β-Lactoglobulin-based amorphous solid dispersions

Abstract

Proteins have recently caught attention as potential excipients for amorphous solid dispersions (ASDs) to improve oral bioavailability of poorly water-soluble drugs. Notably, the studies have highlighted whey protein isolates, particularly β-lactoglobulin (BLG), as promising candidates in amorphous stabilization, dissolution and solubility enhancement, achieving drug loadings of 50 wt% and higher. Consequently, investigations into the mechanisms underlying the solid-state stabilization of amorphous drugs and the enhancement of drug solubility in solution have been conducted. This graphical review provides a comprehensive overview of recent findings concerning BLG-based ASDs. Firstly, the dissolution performance of BLG-based ASDs is compared to more traditional polymer-based ASDs. Secondly, the drug loading onto BLG and the resulting amorphous stabilization mechanisms is summarized. Thirdly, interactions between BLG and drug molecules in solution are described as the mechanisms governing the improvement of drug solubility. Lastly, we outline the impact of the spray drying process on the secondary structure of BLG, and the resulting differences in amorphous stabilization and drug dissolution performance between α-helix-rich and β-sheet-rich BLG-based ASDs.

Introduction

In the pharmaceutical pipeline, a significant proportion of small drug molecules exhibit poor solubility, resulting in low or variable bioavailability upon oral administration. Consequently, even the most promising drug candidates in the lab often are discontinued during the pre-clinical stage [1]. Broadly, these poorly aqueous soluble molecules can be categorized into two types: lipophilic (grease ball) drug molecules and hydrophobic (brick dust) drug molecules [2]. The latter is typically characterized by a high melting temperature (Tm) originating from a strong and tightly bound crystal lattice [2], [3]. Such compounds are well suited for amorphous drug formulations [4].

An amorphous form is disordered like a liquid, but rigid like a solid [5]. The irregular arrangement of molecules leads to unequal intermolecular forces, yielding a higher Gibbs free energy compared to their crystalline counterparts. This inherent high energy proves advantageous regarding improving dissolution rate and the generation of supersaturation upon dissolution [5], [6]. However, the drug concentration of the resulting supersaturation is itself thermodynamically unstable and will eventually approach the crystalline solubility due to the precipitation of drug molecules. Furthermore, an amorphous solid is also physically unstable due to its higher Gibbs free energy, resulting in a tendency to recrystallize over time to reduce this excess energy.

To prevent recrystallization, one can stabilize the amorphous form of a drug by incorporating it into different excipients. This generates a system referred to as an amorphous solid dispersion (ASD). When using polymeric excipients, the drug is converted to and stabilized in its amorphous form by dissolving it in the amorphous carrier. The polymer has the capability to restrict the molecular mobility of or interact with the amorphous drug molecules though various interaction to prevent the nucleation/crystallization process [7], [8]. Additionally, polymers can also play an important role in sustaining supersaturation and inhibiting precipitation [9].

Recently, the utilization of proteins in ASDs has emerged as an appealing alternative to polymeric carriers. Proteins are biodegradable macromolecules [10] and exhibit a remarkable ability to engage in reversible binding with drug molecules. Consequently, they possess the potential of stabilizing drug molecules in the amorphous form and sustaining the supersaturated state of dissolved drug in solution. In some early studies, gelatin, bovine serum albumin, zein, soy protein, and whey protein isolate (WPI), have independently been investigated as excipients for improving solubility of poorly water-soluble drugs [10], [11], [12], [13], [14]. Among these, it has been suggested that WPI is an efficient excipient in amorphous stabilization, dissolution, and solubility enhancement achieving drug loadings (DLs) of 50 wt% and higher [14]. WPI is a protein mixture consisting mainly (up to 92 % in WPI) of the proteins α-lactalbumin and β-lactoglobulin (BLG), with the latter being the main component (up to 75 %) [14]. Hence, more studies have been performed on BLG, systemically investigating the loading limits of BLG, the fundamental mechanism behind the amorphous stabilization, solubilization in supersaturated solution, as well as the influence of the BLG secondary structure on the performance of the ASDs [12], [15], [16], [17], [18], [19]. The purpose of this graphical review is to summarize the state-of-the-art of BLG-based ASDs.