Skip to main content
SpringerLink
Log in

Intact Nanoparticulate Indomethacin in Fast-Dissolving Carrier Particles by Combined Wet Milling and Aerosol Flow Reactor Methods

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

Drug development is often hindered by a drug's low dissolution rate. We present a method to increase dissolution rate of a drug powder by producing crystalline nanoparticles that are dispersed in carrier microparticles.

Methods

Indomethacin crystals of a few hundred nanometers are prepared by media milling using poloxamer 188 as a stabilizer. Nanoparticles are embedded into microparticles with a mannitol matrix and an L-leucine coating layer using an aerosol flow reactor method.

Results

Microparticles stabilize the primary nanoparticles in an intact crystalline form and release them when re-dispersed in aqueous medium. Secondary microparticle structure dissolves rapidly, resulting in a fast release and dissolution of indomethacin. In this manner, it is possible to change the surface layer of the particles from the one needed for nanoparticle production to one more suitable for process formulation of pharmaceuticals for, e.g., tablet or pulmonary products.

Conclusions

Particle assemblies where nano-sized crystalline drug domains are embedded in solid microparticles are presented. The present work is a promising approach towards a “nanos-in-micros” concept as a tool for pharmaceutical nanoparticle processing.

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

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

Similar content being viewed by others

REFERENCES

  1. Rabinow BE. Nanosuspensions in drug delivery. Nature Rev Drug Discov. 2004;3:785–96.

    Article  CAS  Google Scholar 

  2. Müller RH, Keck CM. Challenges and solutions for the delivery of biotech drugs—a review of drug nanocrystal technology and lipid nanoparticles. J Biotechnol. 2004;113:151–70.

    Article  PubMed  Google Scholar 

  3. Peltonen L, Hirvonen J. Pharmaceutical nanocrystals by nanomilling; critical process parameters, particle fracturing and stabilization methods. J Pharm Pharmacol. 2010;62:1569–79.

    Article  PubMed  CAS  Google Scholar 

  4. Urata C, Yamauchi Y, Aoyama Y, Imasu J, Todoroki S-I, Sakka Y, et al. Fabrication of hierarchically porous spherical particles by assembling mesoporous silica nanoparticles via spray drying. J Nanosci Nanotechnol. 2008;8:3101–5.

    Article  PubMed  CAS  Google Scholar 

  5. Gómez-Gaete C, Fattal E, Silva L, Besnard M, Tsapis N. Dexamethasone acetate encapsulation into Trojan particles. J Control Release. 2008;128:41–9.

    Article  PubMed  Google Scholar 

  6. Grenha A, Seijo B, Remuñán-López C. Microencapsulated chitosan nanoparticles for lung protein delivery. Eur J Pharm Sci. 2005;25:427–37.

    Article  PubMed  CAS  Google Scholar 

  7. Mizoe T, Ozeki T, Okada HJ. Preparation of drug nanoparticle-containing microparticles using a 4-fluid nozzle spray drier for oral, pulmonary, and injection dosage forms. J Control Release. 2007;122(1):10–5.

    Article  PubMed  CAS  Google Scholar 

  8. El-Gendy N, Gorman EM, Munson EJ, Berkland C. Budesonide nanoparticle agglomerates as dry powder aerosols with rapid dissolution. J Pharm Sci. 2009;98:2731–46.

    Article  PubMed  CAS  Google Scholar 

  9. Kaye RS, Purewal TS, Alpar HO. Simultaneously manufactured nano-in-micro (SIMANIM) particles for dry-powder modified-release delivery of antibodies. J Pharm Sci. 2009;98:4055–68.

    Article  PubMed  CAS  Google Scholar 

  10. Kho K, Cheow WS, Lie RH, Hadinoto K. Aqueous re-dispersibility of spray-dried antibiotic-loaded polycaprolactone nanoparticle aggregates for inhaled anti-biofilm therapy. Powder Technol. 2010;203:432–9.

    Article  CAS  Google Scholar 

  11. Grenha A, Seijo B, Serra C, Remuñán-López C. Chitosan-nanoparticle loaded mannitol microspheres: structure and surface characterization. Biomacromolecules. 2007;8:2072–9.

    Article  PubMed  CAS  Google Scholar 

  12. Lind A, von Hohenesche CF, Smått J-H, Lindén M, Unger KK. Spherical silica agglomerates possessing hierarchical porosity prepared by spray drying of MCM-41 and MCM-48 nanospheres. Microporous Mesoporous Mater. 2003;66:219–27.

    Article  CAS  Google Scholar 

  13. Eerikäinen H, Peltonen L, Raula J, Kauppinen EI, Hirvonen J. Nanoparticles containing ketoprofen and acrylic polymers prepared by an aerosol flow reactor method. AAPS PharmSciTech. 2004;5:article 68.

  14. Tong HHY, Shekunov BY, York P, Chow AHL. Influence of polymorphism on the surface energetics of salmeterol xinafoate crystallized from supercritical fluids. Pharm Res. 2002;19:640–8.

    Article  PubMed  CAS  Google Scholar 

  15. Eerikäinen H, Watanabe W, Kauppinen EI, Ahonen PP. Aerosol flow reactor method for synthesis of drug nanoparticles. Eur J Pharm Biopharm. 2003;55:357–60.

