The Effect of Excipients on the Permeability of BCS Class III Compounds and Implications for Biowaivers

Abstract

Purpose Currently, the FDA allows biowaivers for Class I (high solubility and high permeability) and Class III (high solubility and low permeability) compounds of the Biopharmaceutics Classification System (BCS). Scientific evidence should be provided to support biowaivers for BCS Class I and Class III (high solubility and low permeability) compounds. Methods Data on the effects of excipients on drug permeability are needed to demonstrate that commonly used excipients do not affect the permeability of BCS Class III compounds, which would support the application of biowaivers to Class III compounds. This study was designed to generate such data by assessing the permeability of four BCS Class III compounds and one Class I compound in the presence and absence of five commonly used excipients. Results The permeability of each of the compounds was assessed, at three to five concentrations, with each excipient in two different models: Caco-2 cell monolayers, and in situ rat intestinal perfusion. No substantial increases in the permeability of any of the compounds were observed in the presence of any of the tested excipients in either of the models, with the exception of disruption of Caco-2 cell monolayer integrity by sodium lauryl sulfate at 0.1 mg/ml and higher. Conclusion The results suggest that the absorption of these four BCS Class III compounds would not be greatly affected by the tested excipients. This may have implications in supporting biowaivers for BCS Class III compounds in general.

Demonstrating suitability of the Caco-2 cell model for BCS-based biowaiver according to the recent FDA and ICH harmonised guidelines

“…Based on the calculated ER of 0.3, active transport of oxacillin with PepT1 can be assumed, even though the level of expression is lower in Caco-2 cells when compared to human in-vivo situation. [37] Previous in-vivo and invitro studies suggest that nadolol is a P-gp substrate, [8,52] what is consistent with our results (ER = 3.6). Chlorothiazide interacts with well-expressed efflux transporter ABCG2 [53] (ER = 5.0).…”

“…Merely limited jejunal permeability studies in humans have been conducted, likely due to the complexity and high costs of each procedure . More information is provided for intestinal perfusion studies and in‐vitro permeation studies by using animal intestinal tissues, mostly from rats . The most popular human intestinal permeability screening method has been Caco‐2 cell monolayers …”

“…[5] More information is provided for intestinal perfusion studies and in-vitro permeation studies by using animal intestinal tissues, mostly from rats. [6][7][8] The most popular human intestinal permeability screening method has been Caco-2 cell monolayers. [5] The Caco-2 cell line originates from human colorectal adenocarcinoma cells [9] and has been widely used in pharmaceutical research over last thirty years within absorption, distribution, metabolism and excretion studies as an invitro cell culture model of the intestinal mucosa.…”

Glycerol Solvates DPPC Headgroups and Localizes in the Interfacial Regions of Model Pulmonary Interfaces Altering Bilayer Structure

“…It is recognised that some pharmaceutical excipients that are commonly used in medicines and categorised as generally-regarded-as-safe by medicines regulatory agencies may exert unanticipated effects on drug permeability [12][13][14] . A number of permeation-enhancing mechanisms have been postulated including direct or indirect interference with membrane integrity, and interactions with enzymes or transporters, e.g.…”

Solvent driven phase transitions of acyclovir – the role of water and solvent polarity

“…ACV belongs to BCS class III (Biopharmaceutical Classification System) indicating the drug to be soluble in water but to have limited permeability. 1 This is in line with its limited bioavailability (5 to 30%), which varies between individuals. 2 Furthermore, it is known that different ACV solid forms display substantial differences in dissolution kinetics, which may affect the bioavailability of the drug.…”