provide stabilization against particle growth resulting from collisions in the expanding jet. The products were evaluated by measuring drug loading with high performance liquid chromatography (HPLC), particle sizing by dynamic light scattering (DLS), and particle morphology by transmission electron microscopy (TEM) and x-ray diffraction. The ability of the surfactant molecules to orient at the surface of the particles and provide steric stabilization could be manipulated by changing process variables including temperature and suspension concentration. Suspensions with high payloads (up to 54 mg/mL) could be achieved with a mean diameter of 500 nm and particle size distribution ranging from 40 to 920 nm. This size range is several hundred nanometers smaller than that produced by RESAS for particles stabilized by Tween 80 alone. The high drug payloads (≈10 times greater than the equilibrium solubility), the small particle sizes, and the long-term stability make this process attractive for development.

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

Similar content being viewed by others

References

  1. Pace SN, Pace GW, Parikh I, Mishra AK. Novel injectable formulations of insoluble drugs.Pharm Technol. 1999;23:116–134.

    CAS  Google Scholar 

  2. Broadhead J, Rouan SKE, Rhodes CT. The spray drying of pharmaceuticals.Drug Dev Ind Pharm. 1992;18(11–12):1169–1206.

    Article  CAS  Google Scholar 

  3. Masters K.Spray Drying Handbook. 3rd ed. Hoboken, NJ: John Wiley and Sons, 1979.

    Google Scholar 

  4. Chasin M, Langer R, eds.Biodegradable Polymers as Drug Delivery Systems. New York, NY: Marcel Dekker, 1990. Swarbick J, ed. Drugs and the Pharmaceutical Sciences; No. 45.

    Google Scholar 

  5. Bakan JA. Microencapsulation. In: Swarbrick J, Boylan JC, eds.Encyclopedia of Pharmaceutical Technology. Vol. 9. New York, NY: Marcel Dekker, 1994:423–441.

    Google Scholar 

  6. Puisieux F, Barratt G, Couarraze G, et al. Polymeric micro- and nanoparticles as drug carriers. In: Dumitriu S, ed.Polymeric Biomaterials. New York, NY: Marcel Dekker, 1994:749–794.

    Google Scholar 

  7. Byers JE, Peck GE. The effect of mill variables on a granulation milling process.Drug Dev Ind Pharm. 1990;16(11):1761–1779.

    Article  Google Scholar 

  8. Aiache JM, Beyssac E. Powders as dosage forms. In: Swarbrick J, Boylan JC, eds.Encyclopedia of Pharmaceutical Technology Vol 12. New York, NY: Marcel Dekker, 1994:389–420.

    Google Scholar 

  9. Illig KJ, Mueller RL, Ostrander KD, Swanson JR. Use of microfluidizer processing for preparation of pharmaceutical suspensions.Pharm Technol. 1996;20:78–88.

    Google Scholar 

  10. Parrott EL. Comminution. In: Swarbrick J, Boylan JC, eds.Encyclopedia of Pharmaceutical Technology. Vol 3. New York, NY: Marcel Dekker, 1994:101–121.

    Google Scholar 

  11. Rubinstein MH, Gould P. Particle size reduction in the ball mill.Drug Dev Ind Pharm. 1987;13(1):81–92.

    Article  Google Scholar 

  12. Subramaniam B, Rajewski RA, Snavely K. Pharmaceutical processing with supercritical carbon dioxide.J Pharm Sci. 1997;86(8):885–890.

    Article  CAS  PubMed  Google Scholar 

  13. Phillips EM, Stella VJ. Rapid expansion from supercritical solutions: application to pharmaceutical processes.Int J Pharm. 1992;94:1–10.

    Article  Google Scholar 

  14. Tom JW, Debenedetti PG, Jerome R. Precipitation of poly(L-lactic acid) and composite poly(L-lactic acid)-pyrene particles by rapid expansion of supercritical solutions.J Supercrit Fluids. 1994;7:9–29.

