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.
This work is the
second in a series of publications outlining the
fundamental principles and proposed design of a biopharmaceutics classifications
system for inhaled drugs and drug products (the iBCS). Here, a mechanistic
computer-based model has been used to explore the sensitivity of the
primary biopharmaceutics functional output parameters: (i) pulmonary
fraction dose absorbed (
F
abs
) and (ii)
drug half-life in lumen (
t
1/2
) to biopharmaceutics-relevant
input attributes including dose number (Do) and effective permeability
(
P
eff
). Results show the nonlinear sensitivity
of primary functional outputs to variations in these attributes. Drugs
with Do < 1 and
P
eff
> 1 ×
10
–6
cm/s show rapid (
t
1/2
< 20 min) and complete (
F
abs
>
85%)
absorption from lung lumen into lung tissue. At Do > 1, dissolution
becomes a critical drug product attribute and
F
abs
becomes dependent on regional lung deposition. The input
attributes used here, Do and
P
eff
, thus
enabled the classification of inhaled drugs into parameter spaces
with distinctly different biopharmaceutic risks. The implications
of these findings with respect to the design of an inhalation-based
biopharmaceutics classification system (iBCS) and to the need for
experimental methodologies to classify drugs need to be further explored.
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