Poly(d,l-lactide-co-glycolide) Nanoparticle Agglomerates as Carriers in Dry Powder Aerosol Formulation of Proteins

Abstract

A dry powder aerosol drug delivery system was designed with both nano- and microstructure to maximize the protein loading via surface adsorption and to facilitate delivery to the deep lung, respectively. Ovalbumin was employed as a model protein to adsorb to and controllably flocculate DOTAP-coated PLG nanoparticles into “nanoclusters” possessing low density microstructure. The mechanism of nanoparticle flocculation was probed by evaluating the effects of ionic strength, shear force, and protein concentration on the geometric and aerodynamic diameters of the nanoclusters as well as the protein adsorption efficiency. Salt ions were found to compete with ovalbumin adsorption to nanoparticles and facilitate flocculation; therefore, formulation of nanoclusters for inhaled drug delivery may require the lowest possible ionic strength to maximize protein adsorption. Additional factors, such as shear force and total protein–particle concentration can be altered to optimize nanocluster size, suggesting the possibility of regional lung delivery. Immediate release of ovalbumin was observed, and native protein structure upon release was confirmed by circular dichroism and fluorescence spectroscopy studies. Controlled flocculation of nanoparticles may provide a useful alternative to spray drying when formulating dry powders for pulmonary or nasal administration of protein therapeutics or antigens.

Evaluating the Controlled Release Properties of Inhaled Nanoparticles Using Isolated, Perfused, and Ventilated Lung Models

“…Positively-and negatively charged biodegradable nanoparticles are brought into contact under vigorous stirring, and spontaneous composite microparticle formation takes place. Nanoparticle aggregation is driven by electrostatic attraction/forces in this case [129,130].…”

Effect of Particle Formulation on Dry Powder Inhalation Efficiency

“…Despite the fact that particles less than 1 μm have challenging delivery limitations, nanoparticles have attracted considerable interest in the dry powder inhalation application [13,73,140,[165][166][167][168][169][170][171][172][173][174][175][176][177][178][179][180][181][182]. Nanoparticles fall in the same size range of different cell organs like ribosomes, cell receptor, transporter, etc.…”

“…It is reported that small nanoparticles have slower clearance than large nanoparticles in the size range of 20-200 nm [203]. rifampicin with PLGA (poly (lactic-coglycolide)) [165], chitosan with lactose and mannitol [176,181], insulin [170], ovalbumin [169], doxorubicin [178] etc. Though nanoparticles pose several health risks such as toxicity and instability [205,206], it provides immense promise in aerosol therapeutics field.…”

Templated Open Flocs of Anisotropic Particles for Pulmonary Delivery with Pressurized Metered Dose Inhalers

“…27 Additionally, high FPFs are achieved with the hollow, porous particles when delivered as a pMDI, ranging from 40% to 70% for a wide variety of drugs. 17,[27][28][29] Particles with a similar morphology to hollow, porous particles include large porous particles (LPP) 4,18 and large porous nanoparticle (LPNP) aggregates, [30][31][32][33][34] which are produced by spray drying and have sizes ranging from 10 to 20 mm. These powders exhibit FPFs as high as 60% when administered as a dry powder due to their low density (<0.4 g/ cm 3 ).…”