PHARMACEUTICALS
About 95 % of BAs are reabsorbed in the distal ileum and recycled four to 14 times / day, maintaining a pool of 1.5-4 g.
The amphipathic nature of BAs arises from their rigid steroidal backbone, bearing hydroxyl groups on the concave α-face( hydrophilic) and methyl groups on the convex β-face( hydrophobic). Due to their weak acid properties, BAs exist in ionised form at physiological conditions( pH 7.4).
The pKa values of unconjugated BAs are approximately 5.0, whereas the conjugation with amino acids further lowers pKa values to around 4.0 in glycine conjugates and less than 2.0 in the taurine conjugates. Conjugated BAs represent slightly stronger acids with lower pKa values, while taurine-conjugated BAs are soluble even at gastric pH values and are thus suitable for designing oral drug delivery systems.
Due to their amphiphilic properties, BAs can self-associate in water, forming supramolecular aggregates or micelles, when their concentration is above a certain critical micelle concentration( CMC). The CMC of BA derivatives varies with their hydrophilic-lipophilic balance( HLB), which is influenced by the number, position and orientation of hydroxyl groups, as well as conjugation with amino acids.
The hydrophilicity of BAs and their conjugated forms decreases in the order: ursodeoxycholic acid( UDCA) > CA > CDCA > DCA > LCA, and among conjugates: taurineconjugated > glycine-conjugated > unconjugated species.
The CMC values correlate inversely with hydrophobicity: more hydrophilic BAs have higher CMCs, while more hydrophobic ones form micelles at lower concentrations. This relationship reflects the thermodynamic drive to minimise the exposure of hydrophobic surfaces in aqueous environments.
Nevertheless, the conjugation of BAs with glycine or taurine results in lower CMC values, which indicates that the complex interplay between the hydrophobic effect and specific hydrogen-bonding interactions may contribute to the micellisation and unexpected CMC values. The stability of the BA micelles depends on both structural properties of BAs and solution conditions, such as temperature, pH and ionic strength.
Mechanism of action as excipients
BAs act as multifunctional excipients by leveraging their unique structural and physicochemical properties to improve the solubility, stability and permeability of both small molecules and biologics. Several mechanisms contribute to their performance-enhancing role in pharmaceutical formulations.
Firstly, BAs can be used to formulate drug delivery carriers such as micelles, mixed micelles and bilosomes that help to encapsulate poorly watersoluble drugs, thereby increasing their apparent solubility in aqueous environments. Moreover, these carriers have additional benefits in protecting small molecule drugs or biologics( i. e. peptides and proteins) that are susceptible to degradation when they are in the presence of low pH and / or lytic enzymes.
Secondly, their amphiphilic structure allows BAs to interact with phospholipid bilayers of epithelial cells, acting as permeation enhancers. In fact, they can fluidise membranes, open tight junctions and increase paracellular and transcellular transport.
This property is particularly valuable for enhancing the bioavailability of conventional drugs and therapeutic peptides and proteins, which otherwise suffer from poor absorption through physiological barriers( e. g. intestinal wall, transdermal, ocular or buccal membranes).
Finally, chemical conjugates of different drugs with BAs can engage BA transporters( e. g. ASBT in the ileum), facilitating drug targeting and absorption via endogenous uptake pathways. This opens new opportunities for pro-drug strategies or drug – BA conjugates, which exploit enterohepatic recirculation to prolong systemic exposure or achieve liverspecific delivery.
Their multi-modal functionality positions BAs as natural and versatile excipients in addressing the bioavailability challenges commonly seen with BCS class II / IV( low solubility) and class III / IV( low permeability) drugs, as well as in novel delivery systems for macromolecular therapeutics involving peptides and proteins.
Application across routes of administration
There are several commercial formulations for parental administration in which BA excipients serve to solubilise lipophilic drugs or vitamins. For parental formulations, their properties can be also exploited to stabilise therapeutic proteins by preventing aggregation and denaturation. Their use in injectables
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