AEROSOL INHALERS

There are three aerosol inhalers designed for pulmonary delivery: the small volume nebulizer, the MDI, and the DPI [173-176]. And “aerosol device” refers to a nebulizer, while “inhaler” most often refers to an MDI; generally, all are classified as aerosol inhalers [117]. Additionally, aerosol refers to a suspension of liquid or solid particles in a carrier gas, not necessarily a liquid spray. Microspray devices have also been developed, which use room air or mechanical force to create pulmonary mists or clouds without another carrier gas or propellant, but these devices have not seen widespread adoption outside controlled research settings due to cost and availability [177].

Each of the commonly encountered aerosol devices has distinctive performance characteristics, making the choice of the system used dependent not only on the solution to be aerosolized but also on the intended target, particle size, etc. Since there is substantial drug loss in the oropharynx, holding chambers and spacers are utilized on many MDIs, which results in a large amount of wastage of the active drug. Also, there are several generalizable advantages and disadvantages of the inhalation route.

The main advantage of aerosol administration over systemic administration is that aerosol doses are usually lower than systemic doses to achieve the same efficacy resulting in considerably less wastage of drug and/or lower drug costs. Also, the drug is carried directly to the desired location limiting the time to onset for the patient primarily due to limiting transit time from the GI tract to the blood stream, that is, the onset of action for inhaled agents is much quicker than an oral dosage regimen (albuterol takes 30 min or less to take effect if taken orally while inhaled albuterol takes 5 min to achieve therapeutic effect in the lung) [178,179]. Some disadvantages are that lung deposition is a relatively low fraction of the total aerosol dose, so there is typically some amount of drug/vaccine loss, and many variables such as breathing pattern among individuals and mucous viscosity and thickness can affect lung deposition and dose reproducibility.

Particle size, particle velocity, and settling times are important in aerosol deposition in the airways [20,78,175,180,181]. Particle deposition in the oropharyngeal cavity increases with large diameter particles (those above 5 qm), while expiration removes particles 1 qm or less; particles 1-5 qm can readily spread in the lung with those 5-10 qm in diameter mostly ending up in larger airways [180,182].

Many aerosolization devices utilize compressed air to disperse dry powders to deliver drugs or vaccines into a spacer before inhalation [183]. The location of deposition of aerosol particles varies with the particle size where particles <10 pm have an increased likelihood of reaching the lower airways [184]. Vaccine deposition in the lungs or lower airways is neither required nor advantageous (and actually may be contraindicated for optimal vaccine efficacy) as most LAIV and related vaccines are not designed to replicate outside of the nasopharynx [103]. Large particle size reduces the likelihood of delivery to the lower lungs, which is a safety benefit.

Notably, there are three major limitations of DPIs: exposure to moisture, chemi- cal/electrostatic interactions between the drug molecules themselves as well as to the administration device, and a dependence on the person’s inspiratory volume that is often limited in both acute and chronic lung disease conditions [185,186]. Further, DPIs are extremely susceptible to moisture accumulation on the unit during exhalation, which means users have to consciously remember to exhale away from the mouthpiece of the DPI unit in order to minimize drug loss due to wetting of the surfaces by previous exhalation. Last, DPIs depend on reasonable inspiration volume, so there is a legitimate question as to whether the very young and very old can generate the tidal volume necessary to achieve optimal dosing with these devices [185].

Nebulization is one of the earliest techniques used to deliver liquid formulations as aerosols. Nebulizers are distinctly different from inhalers in that they typically use battery or mechanical power to convert a liquid solution into a fine mist (in some cases via the generation and incorporation of a compressed gas) and deliver it via a mouthpiece or face mask, instead of a pressurized carrier gas as with most inhalers. Multiple types of nebulizers are commercially available including jet, ultrasonic wave, vibrating mesh, and human powered, as well as several relying on mechanical force [100,187]. However, significant disparities exist in the overall size distribution of droplets and/or particles that an individual nebulizer can generate based mainly on the method used to generate the aerosol [187]. As such, picking a nebulizer suited not only to the liquid being aerosolized but also to the downstream host requirements relative to target area in the respiratory tract, optimum particle size for effective uptake, and potential interactions with host defense mechanisms is critically important to ensure maximal drug or vaccine efficacy. Historically, nebulization was used as a first step in many clinical trials followed quickly by the development of specific inhalers for the drug of interest, due primarily to the lack of portability of many nebulization units as well as their cost and ease of use relative to handheld inhalers. However, nebulizers based on more recent technology may supplant the need for a transition to MDIs as well as allow for a larger array of drugs and vaccines to be delivered via nebulization, including many that are not readily amenable to conversion to an inhaler-based delivery system due to solubility, viscosity, etc.