Many promising new drugs are working their way through clinical development, but bioavailability remains a major challenge for the industry. As is typical in successful development, tackling problems early can make a big difference and lead to optimized timelines. In 2015, Catalent launched a toolkit of technologies – the award winning OptiForm Solution Suite – that was designed to help overcome bioavailability challenges for early-stage small molecules, by pairing their characteristics with suitable drug delivery systems. But what about large biomolecules? Enter the OptiForm Solution Suite Bio, which specifically addresses bioavailability challenges faced in biologic development – with a focus on the ‘holy grail’ of oral delivery. Stephen Tindal, Director, Science and Technology at Catalent, tells us more.
How has the industry reacted to OptiForm Solution Suite? In general, very favorably; companies particularly like the data-driven concept. The OptiForm Solution Suite is all about applying rigorous science to better understand the structure of a molecule and how it might interact with drug delivery technologies that are needed to help with solubility or bioavailability problems. The data can be used to rank options early on and to allow developers to make better-informed developmental decisions. After all, making the wrong decisions concerning a drug delivery technology for a molecule can cost months of extra time, delaying the project. Data from the OptiForm Solution Suite helps justify both to management and regulators why a certain drug delivery technology was selected. Overall, it’s about providing confidence that the right technology was selected from the start, which makes the drug development process smoother. What common challenges plague early drug development? Early characterization and optimization work are crucial, but need to be placed into context with the challenge of drug delivery. If an API is unstable at a given pH, this could change the delivery approach and technology employed. Also, there can be a temptation to work only with the technologies which are familiar, rather than reaching out for external expertise. What are the specific issues around developing oral macromolecules? Many companies have considered OptiForm Solution Suite to help them with poorly soluble small-molecule APIs. Macromolecules’ solubility is less of a concern – the main problems are usually poor absorption due to the size of the molecule, as well as the molecular geometry and lack of flexibility. Macromolecules which can’t squeeze through tight spaces won’t be absorbed into the body because of the permeation limitations of the tight junctions in the gastrointestinal (GI) tract and limited transcellular pathways. In addition, macromolecules demonstrate low stability in the GI tract, so although they’re soluble they tend to be degraded by the harsh acid environment or enzymes before you get any permeation. Only two peptides have been licensed for systemic oral delivery – cyclosporine and desmopressin. And because of limited success, people may come to the assumption that it’s too difficult to make an oral macromolecule product, particularly given the pressure on time and resources in today’s industry. However, we are seeing increasing interest in this area. Few (if any) patients like injections (the delivery method for the majority of biologic medicines), which is one of the reasons why we set up the Catalent Applied Drug Delivery Institute. Indeed, a major area of focus for us is on non-invasive macromolecule delivery.
How has OptiForm® been adapted to work with macromolecules? The new add-on for the Suite – OptiForm Solution Suite Bio – rapidly screens macromolecules to assess stability issues and the potential for delivery via the oral route. The material for the first animal study can be ready in as little as 3 weeks. Even though the biggest problem is permeability, it is possible to enhance this. For example, chemical modification could improve absorption in the small intestine, or permeation enhancers could help the macromolecule pass through tight junctions. In order to help with stability, enteric coatings are also a popular choice, and there may be protection from a lipid formulation as well. As part of OptiForm Solution Suite Bio, we look at whether our proprietary drug delivery technologies – OptiGel Bio or Zydis Bio – can help by performing tests to assess compatibility. A report is produced that delivers the data and suggests potential developmental routes, to exploit any positive findings. Our drug delivery technologies aim to enhance the ability of macromolecules to be delivered orally. Optigel Bio is a lipid formulation with safe and marketed ingredients and formulation options, which accelerates complicated clinical and regulatory pathways. An enteric coating protects the capsule from gastric rupture and thus the macromolecule is protected from enzymatic degradation until it is released with the permeation enhancer to help open up tight junctions for the large molecule to pass through. Only minimal amounts of permeation enhancer are used and the tight junctions recover within 15 minutes to prevent unwanted substances from reaching the blood. Meanwhile, Zydis Bio is an Orally Disintegrating Tablet (ODT) (made through lyophilization) that dissolves in the highly vascularized mucosae within the mouth to give pre-gastric absorption, thus avoiding first-pass metabolism. The oral delivery of macromolecules has been described as the ‘holy grail’ of drug delivery. Is it within reach? It may be. We may see more commercially successful oral biologics in the coming years. However, there is a broad range of macromolecules in terms of size and it will be very challenging to deliver the largest molecules this way; for smaller peptides there is definitely room for optimism. Having access to a toolbox of technologies that target different biological barriers and help screen for oral delivery potential is a big step forward. Catalent Applied Drug Delivery Institute leads the Non-Invasive Macromolecule Delivery Consortium (NMDC) to help connect people who have the expertise to help each other, but also to begin the process of providing innovative solutions. The next Non-Invasive Drug Delivery of Macromolecules Conference, held by NMDC, will be in San Diego (California) from February 21 to 24, 2017, where experts from academia and industry will discuss the new updates for non-invasive macromolecule delivery technologies. We are only at the beginning of our journey towards oral macromolecule delivery, so we’re very excited to contribute to the new delivery technologies of the future.
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