Overcoming the Hurdles to Oral Peptide Development

Experts from Alcami break down the latest innovations in lipid-based permeation matrices, continuous direct compression, and advanced analytical workflows designed to bring oral peptides to market safely and predictably.

Peptide therapeutics have the potential to become blockbusters on a scale that was previously seen within the monoclonal antibody space thanks to their effectiveness and biocompatibility. However, peptides also present a variety of development hurdles, particularly for oral delivery, as they are susceptible to hydrolysis and enzymatic degradation and have poor bioavailability. Therefore, converting a highly predictable, 100% bioavailable injectable peptide into a robust OSD form remains challenging. 

For the latest From Stem to Stern episode, The Pharma Navigator sat down with a panel of experts from Alcami to find out more about the formulation strategies, alternative manufacturing approaches, and analytical testing updates available to overcome the obstacles to oral peptide therapeutic development. The panel for this episode comprised: Robert Sciscento, Senior Scientist, Formulation Development, OSD; Trevor Williams, Senior Scientist, Formulation Solid Dosage; and Zachary Morseth, Manager — Bioseparations/Mass Spectrometry, all from Alcami.

Click above to view the video panel discussion or read on for more…

Molecular and Delivery Strategies

TPN: First of all, could you provide an overview of the potential oral development strategies are available to overcome the obstacles to formulating a broader range of oral peptide therapies?

Sciscento: One way to stabilize peptides for oral formulation development, from a molecular biology standpoint, is actually substitution, small substitutions on the peptide itself. To simplify that, the version of a peptide that is used for injection might be slightly different in an oral format, and that's simply just molecular modifications such as PEGylation, cyclization, and lipidization, which basically means that different groups are added to the peptide chain. 

Now, from a delivery standpoint, one kind of umbrella strategy that we see with peptides is targeted delivery. So, to prevent hydrolysis in the stomach — for example, acid hydrolysis — many peptides typically undergo an enteric coating process, whether that be in tablet form or an enteric capsule delivery. 

Those approaches are two really strong ways to stabilize peptides for oral delivery.

Achieving Synchronicity with Permeation Enhancers

TPN: Focusing on permeation enhancers for a moment, these need to dissolve in a coordinated way along with the peptide in order to work. How can developers optimize a matrix to achieve such synchronicity?

Sciscento: A way to increase the bioavailability of peptides is through the use of lipids, which has been historically done in the soft gel industry, but there are many ways that lipids can be incorporated into an oral formulation. One approach could be as simple as a single lipid system that increases intestinal permeation. An example of that might just be simply dissolving your peptide in medium-chain triglyceride (MCT) oil, and then somehow incorporating that into your oral formulation, whether that be a tablet or a capsule. 

Another strong way to increase bioavailability is to take that approach one step further and incorporate a self-emulsifying drug delivery system (SEDDS). So, that system would include a surfactant, co-solvent, and some other lipid. An example of a SEDDS might build upon the MCT oil, which could be the oil component, with the addition of maybe a polysorbate as a surfactant and a co-solvent, such as PEG or any version of the PEGs. That would be a simple SEDDS that would increase the bioavailability of a peptide. 

Now, as far as evaluating the effectiveness of each of these formulation modifications, what we see is really heavy in vitrodissolution testing. Typically, that would include bio-relevant media such as fasted state simulated intestinal fluid (FaSSIF), fasted state simulated duodenal fluid (FaSSDF), and the fasted state simulated gastric fluid (FaSSGF) medias to evaluate those single lipid modifications of a SEDDS. Typically, if we're formulating down that route. There may be different variations of the SEDDS composition, as well as different oils evaluated, so, that's kind of how the formulations are rank ordered and benchmarked. 

Another common permeation enhancer for peptides is salcaprozate sodium (SNAC). SNAC is commonly used in the rybelsus formulation to increase the permeation enhancement of semaglutide.

Adapting Manufacturing Processes

TPN: Developers aren’t only faced with formulation challenges with oral peptides, as the molecules’ fragilities aren’t compatible with traditional OSD unit operations. Therefore, what process adaptations or alternative manufacturing pathways, such as continuous direct compression or specialized fluid bed processing, are required to handle peptides?

Williams: In most oral solid doses, we work with very small molecules; they're pretty rugged, they can go under a lot of stress, oxidation is not really as much of a problem. So, the main thing with peptides is that they are very structurally complex, and they're very sensitive to the environment, such as added moisture, light, sensitivity, and mechanical stress.