    Article  CAS  Google Scholar 

  15. Mawson S, Johnston KP, Combes JR, DeSimone JM. Formation of poly(1,1,2,2-tetrahydroperfuorodecyl acrylate) submicron fibers and particles from supercritical carbon dioxide solutions.Macromolecules. 1995;28(9):3182–3191.

    Article  CAS  Google Scholar 

  16. Alessi P, Cortesi A, Kikic I, Foster NR, Macnaughton SJ, Colombo I. Particle production of steroid drugs using supercritical fluid processing.Ind Eng Chem Res. 1996;35:4718–4726.

    Article  Google Scholar 

  17. Mohamed RS, Halverson DS, Debenedetti PG, Prud'homme RK. Solids formation after the expansion of supercritical mixtures. In: Johnston KP, Penninger JML, eds.Supercritical Fluid Science and Technology. Vol 406. Washington, DC: American Chemical Society; 1989:355–378.

    Chapter  Google Scholar 

  18. Matson DW. Making powders and films from supercritical fluid solutions.Chemtech. 1989;19(8):480–486.

    CAS  Google Scholar 

  19. Chang CJ, Randolph AD. Precipitation of microsize organic particles from supercritical fluids.AIChE J. 1989;35(11):1876–1882.

    Article  CAS  Google Scholar 

  20. Domingo C, Berends E, van Rosmalen GM. Precipitation of ultrafine crystals from the rapid expansion of supercritical solutions over a capillary and a frit nozzle.J Supercrit Fluids. 1997;10:39–55.

    Article  CAS  Google Scholar 

  21. Lele AK, Shine AD. Effect of RESS dynamics on polymer morphology.Ind Eng Chem Res. 1994;33:1476–1485.

    Article  CAS  Google Scholar 

  22. Krukonis VJ. Processing with supercritical fluids: overview and applications. In: Chapentier BA, Sevenants MR, eds.Supercritical Fluid Extraction and Chromatography: Techniques and Applications. Vol 366. Washington, DC: American Chemical Society; 1988:26–43.

    Chapter  Google Scholar 

  23. Charoenchaitrakool M, Dehghani F, Foster NR, Chan HK. Micronization by rapid expansion of supercritical solutions to enhance the dissolution rates of poorly water-soluble pharmaceuticals.Ind Eng Chem Res. 2000;39:4794–4802.

    Article  CAS  Google Scholar 

  24. Debenedetti PG. Supercritical fluids as particle formation media. In: Kiran E, Levelt Sengers JMH, eds.Supercritical Fluids: Fundamentals for Application. Vol 273. Boston, MA: Kluwer Academic Publishers, 1994:719–729.

    Chapter  Google Scholar 

  25. Young TJ, Mawson S, Johnston KP, Henriksen IB, Pace GW, Mishra AK. Rapid expansion from supercritical to aqueous solution to produce submicron suspensions of water-insoluble drugs.Biotechnol Prog. 2000;16(3):402–407.

    Article  CAS  PubMed  Google Scholar 

  26. Sun YP, Guduru R, Lin F, Whiteside T. Preparation of nanoscale semiconductors through the rapid expansion of supercritical solution into liquid solution.Ind Eng Chem Res. 2000;39:5663–5669

    Google Scholar 

  27. Wabel C.Influence of Lecithin on Structure and Stability of Parenteral Fat Emulsions [dissertation]. Erlangen, Germany: Department of Pharmaceutics, University of Erlangen-Nurnberg; 1998.

    Google Scholar 

  28. Lieberman HA, Rieger MM, Banker GS, eds.Pharmaceutical Dosage Forms: Disperse Systems. 2nd ed. New York, NY: Marcel Dekker, 1998: No. 3.

    Google Scholar 

  29. New RRC, ed.Liposomes: A Practical Approach. New York, NY: Oxford University Press, 1990. Rickwood D, Hames BD, eds. The Practical Approach Series.

