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Development of Inhalable Nanoparticles

Leticia Ely, Raimar Lbenberg Faculty of Pharmacy and Pharmaceutical Sciences lely@pharmacy.ualberta.ca Rloebenberg@pharmacy.ualberta.ca Warren H. Finlay Department of Mechanical Engineering warren.finlay@ualberta.ca

Zhaolin Wang, Yu Zhang Department of Mechanical Engineering zhaolin@ualberta.ca yzhang@ualberta.ca Wilson H.-Y. Roa, Jeffrey O. H.Sham Department of Radiation Oncology wilsonro@cancerboard.ab.ca
with the air and only a very small fraction of a nanoparticle dose is actually deposited in the deeper areas of the lungs. The use of an aerosolized nanoparticle suspension has the disadvantage because the droplet size changes during the evaporation of the solvent at the time of administration. Therefore, it is more difficult to control how much of a dose will reach the deep areas of the lung. Most dry powder inhalers have poor aerosolization efficiency. However, recent developments in dry powder inhaler technology have made the administration of powder particles into an attractive concept [7]. In their invention, a new high efficiency device has been developed for powder aerosolization [7]. In this study, we developed nanoparticles incorporated into carrier particles using spray-drying and spray-freeze drying. The resulting powders were aerosolized by a new high efficiency device for powder aerosolization.

The aim of this study was to develop nanoparticles for lung delivery. Nanoparticles were incorporated into carrier particles using spray drying and a new spray-freeze drying technology. The carrier particles were manufactured with the appropriate size for pulmonary delivery. The new technology has important implications for local drug targeting and drug delivery of nanoparticle based delivery systems to the lungs.

The use of nanoparticles as drug targeting vectors and drug delivery devices has been studied for many years. Most studies have focused on the intravenous administration of nanoparticle suspensions [1]. However, nanoparticles have shown promising properties in overcoming multi drug resistances and poor drug solubility [2]. Furthermore, nanoparticles have shown to be promising vectors for the delivery of fragile biotechnology products [3]. Nanoparticles were used for different routes of administration e.g. intravenous, oral and transdermal [1,4]. The deposition of a particle in the lung depends on its Mass Median Aerodynamic Diameter (MMAD) [5]. Large particles are mostly deposited in the tracheo bronchial area and are cleared via the mucus within minutes. Efficient drug delivery requires small particles with an appropriate MMAD to reach the alveolar regions of the lung. The carrier particles must dissolve and release the nanoparticles in the deep areas of the lung [6]. Pulmonary delivery of nanoparticles is difficult because of their small size nanoparticles are exhaled

Fluorescent labeled poly-butylcyanoacrylate nanoparticles were synthesized by emulsion polymerization using a 10:1 mixture of dextran 70 and FITC-dextran 1% in 10 mL 0.01 N HCl and 100 L butylcyanoacrylate monomer. Fluorescent labeled gelatin nanoparticles were prepared by a two step desolvation process, described by Sham et al. [6]. The particle size was determined by laser light scattering using a Malvern Zetasizer HAS 3000. The nanoparticles were incorporated into lactose carrier particles using a Bchi min spray-dryer at a temperature of 170-180 C. The lactose particles were labeled using either carboxyflourescin or Texas Red. The same procedure was used to incorporate the nanoparticles into the carrier using a new spray-freeze drying process. In brief, the aqueous lactose

Proceedings of the 2004 International Conference on MEMS, NANO and Smart Systems (ICMENS04) 0-7695-2189-4/04 $20.00 2004 IEEE

nanoparticle mixture was atomized through a nozzle into liquid nitrogen and subsequently freeze-dried via vacuum. The carrier particles were measured using a Zeiss LSM 51 confocal laser scanning microscope. The dispersibility of the spray-dried powders was determined using a Mark II Anderson impactor in combination with a new high efficiency inhaler. A paired t-test was performed to compare the sizes of nanoparticles before spray-drying into powders and after release from dissolved powders. The same statistical method was used to compare the size of powders with and without nanoparticles at a P-value of 0.05. The MMAD was calculated by linear interpolation of the cumulative mass distribution to obtain the particle size for which the cumulative mass under this size was 50% [6].