Usually, when we work with smaller molecules, we'll do wet granulation, we'll do prolonged blending, we'll even do some high shear mixing, we'll also do roller compaction. But, with peptides, those approaches would expose them to a lot of moisture, elevated temperatures, some high shear force, and even could have result in oxidation reactions. So, the one thing we really are looking for here is we're trying to monitor and make a more peptide-friendly environment for manufacturing.

One of the ways we can perform more peptide-friendly manufacturing is through continuous direct compression, which we have seen become a very important matrix. With this case, you're kind of feeding all your ingredients in a very closed system and when you are doing this continuous manufacturing, you're really allowed to have a much more sensitive environment and be able to really control your environmental controls and expose the peptides to much less outside forces. 

Also, when you're doing this continuous process, you're basically feeding all of your excipients and your ingredients in a single process, and then it's directly going into tablet compression. This also has a lot less mechanical force involved, because you are not really mixing it for prolonged times, you're not stirring it with high mechanical force as well. So, you're able to really make sure you can preserve the peptide. 

The strategy is also really good because it means you need a much lower amount of API. You're making a much smaller batch here, which reduces the time the peptides are exposed and also makes it so if you do, if there is a problem with the batch, you're not wasting a large amount of money here because peptides are very expensive and we are trying to introduce fewer processing steps and also help make sure we're not wasting them if something goes wrong during the batch.

Another innovation here would also be a difference in the way fluid beds are being made. Fluid beds are becoming a lot more controlled, whereas, for traditional fluid beds, there's a very high amount of force being added into it from a shearing perspective. Additionally, a lot of heat is added during drying, but, as Bobby mentioned, by adding lipid granulations, you really don't need to introduce heat because you're not adding water into the system. So, we're getting a lot more of these controlled modern fluid bed systems that are designed to be a lot less intensive on the peptide itself, meaning we're able to still have that granulation or uniform coating process without adding that much mechanical strength. 

Also, what we really need to work on here is just making sure that the manufacturing sites themselves have a lot of environmental controls in setup, which can be done by having multiple digital manufacturing technologies that can actually do your analytical testing while you're running the batches. Therefore, there are many tools out there that can give you blend uniform, moisture content, tablet weight, and compression force in real time, so instead of having to rely on external forces, you can do this at the same time and make sure that your batch throughout the whole process is showing the results that you want. 

Really, even from the R&D stage, I think you're going to see a lot of these continuous manufacturing processes being introduced rather than in older times where we would basically make the formulation and scale up and then think about scale up once we got a good formulation. I feel like at this point now, we really need to focus on the manufacturing process from the get-go so that when we do scale it up, we can reduce the troubles that we would see in scalability.

Overcoming the Analytical Matrix Challenge

TPN: Additionally, analytical testing for oral solid peptides is complex because degradation products can be subtle and easily masked by dense excipient matrices or permeation enhancers. How are analytical and stability testing workflows evolving to ensure precise quantitation during real-time release testing and long-term stability studies?

Morseth: Peptides are already complex molecules, but when you put them into a solid dosage form, you're going to add a whole layer of excipients and permeation enhancers that are designed to help the peptide survive the gastrointestinal (GI) tract and get absorbed. Now, the problem is those same excipients can interfere with the degradation products that we're trying to monitor. So, a subtle change, like a peptide that gets oxidized or maybe loses in a mid-group, can get buried within that formulation matrix. 

Now, when it comes to analytical techniques, ultra-high performance liquid chromatography or UPLC remains our primary quantitative workhorse. First, we start with chemical separation and we're moving toward UPLC with the sub 2 micron particle columns, where these smaller column particles mean sharper peaks and better resolution. So, these degradation products that used to co-elute with the excipient peaks can now be separated and quantified. We also look at column chemistry, and we know that not every column is created equal. So, we're experimenting with core shell particles and alternative phases to find the selectivity that actually distinguishes our peptide degradants from the surrounding matrix. 

Alongside this UPLC, there are a few complementary methods that we also use. So, UV/Vis spectroscopy, that gives us a fast orthogonal check on the assay value — it's not as selective as UPLC, because it can't distinguish intact peptide from certain degradants, but it's useful during method development or even in-process testing.

We also have circular dichroism (CD), and that covers the secondary or higher order structure. Peptides can generally pass these purity checks when we do liquid chromatography, but they can still have a shifted secondary structure. So, CD gives us that missing piece by confirming the molecule's confirmation hasn't changed during these stability studies. 

