The impact of endogenous gastrointestinal molecules on the dissolution and precipitation of orally delivered hydrophobic APIs

ABSTRACT

Introduction

Given that hydrophobic active pharmaceutical ingredients (APIs) intended for oral delivery comprised about 68% of US FDA approvals in 2019 alone, the impact of endogenous gastrointestinal (GI) molecules on their inherently unstable solution behavior needs to be elucidated.

Areas covered

The interactions between hydrophobic API’s and GI phospholipids, bile acids/salts and digestive proteins are explored. The impact of the complex relationship between the GI molecules and hydrophobic APIs on solubilization by micelle formation, complexation or by inhibiting the nucleation of high energy forms of hydrophobic APIs, so called supersaturating drug delivery systems is complex. The ability of these endogenous GI molecules to manipulate the solution behavior of hydrophobic APIs has been demonstrated both at their native concentrations and when included as exogenous formulation additives. Specific studies of the impact of proteins and mixed micelles on solubilization and crystallization are reported.

Expert opinion

Elucidation of the complex molecular interactions between orally administered hydrophobic APIs and endogenous GI molecules will enable better in vivo/in vitro correlation and potentially lead to formulation strategies that avoid the stochastic nature of hydrophobic API precipitation in the GI tract.

KEYWORDS:

• Drug delivery
• gastrointestinal Molecules
• pharmaceutical
• oral Administration
• hydrophobic
• formulation

Article highlights

• For active pharmaceutical ingredients with extensive hydrophobic properties (Biopharmaceutics Classification System class II and class IV), oral absorption remains very difficult to predict without extensive in vivo testing.

• Endogenous molecules in the gastric and intestinal systems can be broadly categorised as phospholipids (PLs), bile acids/salts, and digestive proteins.

• In the GI tract, bile salts associate at a molecular level with PLs, fatty acids and/or monoglycerides, forming mixed micelles to support lipid absorption. However mixed bile salt and PL micelles are rarely used in the formulation of new API products.

• Absorption advantages obtained by mixed micelles may be restricted to truly hydrophobic compounds that exhibit very low or no water solubility.

• Multiple recent reports show that bile salts can act as crystallisation inhibitors for so-called supersaturating drug delivery systems (SDDS) but the effect is better when the bile salt is monomeric, and not in a micelle. Considering that mixed micelles are more prevalent in GI than monomeric bile salts, crystallization inhibition using bile salts may not be a good formulation strategy.

• Digestive proteins may play a role in the solubilization of hydrophobic active pharmaceutical ingredients through binding to hydrophobic sites on the protein surfaces – a role that has been nearly completely neglected in the literature to date.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was financed by Science Foundation Ireland under the Bioavailing of Antimicrobial Resources (BAR) project (13/CDA/2122), with additional support from the SSPC, the SFI Research Centre for Pharmaceuticals, funded by Science Foundation of Ireland (SFI) under grant number 12/RC/2275_p2.