dissolution testing is well established for solid oral dosage forms as both a quality control test to assess batch-to-batch consistency and to predict in vivo
drug release profiles for both immediate and modified release dosage forms (1
). For many solid oral products, an in vitro–in vivo
correlation can be established between in vitro
dissolution data and pharmacokinetic (PK) data. Such a correlation enables use of dissolution data as an important tool for assessing postapproval changes to the formulation or manufacturing process, as well as for the development and approval of generic products.
The clinical safety and efficacy of orally inhaled products (OIPs) is understood to be influenced by the total aerosolized dose delivered to lung and by the aerodynamic particle size distribution (APSD). Consequently, dose content uniformity and APSD are generally viewed as critical quality attributes of inhaled products and corresponding testing is required by regulatory guidances for characterization and quality control purposes (3
). Testing for these attributes is also required for demonstrating in vitro
equivalence of generic/second-entry or modified OIPs to the original (reference) product (7
), with an understanding that these in vitro
tests are not fully predictive of in vivo
performance and that in vivo
assessment may also be required. In particular, it has been emphasized that multistage cascade impactors are not surrogates for the human respiratory system and that an APSD does not have a direct relationship to pulmonary deposition profile (11
Many commonly used inhaled products such as metered-dose inhalers (MDIs), dry powder inhalers (DPIs) and suspensions for nebulization deliver the active pharmaceutical ingredient (API) to the lung in a solid form. A variety of competing mechanisms exist for the clearance of aerosol particles after deposition in the airways (13
). Undissolved particles may be cleared either from the conducting airways by the mucociliary escalator to the trachea and into the gastrointestinal tract or from the lower airways by uptake into alveolar macrophages and elimination through the lymphatic system. However, the bioavailability and therapeutic action, as well as systemic absorption of inhaled APIs, depend on the dissolution of the deposited aerosol particles in the limited volume of fluid that lines the respiratory tract.
Currently, there are no regulatory requirements or pharmacopeial techniques for dissolution testing of OIPs. In 2008, the Inhalation Ad Hoc
Advisory Panel of USP evaluated the scientific rationale for in vitro
dissolution tests for inhalation dosage forms and concluded that there was no compelling evidence that dissolution was “kinetically and/or clinically crucial for currently approved” OIPs (14
). Nevertheless, there has continued to be considerable academic and industrial interest in the development of in vitro
techniques to determine the dissolution profile of inhaled products (15
The nature and strength of relationships among dissolution and PK, pharmacodynamic (PD), and/or other clinical data have yet to be demonstrated, and they may well be product- and patient-specific, i.e., dependent on the inhalation maneuver, inspiratory flow profile, physiology and anatomy of lungs in the target population, treated condition (e.g., asthma vs COPD), disease state (moderate vs severe), etc.
The purpose of this article is to review the suitability of the analytical and statistical techniques that have been developed to date to assess the dissolution behavior of particles in the respirable aerodynamic size range. The current state of knowledge concerning clinical relevance of dissolution data is discussed with the objective of making a recommendation on the utility of measuring dissolution profiles for orally inhaled products.
This article is authored by the Dissolution Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS), which is an international association of companies that develop and manufacture OIPs.