Langmuir 2007, 23, 10897-10901
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Biodegradable Nanoparticle Flocculates for Dry Powder Aerosol Formulation Lianjun Shi, Carl J. Plumley, and Cory Berkland* Department of Chemical and Petroleum Engineering, and Department of Pharmaceutical Chemistry, The UniVersity of Kansas, Lawrence, Kansas 66047 ReceiVed July 5, 2007. In Final Form: August 31, 2007 Uncontrolled agglomeration presents a formidable encumbrance to nanoparticle formulation as a dry powder for inhalation therapy. Spray-drying and freeze-drying of nanosuspensions has demonstrated some success in creating dry powders composed of agglomerated nanoparticles with appropriate aerodynamic properties. These controlled drying processes, however, may require an undesirable amount of excipient to maintain an active therapeutic while generating dry powders and may not offer the desired control over agglomerate size and aerosolizability. As a potential alternative approach, a method for flocculating nanoparticles in solution followed by freeze-drying is reported. Biodegradable poly(DL-lactic-co-glycolic acid) nanoparticles were self-assembled into flocs via electrostatic interactions between nanoparticles coated with oppositely charged polyelectrolytes. The size of the nanoparticle flocs was readily controlled by manipulating the mixing ratio of charged nanoparticles. Freeze-drying the flocculated nanoparticles produced dry powders exhibiting low density (∼0.1 g/cm3), a weblike morphology, and desirable aerodynamic properties suited for dry powder aerosols.
Introduction Nanoparticle technology is dramatically impacting the pharmaceutical industry.1 Particles at this scale facilitate dissolution of poorly water soluble drugs2,3 and may be designed to selectively extravasate,4 permeate tissue,5 and enter cells.6 A common problem with nanoparticles is their propensity to agglomerate, often irreversibly, upon drying or lyophilization. A wave of research has attempted to address this issue by employing surface stabilizers7 or lyoprotectants8 to enable efficient nanoparticle redispersion. Contrary to this effort, micrometer-sized nanoparticle agglomerates may be preferred for certain indications, such as dry powder formulations for inhalation therapy. Controlling nanoparticle assembly a priori via flocculation produces agglomerates or “floc” with distinct micro- and nanostructure, which may be discretely leveraged to modulate the dried powder aerosol properties and drug pharmacokinetics, respectively. We demonstrate the effect of nanoparticle concentration on the flocculation of oppositely charged poly(DL-lactic-co-glycolic acid) * To whom correspondence should be addressed. The University of Kansas, 2030 Becker Drive, Lawrence, Kansas 66047. Phone: (785) 864-1455. Fax: (785) 864-1454. E-mail:
[email protected]. (1) Rabinow, B. E. Nanosuspensions in drug delivery. Nat. ReV. Drug DiscoVery 2004, 3 (9), 785-796. (2) Hoeben, B. J.; Burgess, D. S.; McConville, J. T.; Najvar, L. K.; Talbert, R. L.; Peters, J. I.; Wiederhold, N. P.; Frei, B. L.; Graybill, J. R.; Bocanegra, R.; Overhoff, K. A.; Sinswat, P.; Johnston, K. P.; Williams, R. O. 3rd In vivo efficacy of aerosolized nanostructured itraconazole formulations for prevention of invasive pulmonary aspergillosis. Antimicrob. Agents Chemother. 2006, 50 (4), 15521554. (3) Xie, J.; Wang, C. H. Self-assembled biodegradable nanoparticles developed by direct dialysis for the delivery of paclitaxel. Pharm. Res. 2005, 22 (12), 20792090. (4) Son, Y. J.; Jang, J. S.; Cho, Y. W.; Chung, H.; Park, R. W.; Kwon, I. C.; Kim, I. S.; Park, J. Y.; Seo, S. B.; Park, C. R.; Jeong, S. Y. Biodistribution and anti-tumor efficacy of doxorubicin loaded glycol-chitosan nanoaggregates by EPR effect. J. Controlled Release 2003, 91 (1-2), 135-145. (5) Loo, C.; Lowery, A.; Halas, N.; West, J.; Drezek, R. Immunotargeted nanoshells for integrated cancer imaging and therapy. Nano Lett. 2005, 5 (4), 709-711. (6) Panyam, J.; Labhasetwar, V. Sustained cytoplasmic delivery of drugs with intracellular receptors using biodegradable nanoparticles. Mol. Pharm. 2004, 1 (1), 77-84. (7) Sommerfeld, P.; Sabel, B. A.; Schroeder, U. Long-term stability of PBCA nanoparticle suspensions. J. Microencapsul. 2000, 17 (1), 69-79. (8) Wendorf, J.; Singh, M.; Chesko, J.; Kazzaz, J.; Soewanan, E.; Ugozzoli, M.; O’Hagan, D. J. Pharm. Sci. 2006, 95 (12), 2738-2750.
