Bridging the Solubility Barrier with Bile Acids

As poor solubility continues to plague development pipelines, alternative biocompatible permeation enhancers are becoming increasingly beneficial for formulation scientists notes Roger Viney from ICE Pharma.

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Modern drug discovery is yielding increasingly complex, highly lipophilic molecules, driving formulation scientists to seek out alternative approaches to enhance permeation. In this latest episode of All Points of the Pharma Compass, Roger Viney, Chief Commercial Officer of ICE Pharma, talks about the dual solubility and permeability benefits of bile acid derivatives, their inherent advantages in manufacturing scale-up, and their emerging potential in targeting the gut-brain axis.

Click above to listen to the full conversation in the latest episode of All Points of the Pharma Compass.

Breaking the Solubility Bottleneck

TPN: With a huge percentage of the pipeline falling into BCS Class II and IV, solubility is the industry's biggest bottleneck. How are bile acid derivatives being utilized as functional excipients to enhance the permeability and solubility of these difficult molecules?

Viney: Increasingly, excipients are serving an active role in enhancing drug delivery. Bile acids have emerged as a versatile agent capable of addressing solubility and permeability issues. The benefits are as follows: firstly, bile acids are natural, they're endogenous, and so they'll be reprocessed in the liver after use; secondly, there are a range of bile acids chemically, so they can address different formulation needs as their properties vary depending on the number of hydroxyl groups they have or their conjugation with amino acids. Bile acids form micelles, mixed micelles, and bilosomes, that encapsulate poorly soluble drugs, increasing their bioavailability. 

Additionally, bile acids have the benefit of protecting peptides and proteins that are susceptible to degradation at the low pH of the stomach. Bile acids also interact
with the phospholipid layers of cells acting as permeation enhancers, so, they can fluidize membranes, open tight junctions, and increase paracellular and transcellular transport. 

We're seeing an increased use of bile acids as excipients in clinical trials, particularly for the reformulation of GLP-1s from injectable to oral, where bile acids offer an alternative to SNAC as a permeation enhancer. We're working on projects both with small molecules, large molecules, and in modes of administration such as injectable, oral, transdermal, nasal, and even buccal.

Navigating Enabling Technologies

TPN: Given that there are numerous enabling technologies available, what should developers consider about their formulation when looking to employ bile acids for their solubility enhancement strategy over other options? Are there specific benefits or limitations of bile acids, for example?

Viney: Bile acid based solubilization systems offer several advantages over other drug enhancement strategies, particularly for highly lipophilic and poorly water-soluble drugs. One of the major advantages of bile acids is their dual functionality. So, unlike many conventional surfactants or polymers that only improve dissolution,
bile acids can also enhance both solubility and intestinal permeability. 

The structure of bile acids enables micelle formulation while also interacting with the biological membranes to improve drug absorption. Bile acids are also endogenous, so they're naturally present in the gastrointestinal tract giving them greater biocompatibility compared with some synthetic surfactants and this can also help to address any toxicity concerns as well. 

Compared with amorphous solid dispersions, bile acid systems also show a lower risk of long-term recrystallization because the drug solubilization is maintained dynamically
within the micelles rather than relying solely on maintaining an unstable amorphous state. So, bile acids can require lower polymer or excipient content, thereby reducing tablets or capsule size. 

Finally, bile acids can stabilize supersaturated drug concentrations after administration, helping prevent precipitation and maintaining improved drug absorption.

Simplifying Scale-Up

TPN: Another common issue with solubility-enhancement can be in the form of scale-up. Is it relatively simple to scale up using bile acid derivatives to improve solubility?

Viney: I think it's a good point and I think scale up is often not straightforward. Bile acid solubilization systems offer several scale-up advantages over other pharmaceutical, particularly for poorly soluble drugs. Bile acids, such as sodium dioxycholate or sodium cholate are efficient at forming micelles and they have strong solubilization capacity, so it can reduce the need for larger quantities of synthetic surfactants or polymers. So, lowering the formulation complexity and excipient burden. 

Compared with some of the nanotechnology-based systems, bile acid formulations,
require simpler manufacturing processes, such as mixing and hydration, rather than high energy milling and homogenization, which can reduce processing costs and improve scalability. 

Other advantages include their biocompatibility. As I said earlier, bile acids are endogenous, so they're already present in the gastrointestinal tract, and they can support regulatory acceptance if they're kept within the normal concentration range, which is helpful.

Finally, I think the hybrid bile acid polymer or lipid systems can also be developed to improve long-term stability and commercial manufacture ability during scale-up.

Shaping the Gut Microbiome

TPN: What is the current scientific opinion on how bile acid supplementation can meaningfully influence the gut microbiota for metabolic and inflammatory conditions?  

Viney: it's a good question and one without a very sort of simple answer, but I can say that nature and evolution are the greatest chemists. Bile acids are natural products, they've evolved over millions of years to have unique properties, and it was in 1900 that Alfred MacConkey developed a cell culture media based on bile acids because he recognized that bacterial growth was modified by the presence of bile acids. 

Today, what we can say, of course, is that bile salts, which are synthesized in the liver and released into the gut, have a significant synergistic impact on the gut microbiome.
So, firstly, the microbiome converts primary bile salts into secondary bile acids, and then the secondary bile acids work on the bacteria of the gut to reshape it and determine its ecology — the gut microbiome produces metabolites, short chain fatty acids that have health benefits.

By promoting the growth of certain bacteria, we can increase the production of specific metabolites that then target health conditions. So many health conditions such as high cholesterol, diabetes, irritable bowel syndrome, of course, by sort of the modern lifestyle, if you like, being overweight, lack of exercise and poor diet. And at ICE, we're leading research with academic partners looking into these areas to exploit the link between the gut microbiome and health outcomes using bile acids. 

So, I think it is a complicated field, but what I can say is that we have every confidence that ICE will be commercially on the market with a bile acid, a nutraceutical product in 2027.

About the Interviewee

Roger Viney, PhD,is the Chief Commercial Officer for ICE Pharma where he is responsible for global sales and marketing activities, managing a team of over 30 people. Roger has 30+ years’ experience in the chemical and pharmaceutical industries, transitioning through R&D at the beginning of his career into sales, marketing, and business management.

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