And then when UPLC shows peaks that we can't identify, that's where mass spectrometry (MS) comes in. So, with liquid chromatography tandem mass spectrometry (LC–MS-MS), we perform identity confirmation and we pinpoint exactly where a degradation event happened, like a specific oxidation or a deamination site.

Lastly, dissolution testing gives us that release behavior context. So, combined with UPLC quantitation, we can see these dissolved fractions and tell us whether the peptide is releasing on the timeline that the formulation was designed for.

Underneath all of this, we're doing forced degradation studies to stress our methods with heat, light, oxidation, and even pH extremes to confirm that our method can detect solid-state relevant degradants before we trust it for release or stability testing. So, together, these methods and techniques really let us trust what the data is telling us,
even when the formulation is doing its best to hide it.

The Future Benchmark 

TPN: Looking ahead, as the industry advances, should our primary benchmark for success be pushing the envelope to achieve higher absolute bioavailability, or should we accept low bioavailability and focus on engineering technologies that minimize patient variability instead?

Williams: The way I'm looking at it is this: are you trying to get a more optimized formula or are you trying to show very good clinical relevant results with your formulation? Historically, peptides really have been pretty highly available. The formulations have been focused on getting the most bioavailability, but that's because it was an injectable. You inject the peptide, you're really not seeing any major issues within the body system and no systematic issues happen when it is being absorbed in the body. The problem is that when you do move into oral solid doses, there are a lot more factors, with where it goes through the stomach, and you have to make sure it's going through all the different processes and organs in the body. So that's why, in this case, you might need to look at the benchmark in a different way. 

I would say, a more predictable model is much better than a more variable model. So, you're going to see this if from a clinical standpoint, you'd rather have a drug that is consistently giving 3 to 5% in about all patients rather than a drug that has a very high absorbance in some patients and a very low in other patients. Because when we are looking at clinical models and patient safety, you really want to make sure you're giving a very predictable amount of this bioavailability. In that case, we should really focus on making sure that we have a drug that is very predictable, gives a solid bioavailability from the beginning. 

But, really, you have to look at bioavailability and variability in two parallel questions, because as technologies get better and as we move forward with learning more about the peptide themselves, I see both of these fields going in the right direction. You're going to see the formulations be optimized, we're going to be able to get more excipients that are more peptide friendly, we're going to have better engineering around the peptide molecules themselves, so, that should also increase your bioavailability and also should increase your accuracy.

However, in my opinion, I think from a patient safety perspective, I'd rather have a drug that's giving 3 to 5% in everyone and it's very reproducible and safe, rather than a drug that's very variable and where you're seeing sometimes 10%, but then 1% exposure in someone else. So, I think that's really what we need to work on here is just making sure we're delivering a clinically consistent amount of peptide to everyone and making sure the patients are safe throughout the process. 

About the Panelists:

Bobby Sciscento works at Alcami Corporation’s OSD facility located in Wilmington, NC as a Sr Scientist, Formulations. He holds a Master’s degree in Pharmaceutical Science from Campbell University. He has worked at Alcami for 5 years and in oral solid dose formulation development for 11 years. Bobby has supported multiple successful first in human IND applications and maintains a working knowledge of applying various drug development techniques to scalable industrial based formulations.

Trevor Williams works at Alcami Corporation’s OSD facility located in Wilmington, NC as a Sr Scientist, Formulations. He holds a master’s degree in Drug Discovery and Development from Rutgers University and an MBA from Quantic School of Business and Technology. He has worked at Alcami for 4 years and 11 years in total. Trevor has worked in both formulation development and analytical development over his career, currently supporting R&D development for multiple first in human IND applications. Trevor maintains a working knowledge of applying various drug development techniques to scalable industrial based formulations as well as doing early stage analytical development to help accelerate development timelines.

Zachary Morseth works at Alcami Corporation's Durham, NC facility as a Manager in the Bioseparations and Mass Spectrometry group. He holds a Ph.D. in Physical Chemistry from the University of North Carolina at Chapel Hill. He has over 15 years of combined academic and industry experience characterizing a wide range of macromolecules, including peptides, proteins, oligonucleotides, and polymers. He maintains a working knowledge of analytical techniques such as LC, CE, mass spectrometry, and biophysical characterization methods, supporting method development and validation for biologics across the drug development lifecycle.

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