(PLGA) nanoparticles and provide an analysis of the resulting powder properties. The pulmonary system represents a largely untapped avenue of local and systemic therapy.9 Exciting possibilities exist for locally treating cystic fibrosis, asthma, or even lung cancer or for delivering large immunoglobulins or genetic material across the thin lung epithelium.10-13 A major deterrent to utilizing the lung for systemic drug delivery is the inability to efficiently deliver drugs into the deep lung periphery.14-16 It is wellestablished that particles exhibiting an aerodynamic diameter from 1 to 5 µm are more likely to bypass the filtering mechanism of the mouth and throat, resulting in increased “deep lung” deposition.17 Conventional particle processing techniques rely on crushing, grinding, milling, or spray-drying. Such methods typically produce broad particle size distributions with only small percentages of particles in the desired size range.18 Recently, researchers have engineered particle microstructure as a method to effectively deliver drugs to the deep lung. For (9) Labiris, N. R.; Dolovich, M. B. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br. J. Clin. Pharmacol. 2003, 56 (6), 588-599. (10) Gautam, A.; Waldrep, C. J.; Densmore, C. L. Delivery systems for pulmonary gene therapy. Am. J. Respir. Med. 2002, 1 (1), 35-46. (11) Densmore, C. L. The re-emergence of aerosol gene delivery: a viable approach to lung cancer therapy. Curr. Cancer Drug Targets 2003, 3 (4), 275286. (12) Yoshizawa, Y.; Ohtani, Y.; Inoue, T.; Miyake, S.; Ikeda, A.; Tanba, M.; Kurup, V. P. Immune responsiveness to inhaled antigens: local antibody production in the respiratory tract in health and lung diseases. Clin. Exp. Immunol. 1995, 100 (3), 395-400. (13) Geller, D. E.; Rosenfeld, M.; Waltz, D. A.; Wilmott, R. W. Efficiency of pulmonary administration of tobramycin solution for inhalation in cystic fibrosis using an improved drug delivery system. Chest 2003, 123 (1), 28-36. (14) Edwards, D. A.; Hanes, J.; Caponetti, G.; Hrkach, J.; Ben-Jebria, A.; Eskew, M. L.; Mintzes, J.; Deaver, D.; Lotan, N.; Langer, R. Large porous particles for pulmonary drug delivery. Science 1997, 276, 1868-1871. (15) Newman, S. P. Drug delivery to the lungs from dry powder inhalers. Curr. Opin. Pulm. Med. 9 Suppl. 2003, 1, S17-20. (16) Newman, S. P.; Pitcairn, G. R.; Hirst, P. H.; Bacon, R. E.; O’Keefe, E.; Reiners, M.; Hermann, R. Scintigraphic comparison of budesonide deposition from two dry powder inhalers. Eur. Respir. J. 2000, 16 (1), 178-183. (17) Pritchard, J. N. The influence of lung deposition on clinical response. J. Aerosol Med. 14 Suppl. 2001, 1, S19-26. (18) Rasenack, N.; Muller, B. W. Micron-size drug particles: common and novel micronization techniques. Pharm. DeV. Technol. 2004, 9 (1), 1-13.
10.1021/la7020098 CCC: $37.00 © 2007 American Chemical Society Published on Web 09/26/2007
10898 Langmuir, Vol. 23, No. 22, 2007
Letters
example, porous microparticles possess large geometric diameters,14,19,20 but exhibit much smaller aerodynamic diameters as described by the equation
daero ) dgeo
( ) Fparticle Fref ‚ γ
Table 1. PLGA Nanoparticle Properties PLGA zanoparticle
size (nm)a
zeta potential (mV)
PVAm-coated PEMA-coated
498.5 ( 8.4 262.7 ( 11.3
+30.7 ( 1.0 -52.3 ( 1.2
1/2
(1)
where daero is the aerodynamic particle diameter, dgeo is the geometric particle diameter, F is the particle density, Fref is a reference density (typically 1 g/cm3), and γ is a shape factor (typically 1 for a sphere). These “large porous” particles possess geometric diameters of >10-20 µm, thus reducing powder agglomeration, improving powder flow, decreasing clearance by alveolar macrophages, and improving powder deposition.14 Nanoparticles have been somewhat disregarded in dry powder formulations, since particles of