18 16 14 Weight Fraction (%) 12 10 8 6 4 2 0 5.6 4.3 3.4 2 1.1 0.51 Cut Point (mm) Lactose & polycyanoacrylate nanoparticles Lactose Lactose & gelatin nanoparticles

Figure 2. Comparison of the powder dispersion among different spray-dried powders using an Andersen impactor (scale in m). Each bar represents the mean of three experiments standard deviation. Data from [6]. butylcyanoacrylate particles was 173.059nm before conventional spray-drying and 231.733nm after spray-drying which was a statistically insignificant difference. The mean particle size of gelatin nanoparticles increased from 242.217nm to 319.958 nm after spray-drying, which was statistically significant. This might be due to particle clusters which were not de-aggregated and could lead to an increase of the particle size. The particle size of spray-freeze dried nanoparticles was 17212 nm; the size of the non spray freeze-dried particles was 13416 nm. The powder recovery from the cascade impaction test exceeded 90% for the conventionally spray-dried carrier particles. Figure 2 shows particle fractions of particles smaller than 5.6 m. The results indicate that the fine particle fraction (FPFED<5.6m) varied within a narrow range of 38 %-42 %.

Figure 1. CLSM picture in negative S/W mode of a carrier particle containing nanoparticles. A) showing the lactose particle B) showing the nanoparticles, picture from [6].

3. Results and Discussion

The particle size of the lactose particles obtained by conventional spray-drying was independent from the presence or absence of nanoparticles. CLSM cross-sections through the powders showed that some particles were hollow while other particles had a continuous matrix. Most nanoparticles were homogeneously distributed throughout the carrier particles as shown in figure 1. However, some clusters of nanoparticles were visible within the carriers. The average size of the poly-

4. Conclusion
The present study investigated a new concept of nanoparticle delivery to the lung using micrometer sized-carrier particles. The data presented in this study show that nanoparticle delivery to the deep areas of the lung is a feasible concept if the carrier particles have an appropriate MMAD. Such a delivery system can be used to develop a new platform for pulmonary drug targeting strategies and local pulmonary drug delivery using nanoparticles as drug vectors. The use of high and low temperature spray-drying technology enables

Proceedings of the 2004 International Conference on MEMS, NANO and Smart Systems (ICMENS04) 0-7695-2189-4/04 $20.00 2004 IEEE

the incorporation of heat-stable and heat-sensitive molecules in such carrier systems. Acknowledgement: The study was supported financially by an NSERC strategic grant.

5. References.
[1] Lobenberg, R. & Kreuter, J.. Macrophage targeting of azidothymidine: a promising strategy for AIDS therapy. AIDS Res Hum Retroviruses, (1996). 12, 1709-15. [2]Vauthier, C., Dubernet, C., Chauvierre, C., Brigger, I. & Couvreur, P. Drug delivery to resistant tumors: The potential of poly(alkyl cyanoacrylate) nanoparticles. Journal of Controlled Release, (2003) 93, 151-160.

[3] Kreuter, J. Liposomes and nanoparticles as vehicles for antibiotics. Infection, (1991). 19, S224-S228. [4] Araujo, L., Sheppard, M., Lobenberg, R. & Kreuter, J. Uptake of PMMA nanoparticles from the gastrointestinal tract after oral administration to rats: Modification of the body distribution after suspension in surfactant solutions and in oil vehicles. International Journal of Pharmaceutics, (1999) 176, 209-224. [5] Finlay, W.H The Mechanics of Inhaled Pharmaceutical Aerosols: An Introduction. Academic Press. (2001) [6] Sham, J.-H., Zhang, Y., Finlay, W.H., Roa, W.H. & Lobenberg, R. Formulation and characterization of spraydried powders containing nanoparticles for aerosol delivery to the lung. International Journal of Pharmaceutics, (2004)269, 457-467. [7] Finlay, W.H. & Wang, Z. Device and method for deagglomeration of powder. In provisional patent (2002).pp. #60/430,085: Canada.

Proceedings of the 2004 International Conference on MEMS, NANO and Smart Systems (ICMENS04) 0-7695-2189-4/04 $20.00 2004 IEEE