Inhaled dry powder aerosols are effective therapeutic carriers for target-specific treatments of various pulmonary diseases, such as asthma, cystic fibrosis, chronic pulmonary infections, lung cancer, etc. Owing to high permeability of human lungs epithelia toward therapeutic agents, inhaled dry powder aerosols also serve as an attractive alternative to oral and parenteral routes for systemic delivery of biotherapeutic agents i.e. insulin, growth hormone, proteins, peptides, etc. that currently can only be delivered through gastrointestinal tract or parenterally by either intravenous or intramuscular injections.1 The effectiveness of inhaled aerosol drug delivery largely depends on its ability to provide a controlled and sustained release of the therapeutic agents once they reach the lungs. Furthermore, the inhaled aerosols must be able to escape the natural clearance mechanisms in the lungs i.e. mucociliary and phagocytic clearances until the drugs have been effectively delivered. In addition, the inhaled aerosols must possess a very narrow range of aerodynamic diameters (1< <3 ) in order to minimize deposition of the aerosols in the mouth-throat region; hence maximize the deposition in the targeted deep-lung or alveolar region. The aerodynamic diameter given in Equation (1) is defined as the diameter of a unit density spherical particle that settles through the air with the velocity equal to that of the particle in question. The aerodynamic diameter is used to characterize the distance travelled by the inhaled particles in the human respiratory airways. (1) where and are the particle geometric diameter and the particle mass density, respectively. In order to accommodate the narrow range of the aerodynamic diameters, aerosol particle design engages two strategies. The first strategy is where the particles are made with standard mass density and geometric diameter in the range of 1 to 3 . In the second strategy, the particles are made with much lower mass density , but with larger geometric diameter ( >5 ), such that both strategies result in particles having the same aerodynamic diameters .The first strategy in which small non-hollow drug particles are formulated has been the conventional approach due to its simpler manufacturing process. However, their small size leads to a severe aggregation problem that makes physical handling of the particles difficult and results in very low aerosolization efficiency. Also, because of their small size, a large fraction of these particles can hardly avoid the phagocytic clearance mechanism taking place in the lung alveolar region due to the scavenging macrophages, which are capable of engulfing foreign substances smaller than 5 in diameter.2 The resulting low therapeutic efficacy leads to a high inhaled dose requirement for the drug to have its therapeutic effects. On the other hand, the second strategy has shown that large hollow particles ( ) having very low mass density aggregate less and de-aggregate more easily under shear forces, which result in a higher aerosolization efficiency than the small non-hollow particles with the same aerodynamic diameters.3 More importantly, by virtue of their larger size, these large hollow particles are capable of avoiding the phagocytic clearance mechanism more effectively, which improves the therapeutic efficacy of the inhaled drugs. Due to rapid advances in nanotechnology, the use of inhaled aerosol nanoparticles as therapeutic carriers has the promise to be a subject of very active research.4, 5 The therapeutic agents can be either dispersed within the matrix of polymer or protein-based nanoparticles carriers or adsorbed on the surface of the nanoparticles carriers.6 Inhaled drug nanoparticles have an enormous potential in significantly improving the drug systemic bioavailability, which is defined as the rate and extent of the therapeutically active drug that reaches the systemic circulation.7 The high systemic bioavailability of the nanoparticles drugs is attributed to their higher dissolution rate in the aqueous environment of the lungs epithelia as a result of their larger surface areas compared to the micron-size particles.8 In addition, colloidal surface properties of the nanoparticles enable them to overcome both the mucociliary and phagocytic clearance mechanisms of the lungs5, so that they can reach the desired targets more effectively compared to the micron-size particles.6 However, aerosol nanoparticles still present a serious segregation problem and are predominantly exhaled from the lungs due to their extremely low inertia. Therefore, formulation of micron-size particles as carriers of drug nanoparticles is necessary in order to deliver the drug nanoparticles by inhalation. The approach pursued in this work is to combine the high aerosolization efficiency and therapeutic efficacy of the large hollow porous particles with the high systemic bioavailability of the nanoparticles. Large hollow micron-size particles, whose shells are made up of nanoparticles aggregates, have been formulated employing the spray drying technique. The spray-drying technique is employed in the study due to its one-step process simplicity, cost effectiveness and scale-up capability. Once these carrier particles are deposited in the aqueous environment of the lungs epithelia, they disassociate to disperse the nanoparticles. The study includes formulation using a wide range of nanoparticles having different chemical natures (polymers and colloidal silica), sizes and concentrations. The objective of the study is to examine the effects of chemical nature, size and concentration of the nanoparticles, and also the spray drying operating conditions on the carrier particles assembly. In the study, the morphology of the particles is characterized using scanning electron microscope, the average geometric size of the particles are measured using Malvern's Master and Zeta Sizers for micron and nano-size particles, respectively. The aerodynamic diameter is determined using TSI's Particle Aerodynamic Sizer. To quantify the degree of hollowness, the bulk and true densities of the particles are determined using auto-tap density meter and pycnometer, respectively.

References:

1) Edwards D.A. Delivery of Biological Agents by Aerosols. AIChE Journal. 2002, 48 (1), 2-6. 2) Hardy J.G.; Chadwick T.S. Sustained Release of Drug Delivery to the Lungs. Clin. Pharmacokinetics. 2000, 39, 1-4. 3) Edwards D.A.; Hanes J.; Caponetti G.; Hrkach J.; Ben-Jebria A.; Eskew M.; Mintzes J.; Deaver D.; Lotan N.; Langer R. Large Porous Particles for Pulmonary Drug Delivery. Science. 1997, 276, 1868-1871. 4) Tsapis N.; Bennet D.; Jackson B.; Weitz D.A.; Edwards D.A. Trojan Particles: Large Porous Carriers of Nanoparticles for Drug Delivery. Proceeding of National Academy of Sciences. 2002, 99 (19), 12001-12005. 5) Sham J.; Zhang Y.; Finlay W.; Roa W.; LÖbenberg R. Formulation and Characterization of Spray-Dried Powders Containing Nanoparticles for Aerosol Delivery to the Lung. Intl. J. Pharmaceutics. 2004, 269, 457-467. 6) Chattopadhyay P.; Gupta R.B. Production of Antibiotic Nanoparticles Using Supercritical CO2 as Antisolvent with Enhanced Mass Transfer. Ind. Eng. Chem. Res. 2001, 40, 3530-3539. 7) Shargel L.; Yu A.B. Applied Biopharmaceutics & Pharmacokinetics 4th Edition; McGraw Hill: New York, 1999. 8) Lee J.H. Drug Nano and Microparticles Processed into Solid Dosage Forms: Physical Properties. J. Pharmaceutical Sciences. 2003, 92 (10), 2057-2068.

Extended Abstract Status: Not Uploaded