    Google Scholar 

  30. Sujatha J, Mishra AK. Effect of ionic and neutral surfactants on the properties of phospholipid vesicles: investigation using fluorescent probes.J Photochem Photobiol A, Chem. 1997;104:173–178.

    Article  CAS  Google Scholar 

  31. Weiner N, Martin F, Riaz M. Liposomes as a drug delivery system.Drug Dev Ind Pharm. 1989;15(10):1523–1554.

    Article  CAS  Google Scholar 

  32. Crowe JH, Crowe LM, Carpenter JF, Wistrom CA. Stabilization of dry phospholipid bilayers and proteins by sugars.Biochem J. 1987;242:1–10.

    PubMed Central  CAS  PubMed  Google Scholar 

  33. Talsma H, van Steenbergen MJ, Crommelin DJA. The cryopreservation of liposomes: 3. Almost complete retention of a water-soluble marker in small liposomes in a cryoprotectant containing dispersion after a freezing/thawing cycle.Int J Pharm. 1991;77:119–126.

    Article  CAS  Google Scholar 

  34. Cevc G, ed.Phospholipids Handbook. New York, NY: Marcel Dekker, 1993.

    Google Scholar 

  35. Socaciu C, Jessel R, Diehl HA. Competitive carotenoid and cholesterol incorporation into liposomes: effects on membrane phase transition, fluidity, polarity and anisotropy.Chem Phys Lipids. 2000;106:79–88.

    Article  CAS  PubMed  Google Scholar 

  36. Yang J, Appleyard J. The main phase transition of mica-supported phosphatidylcholine membranes.J Phys Chem B. 2000;104:8097–8100.

    Article  CAS  Google Scholar 

  37. Grau A, Ortiz A, de Godos A, Gomez-Fernandez JC. A biophysical study of the interaction of the lipopeptide antibiotic iturin A with aqueous phospholipid bilayers.Arch Biochem Biophys. 2000;377(2):315–323.

    Article  CAS  PubMed  Google Scholar 

  38. Fresta M, Ricci M, Rossi C, Furneri PM, Puglisi G. Antimicrobial nonapeptide leucinostatin A-dependent effects on the physical properties of phospholipid model membranes.J Colloid Interface Sci. 2000;226:222–230.

    Article  CAS  Google Scholar 

  39. Moya S, Donath E, Sukhorukov GB, et al. Lipid coating on polyelectrolyte surface modified colloidal particles and polyelectrolyte capsules.Macromolecules. 2000;33:4538–4544.

    Article  CAS  Google Scholar 

  40. Shobini J, Mishra AK. Effect of leucinyl-phenylalanyl-valine on DMPC liposome membrane.Spectrochim Acta [A]. 2000;56:2239–2248.

    Article  Google Scholar 

  41. Shine AD, inventor, University of Delaware, assignee. Precipitation of Homogeneous Mixtures From Supercritical Fluid Solutions. US patent 5 290 827. March 1, 1994.

Download references

Author information

Author notes

  1. Timothy J. Young

    Present address: Dow Chemical Company, Midland, MI

Authors and Affiliations

  1. Department of Chemical Engineering, University of Texas, 78712-1062, Austin, TX

    Timothy J. Young & Keith P. Johnston

  2. RTP Pharma Inc, H3E 1A8, Quebec, Canada

    Gary W. Pace & Awadhesh K. Mishra

Authors
  1. Timothy J. Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keith P. Johnston
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gary W. Pace
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Awadhesh K. Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Keith P. Johnston.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Young, T.J., Johnston, K.P., Pace, G.W. et al. Phospholipid-stabilized nanoparticles of cyclosporine a by rapid expansion from supercritical to aqueous solution. AAPS PharmSciTech 5, 11 (2004). https://doi.org/10.1208/pt050111

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/pt050111

Keywords

Search

Navigation