Challenges with Developing In Vitro Dissolution Tests for Orally Inhaled Products (OIPs)

Abstract

The purpose of this article is to review the suitability of the analytical and statistical techniques that have thus far been developed to assess the dissolution behavior of particles in the respirable aerodynamic size range, as generated by orally inhaled products (OIPs) such as metered-dose inhalers and dry powder inhalers. The review encompasses all analytical techniques publicized to date, namely, those using paddle-over-disk USP 2 dissolution apparatus, flow-through cell dissolution apparatus, and diffusion cell apparatus. The available techniques may have research value for both industry and academia, especially when developing modified-release formulations. The choice of a method should be guided by the question(s) that the research strives to answer, as well as by the strengths and weaknesses of the available techniques. There is still insufficient knowledge, however, for translating the dissolution data into statements about quality, performance, safety, or efficacy of OIPs in general. Any attempts to standardize a dissolution method for compendial inclusion or compendial use would therefore be premature. This review reinforces and expands on the 2008 stimulus article of the USP Inhalation Ad Hoc Advisory Panel, which "could not find compelling evidence suggesting that such dissolution testing is kinetically and/or clinically crucial for currently approved inhalation drug products."

In Vitro Testing for Orally Inhaled Products: Developments in Science-Based Regulatory Approaches

“…A working group of IPAC-RS concluded in 2012 that any attempts to standardize a dissolution method for compendial inclusion would be premature since there is insufficient knowledge to translate dissolution data into statements about quality, safety, and efficacy (36). Forbes (11) presented on the difficulty in relating in vitro dissolution data to therapeutic effect.…”

“…For example, epithelial permeability for many compounds (depending upon molecular properties) is significantly higher in respiratory regions compared to the conducting airways and permeation could conceivably replace dissolution as the rate limiting step as the deposition site moves from peripheral to central lung. Causality between rate of dissolution and the clinical performance of an OIP is complex, but differences in dissolution rate between different OIP's with otherwise similar aerosol performance (with potential effects on local and systemic bioavailability, and drug safety) have been demonstrated in several recent publications (11,25,(35)(36)(37)(38). A variety of dissolution test methods have been developed (35)(36)(37)(38)(39)(40)(41), and it is generally accepted that these methods may have value, even if they are not strictly in vivo predictive, by discriminating between formulations with similar aerodynamic properties but different release properties.…”

In Vitro–In Vivo Correlation: Shades on Some Non-Conventional Dosage Forms

“…However, its relevance to the biological situation is a matter of discussion (17,18). The USP Inhalation Ad Hoc Advisory Panel "could not find compelling evidence suggesting that such dissolution testing is kinetically and/or clinically crucial for currently approved inhalation drug products (19). "…”

Meeting Report: AAPS Workshop on Inhalation Product Biopharmaceutical Classification System Development: Challenges and Opportunities

“…Examples of this idea are improving absorption across the air-blood barrier, controlling and avoiding pulmonary clearance, and cell-specific targeting. Dissolution testing of inhalation products was described in historical terms where in 2008, an ad hoc advisory panel of the USP stated there was no need for dissolution testing of the products presently on (2), flowthrough cell (3-5), USP Apparatus 2 (4-6), Franz cell (4,5), and Transwell (7,8) were in the literature. He concluded with recent applications of inhalation nanocarriers for advanced pulmonary drug delivery.…”

“…He first asked if particle dissolution would be a critical quality attribute (CQA) in the Quality by Design (QbD) of orally inhaled products (OIP). He mentioned that there are currently no regulatory requirements or pharmaceutical techniques for dissolution testing of OIPs (8). He quoted the 2008 publication that states that there was no compelling evidence that dissolution was "kinetically and/ or clinically critical for currently approved" OIPs (1).…”