Designing Aerosols for Improved Dispersion

Atomization. The main mechanism used for deaggregation of aerosol particles is the atomization process. Various mechanisms, such as a turbulent airstream and ultrasonication, are used in inhaler devices to separate dry particles or create fine liquid droplets. Methods of aerosol generation and the characterization of the various inhalers are available elsewhere [264].

Inhalation Flowrate. Particles that do not deaggregate upon atomization must separate within the oropharyngeal cavity to avoid excessive deposition in the mouth and throat. Increasing inspiratory flowrate can significantly help separate aggregated particles. By numerical simulation, Li et al. determined that dry particles less than 10 mm in diameter have little chance of deaggregation in the mouth and throat at flowrates of 30L/min or less [52]. Flow rates of 60L/min or higher were necessary for these particles to separate and may be required for particles to deposit in the deep lung [271]. Their results were consistent with the high flowrates needed for proper function of dry powder inhalers [272].

Physical Properties of Aerosols. Physical properties of aerosols, including size, shape, and surface roughness, are important factors in determining aerosol deaggregation [273]. Traditionally, aerosols under investigation for therapeutic purposes were small, dense particles or droplets. However, large, low-density particles with aerodynamic diameters between 2 and 5 mm have more recently shown considerable potential for alveolar deposition and systemic delivery [263,274]. Particle aggregation due to van der Waals forces is greatly reduced with larger particles, resulting in an increase in aerosolization efficiency [275]. The number of contact points between particles per unit volume is smaller for larger particles, thus decreasing the net interparticle force. Similarly, hollow, porous particles dispersed in a propellant (for use in a metered-dose inhaler) possessed decreased interparticle attractive forces, which improved their delivery efficiency to the lung [276,277].

Particles that are elongated or have flat edges tend to align along their long axis, thereby increasing their contact area and adhesive force [278]. Similarly, irregularly shaped particles typically have a decrease in adhesion force due to a reduction in their contact area [268]. A rough surface tends to decrease the force of adhesion in the absence of capillary forces, due to a reduced area of surface contact [279-281]. However, if surface asperities become too large, interparticle adhesion may increase, owing to an increase in surface contact area as smaller particles nest within the asperities [268].

Chemical Properties of Aerosols. Surface chemical properties of aerosol particles can also be tailored to improve deaggregation [273]. Hygroscopic particles absorb water when inhaled into the humid airways [282-284], increasing particle size and density in the process, as well as creating the potential for capillary bridge formation between particles. Hygroscopic growth can be reduced by the use of hydrophobic additives [285] or compounds with low aqueous solubility [286,287].

The adsorption or incorporation of molecules, such as surfactants and polymers, can create a steric repulsion that prevents aggregation [288-290]. This can also increase suspension stability, important for metered-dose inhaler formulations [291]. Lung surfactant coating on the surface of poly(lactic-co-glycolic) acid microparticles has been shown to dramatically improve dry powder aerosol performance by reducing particle-particle interactions [134,292].

New Polymers for Controlled Delivery Via the Lung. New materials can be created to tailor particle surface properties. In addition, producing materials that can achieve sustained release is important in gene therapy, since gene expression is often inadequately brief [213]. Toward this end, we have recently synthesized a new family of biodegradable poly(ether-anhydrides) composed of monomers with FDA approval for other uses: 1,3-bis(carboxyphenoxy)propane (CPP), sebacic acid (SA), and poly(ethylene glycol) (PEG) [229,293]. Sebacic acid is a flexible monomer that allows polymerization of high-molecular-weight polymers and imparts improved solubility and mechanical strength to the polymers; CPP is a hydrophobic monomer, which adds control over degradation time scales of the polymer (higher amounts of CPP in the polymer led to longer release times); PEG allows control of the hydrophilicity of polymer particulates, which in turn significantly improves particle aerosolization efficiency by decreasing aggregation due to VDW forces [262]. PEG may also create a steric repulsion that does not allow particles to come into direct contact, thereby reducing adhesion forces. The new polymers were used to encapsulate plasmid DNA into exceptionally large ( ~ 5-15 mm) and light (< 0.4 g/cm3)

aerosol carriers for controlled delivery to the lung [293]. Particles were made with aerodynamic diameters appropriate for targeted delivery to either the upper airways or the deep lung. By changing the ratio of monomers in backbone, we were able to control the degradation and erosion of the polymer, thereby controlling the release of DNA for up to one week in a continuous fashion.

In a related study, PEI was used to complex LacZ plasmid DNA and the resulting complexes were encapsulated within porous polymeric microparticles with properties suitable for efficient inhalation [294]. Microparticle sizes were between 1 and 10 |m, but their density was much lower, leading to aerodynamic diameters in the range appropriate for delivery to the lung. Time-resolved multiangle laser light scattering (TR-MALLS) was used to show that 150 nm PEI/DNA complexes were encapsulated and subsequently released for more than 75 days in vitro. Released complexes were capable of transfection over the entire period of release in both HeLa and Cos-7 cells. The longest previous release of active DNA from biodegradable microparticles was only 21 days and used naked DNA.

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