Reformulating Injectables for Oral Delivery - Pharmaceutical Technology

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Reformulating Injectables for Oral Delivery
Could oral absorption-enhancing technologies change the shape of protein delivery?

Pharmaceutical Technology
Volume 35, Issue 10, pp. 48-56

Unigene’s tablet formulations use an enteric coat, protease inhibitors, and absorption enhancers to deliver peptides and proteins orally. (IMAGE IS COURTESY OF UNIGENE LABORATORIES)
Manufacturing obstacles. In addition to formulation challenges, manufacturing a protein-based tablet would entail many production difficulties. "The way that tablets and capsules are made today is not at all conducive to making a protein product," says Mike Pikal, Pfizer distinguished chair in pharmaceutical technology and professor of pharmaceutics at the University of Connecticut.

One major problem is that proteins must be incorporated into a matrix, typically a disaccharide. Most tablet-production facilities run at a controlled humidity of 40%, but because the disaccharide matrix is extremely hygroscopic, the formulation becomes a paste under those conditions, "and it's a mess," says Pikal. Operating a plant at 2% humidity would avoid this problem, but this solution could be impractical because the technology would be extremely expensive for a tablet manufacturing facility.

Another strategy might be to enclose much of the production line with barrier technology to keep oxygen and moisture out until the tablets are packaged. "Using the best of the techniques that are available, you can probably do that, but it's a significant engineering challenge," says Pikal. "While barrier systems are becoming common in parenteral operations, as far as I know, such systems are not available for tablet operations," he adds. It's also conceivable that a manufacturer would have to make major changes to the air-handling and humidity-control systems for its plant.

In addition, amorphous disaccharide matrices that contain proteins are not particularly compressible, so formulators would have to add ingredients (e.g., diluents or disintegrants) to achieve a mixture that could be made into a tablet more readily. Also, it seems unlikely that a protein formulation could be wet granulated, so processing methodology would be limited, says Pikal. The amount of excipients required likely would limit the amount of protein that the tablet could contain. As a result, the amount of protein in the tablet "is going to have to be awfully small," according to Pikal, and manufacturers might be limited to working only with potent proteins for their tablet.

Besides causing problems for the manufacturing process, moisture also can degrade the protein itself. "In some cases, you can break just one of those amino acid or disulfide bonds, and the activity of the molecule is destroyed," says Velez. A traditional wet granulator and tablet punch may not be peptide-friendly, he adds. A tableting method would need to ensure protein stability and activity throughout the process. This tableting process would have to include analytical methods to monitor the protein's structure. Personnel possibly could extract sample tablets during the process, for example, then extract the protein and analyze it with X-ray crystallography.


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