    Article  PubMed  Google Scholar 

  16. Lucas P, Anderson K, Potter UJ, Staniforth JN. Enhancement of small particle size dry powder aerosol formulations using an ultra low density additive. Pharm Res. 1999;16:1643–7.

    Article  PubMed  CAS  Google Scholar 

  17. Raula J, Kurkela JA, Brown DP, Kauppinen EI. Study of the dispersion behaviour of L-leucine containing microparticles synthesized with an aerosol flow reactor method. Powder Technol. 2007;177:125–32.

    Article  CAS  Google Scholar 

  18. Raula J, Lähde A, Kauppinen EI. Aerosolization behavior of carrier-free L-leucine coated salbutamol sulphate powders. Int J Pharm. 2009;365:18–25.

    Article  PubMed  CAS  Google Scholar 

  19. Raula J, Thielmann F, Naderi M, Lehto V-P, Kauppinen EI. Influence on particle surface characteristics vs. dispersion behaviour of L-leucine coated carrier-free inhalable powders. Int J Pharm. 2010;385:79–85.

    Article  PubMed  CAS  Google Scholar 

  20. Raula J, Lähde A, Kauppinen EI. A novel gas phase method for the combined synthesis and coating of pharmaceutical particles. Pharm Res. 2008;25:242–5.

    Article  PubMed  CAS  Google Scholar 

  21. Lähde A, Raula J, Kauppinen EI. Simultaneous synthesis and coating of salbutamol sulphate nanoparticles with L-leucine in the gas phase. Int J Pharm. 2008;358:256–62.

    Article  PubMed  Google Scholar 

  22. Raula J, Thielmann F, Kansikas J, Hietala S, Annala M, Seppälä J, et al. Investigations on the humidity-induced transformations of salbutamol sulphate particles coated with L-leucine. Pharm Res. 2008;25:2250–61.

    Article  PubMed  CAS  Google Scholar 

  23. Raula J, Kuivanen A, Lähde A, Kauppinen EI. Gas-phase synthesis of L-leucine-coated micrometer-sized salbutamol sulphate and sodium chloride particles. Powder Technol. 2008;187:289–97.

    Article  CAS  Google Scholar 

  24. Raula J, Kauppinen EI, Huck D, Kippax P, Virden A. Characterizing carrier-free DPI formulations: using laser diffraction and morphological imaging to examine aerosolization performance of carrier-free inhalation powders. Inhalation. 2010;4(4):8–11.

    Google Scholar 

  25. Paajanen M, Katainen J, Raula J, Kauppinen EI, Lahtinen J. Direct evidence on reduced adhesion of salbutamol sulphate particles due to L-leucine coating. Powder Technol. 2009;192:6–11.

    Article  CAS  Google Scholar 

  26. Liu P, Rong X, Hirvonen J, Laaksonen T, Peltonen L. Nanosuspension of poorly soluble drugs: preparation and development by wet milling. Int J Pharm. 2011. 10.1016/j.ijpharm.2011.03.050.

  27. Hillamo R, Kauppinen EI. On the performance of the Berner low pressure impactor. Aerosol Sci Tech. 1991;14:33–47.

    Article  CAS  Google Scholar 

  28. Leroueil-Le Verger M, Fluckiger L, Kim Y-I, Hoffman M, Maincent P. Preparation and characterization of nanoparticles containing an antihypertensive agent. Eur J Pharm Biopharm. 1998;46:137–43.

    Article  PubMed  CAS  Google Scholar 

  29. Raula J, Kuivanen A, Lähde A, Jiang H, Antopolsky M, Kansikas J, et al. Synthesis of L-leucine nanoparticles via physical vapor deposition under various saturation conditions. J Aerosol Sci. 2007;38:1172–84.

    Article  CAS  Google Scholar 

  30. Savolainen M, Heinz A, Strachan C, Gordond KC, Yliruusi J, Rades T, et al. Screening for differences in the amorphous state of indomethacin using multivariate visualization. Eur J Pharm Sci. 2007;30:113–23.

    Article  PubMed  CAS  Google Scholar 

  31. Chaubal MV, Popescu C. Conversion of nanosuspensions into dry powders by spray drying: a case study. Pharm Res. 2008;25:2302–8.

    Article  PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS

JR, AR, and EK acknowledge support from the Academy of Finland (project no. 133407).

Author information

Authors and Affiliations

  1. Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland

    Timo Laaksonen, Peng Liu, Leena Peltonen & Jouni Hirvonen

  2. Department of Applied Physics, Aalto University School of Science, P.O. Box 15100, 00076, Aalto, Finland

    Antti Rahikkala, Esko I. Kauppinen & Janne Raula

  3. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211, Kuopio, Finland

    Kristiina Järvinen

Authors
  1. Timo Laaksonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antti Rahikkala
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leena Peltonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Esko I. Kauppinen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jouni Hirvonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kristiina Järvinen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Janne Raula
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Timo Laaksonen or Janne Raula.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Laaksonen, T., Liu, P., Rahikkala, A. et al. Intact Nanoparticulate Indomethacin in Fast-Dissolving Carrier Particles by Combined Wet Milling and Aerosol Flow Reactor Methods. Pharm Res 28, 2403–2411 (2011). https://doi.org/10.1007/s11095-011-0456-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-011-0456-z

KEY WORDS

Search

Navigation