iBCS: 1. Principles and Framework of an Inhalation-Based Biopharmaceutics Classification System

Abstract

For oral drugs, the formulator and discovery chemist have a tool available to them that can be used to navigate the risks associated with the selection and development of immediate release oral drugs and drug products. This tool is the biopharmaceutics classification system (giBCS). Unfortunately, no such classification system exists for inhaled drugs. The perspective outlined in this manuscript provides the foundational principles and framework for a classification system for inhaled drugs. The proposed classification system, an inhalation-based biopharmaceutics classification system (iBCS), is based on fundamental biopharmaceutics principles adapted to an inhalation route of administration framework. It is envisioned that a classification system for orally inhaled drugs will facilitate an understanding of the technical challenges associated with the development of new chemical entities and their associated new drug products (device and drug formulation combinations). Similar to the giBCS, the iBCS will be based on key attributes describing the drug substance (solubility and permeability) and the drug product (dose and dissolution). This manuscript provides the foundational aspects of an iBCS, including the proposed scientific principles and framework upon which such a system can be developed.

iBCS: 2. Mechanistic Modeling of Pulmonary Availability of Inhaled Drugs versus Critical Product Attributes

“…Supporting Information Section C for the full data set). The response in the primary functional outputs to variations in regional dose ( M j ) and ELF solubility ( C s,ELF ) is depicted in Figure 2 as a variation with the regional dose number (Do,j) calculated according to eq 3 4 …”

“…The first paper in this series 4 outlined the foundational principles and framework for an iBCS. The basic hypothesis behind the adopted approach is that an iBCS can classify drugs based on the rate and extent of absorption from the airway lumen into lung tissue.…”

“…To exemplify this, a typical iBCS class 1 inhaled drug could be defined as a drug residing in a parameter space where absorption from lumen is rapid and complete, whereas iBCS class 2–4 drugs would be characterized by slower and/or incomplete absorption from lumen due to low permeability, low solubility, or both. 4 As is the case for GI absorption of oral drugs in giBCS class 2–4, assignment of inhaled drugs to these drug classes would suggest that absorption from the lung could be affected by dissolution rate (classes 2 and 4) and by variations in permeability due to drug and excipients (class 3 and 4). Obviously, the design of an inhaled drug or drug product requires consideration also of other key properties such as receptor affinity, mean residence time in lung, local and systemic tolerability, and systemic disposition.…”

“…Obviously, the design of an inhaled drug or drug product requires consideration also of other key properties such as receptor affinity, mean residence time in lung, local and systemic tolerability, and systemic disposition. However, as discussed in paper 1 of this series, 4 descriptions of these processes require consideration of processes downstream to absorption and are thus outside the scope of an inhaled biopharmaceutics classification system. 5 …”

“…Although the Do can be adopted for an iBCS as long as modifications are made to account for the physiology of the lung airway lumen (e.g., by replacing the gastric volume in the giBCS Do with the volume of the epithelial lining fluid (ELF) in the lung), adapting the absorption number and the dissolution number is more complicated given that there is no plug flow of drug through a tube in the lung airways. 4 The first paper in this series 4 outlined the foundational principles and framework for an iBCS. The basic hypothesis behind the adopted approach is that an iBCS can classify drugs based on the rate and extent of absorption from the airway lumen into lung tissue.…”