Airway Selectivity: An Update of Pharmacokinetic Factors Affecting Local and Systemic Disposition of Inhaled Steroids

Abstract

Topical corticosteroids remain the most efficacious single treatment for asthma and rhinitis, despite the emergence of newer drugs in recent years. The antiinflammatory properties of these products, combined with the targeting of formulations and optimization of the intrinsic pharmacokinetic features of the newer corticosteroid molecules has resulted in substantially improved airway selectivity. This review sets out to summarize the pharmacokinetic properties of inhaled corticosteroids that are important for the achievement of high levels of airway selectivity, with additional focus on the use of prodrugs/softdrugs relative to those of conventional corticosteroid molecules, mechanisms (such as esterification) by which retention at the target site is achieved while minimizing systemic exposure, and the role of plasma protein binding.

In Vitro Aqueous Fluid-Capacity-Limited Dissolution Testing of Respirable Aerosol Drug Particles Generated from Inhaler Products

“…Aerosol drug particles generated from inhaler products may alter their dissolution kinetically (e.g., rate, extent and/or apparent order) from the bulk drug materials due to different crystallinity, wettability and/or solubility by polymorphism, amorphism and/or formulation excipients, as a result of aerosol generation (4)(5)(6)(7)(8)14). Such dissolution kinetics could be also dependent upon the aerosol particle size and distribution, as the surface area per unit weight is greater for the smaller-size aerosol particles.…”

“…Moreover, the use of the flow-through dissolution system provided rather favorable flowing fluid dynamics that were unlimited in volume for dissolution. On the contrary, the lung lining fluid is known to be fairly stationary and limited in volume only by 10-30 ml in humans, which should serve the maximum dissolution capacity for deposited drugs (4,6,8). Therefore, ideally, the method should enable the kinetic assessments of dissolution for defined-size and respirable aerosol drug particles generated from inhaler products, into the limited volume of the stationary fluid, like actual aerosol particle dissolution on the lung surface.…”

“…Two most popular inhaled dosage forms are pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs), both of which deliver their APIs, along with formulation excipients, onto the lung surface in a solid or semi-solid form. Hence, the lung cellular disposition of such inhaled molecules (i.e., APIs) can be considered as a sequential cascade of aerosol deposition onto, and API dissolution into, the limited volume of the lung lining fluid (10-30 ml in humans), preceding cellular uptake and/or absorption (4). In this context, evidence exists in the literature that the aqueous solubility values of APIs for inhaled dosage forms are considerably diverse and possibly altered by formulation excipients and/or via aerosol generation (4)(5)(6)(7)(8).…”

“…Hence, the lung cellular disposition of such inhaled molecules (i.e., APIs) can be considered as a sequential cascade of aerosol deposition onto, and API dissolution into, the limited volume of the lung lining fluid (10-30 ml in humans), preceding cellular uptake and/or absorption (4). In this context, evidence exists in the literature that the aqueous solubility values of APIs for inhaled dosage forms are considerably diverse and possibly altered by formulation excipients and/or via aerosol generation (4)(5)(6)(7)(8). As a result, the kinetics of dissolution for such aerosol particles could differ from those for the APIs, and in certain cases, rate-determining in their lung biopharmaceutics following inhalation (6)(7)(8).…”

New techniques for studying airway drug pharmacokinetics for asthma therapeutics

“…Lung deposition and retention: patient inhalation technique and the inhaler device (whether a nebulizer, pressurized metered dose inhaler (pMDI), or dry powder inhaler (DPI)) affect the variability in drug dosing; lung retention differs when a drug is inhaled vs. other routes of administration, e.g. through slow dissolution or lung metabolism such as reversible esterification [1]. b. Bioavailability: for drugs not metabolized in the lung, the efficiency of dose delivery via inhalation can generally be determined by the lung availability, but pulmonary metabolism and mucociliary clearance may reduce availability.…”