Use of the IDAS system to assess food intake effects on drug diffusion and permeation

The pharmaceutical industry is feeling the acute effects of disruption caused by the COVID-19 pandemic. With most human trials on hold, drug developers and generics companies will be looking for new ways to progress product portfolios. This series of blog posts aims to highlight BCS and BCS-based biowaiver applications as such an opportunity.

In our previous blogs, we highlighted BCS and BCS-based biowaivers. Furthermore, we discussed experimental approaches to guide drug development of complex compounds. In this blog, we will discuss the use of the IDAS system to assess the effects of food intake on drug dissolution and permeation.

Many factors affect the dissolution, absorption, and permeation of drug compounds in patients. Diffusion and permeation may be affected by, for instance, variation in pH levels, fluid volume, and viscosity. To guide drug development, knowledge of regional changes in dissolution and permeation is essential.

One of the main factors that affect drug dissolution is food intake. Upon meal intake, gastric viscosity increases and subsequently declines due to gastric secretion. In contrast, in the intestinal environment, the viscosity increases over time, resulting in poor conditions for drug dissolution.

These effects are challenging to mimic in vitro. For in vitro systems, the use of high and low viscosity dissolution medium helps determine the impact on permeation. However, dissolution is also affected by the final drug formulation, which cannot be tested in most systems.

Measuring effects of viscosity

Our in vitro dissolution and absorption system (IDAS) is comprised of dissolution and permeation chambers, separated by a human Caco-2 cell monolayer as a biorelevant membrane, allowing for simultaneous measurements of drug dissolution and permeation.

With this system, we can test the effects of medium viscosity (mimicking food viscosity) on diffusion and permeation of the active pharmaceutical ingredient (API) across the Caco-2 cell membrane.

Both the IDAS1 and IDAS2 systems can be used for the measurement of permeation of API in high and low viscosity. The main difference between the two systems is that with IDAS2, drugs can be added in their final formulation (as capsules or tablets). This allows for the additional assessment of the role of oral drug product dissolution in high and low viscosity conditions. Sample collection can be performed at predefined time points from both the dissolution and permeation chambers. Analysis of the API in samples is conducted using techniques such as reverse-phase high-performance liquid chromatography-mass spectrometry (LC-MS/MS).

Assessment of BCS classes

We assessed the effect of the viscosity of the dissolution medium on the permeation and dissolution of compounds in all four BCS classes. We tested propranolol (class I), carbamazepine (II), atenolol and ranitidine (III), and acetazolamide (IV) in high and low viscosity medium using the IDAS systems.

For these BCS classes, no apparent effect of medium viscosity was found on the permeation of all four compounds tested in IDAS1.

However, when tested in their final formulation in IDAS2, high viscosity did cause an apparent reduction in the dissolution and permeation for all compounds. The viscosity of the medium mostly affected the dissolution and permeation of intact oral solid dosage forms of poorly water-soluble APIs (Class II and IV). This may be caused by the delayed disintegration of the dosage form in the higher viscosity environment.

Figure 1: In vitro dissolution and permeation measurements using IDAS2 of highly soluble API propranolol (A), ranitidine (B), and low soluble API carbamazepine (C) and acetazolamide (D) in low viscosity (LV )  and high viscosity (HV) medium.

Guiding drug development with IDAS

For drug development, an excellent translation between in vitro permeation, dissolution, and absorption data and the in vivo situation is essential. Meal intake is a crucial factor affecting these characteristics in vivo. In particular, the absorption of poorly water-soluble compounds may be modified if the dissolution of the API from the dosage form is delayed due to high viscosity, leading to most absorption taking place in the upper small intestine. Therefore, increases in the viscosity of the dissolution medium following the ingestion of a solid meal may drastically reduce disintegration and dissolution.

The combination of IDAS1 and IDAS2 enables distinction between the roles of intrinsic drug properties and product-related factors that may affect drug dissolution and/or permeation. Contact us to learn more about the IDAS systems and how we can help guide your new drug or generics formulation development process.

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