No More Needles: Minitab Aids Pharmaceutical Research in Oral Protein Delivery

For patients diagnosed with chronic diseases such as diabetes, managing symptoms often requires multiple daily injections of medications, such as insulin.

Unfortunately, insulin and many other injectable treatments are only effective when inserted with a needle and syringe into the fat underneath human skin. The proteins in these drugs are extremely sensitive to the human digestive tract, and are often digested before they can enter the patient’s bloodstream and take effect.

But what if protein-based drugs like insulin could be taken orally, rather than being injected? Patients dealing with diabetes could do away with unpleasant injections, and instead rely on the convenience of pills to take their treatments.

Dr. Hajaratul Najwa Mohamed, lecturer and researcher at the Terengganu Advanced Technical University College (TATIUC) in Malaysia, lead a clinical research study to encapsulate protein into a pill-based formula that would resist deterioration in the human gastrointestinal tract and release effectively into a patient’s bloodstream. To optimize the protein encapsulation formula that delivers the controlled and targeted release of drugs orally to patients, Dr. Mohamed used Minitab Statistical Software.

Recent research has indicated that biodegradable and biocompatible polymers could successfully be used for the encapsulation of protein after they’ve undergone a special process to become structured into bead-like formulations. But which types of polymer beads and at what levels would provide the optimal release of protein into the bloodstream?

Dr. Mohamed studied two biodegradable polymers—alginate and konjac glucomannan (KGM). These polymers are both naturally occurring and indigestible, making their bead-like formulations excellent vehicles for carrying proteins through the harsh environment of the human gut.

Applying a statistical technique known as design of experiments (DOE), Dr. Mohamed used Minitab to plan and perform an experiment to assess three response variables—overall protein encapsulation efficiency (PEE), protein release percentage at 2 hours after ingestion, and the time for the ingested protein to be fully released—on varying amounts of alginate and KGM beads. The experiment itself was done “in vitro,” or in a simulated environment to mimic how the encapsulated pills would behave after being ingested. A model protein, bovine serum albumin (BSA), was chosen for the experiment because it is representative of the typical protein that would be encapsulated.

Dr. Mohamed chose to run a central composite DOE, which is a commonly used response surface design. “Using a statistical tool like Minitab and choosing a central composite design is very useful in pharmaceutical research because it helps us to study the effect of independent variables and how they influence responses when changed simultaneously,” Mohamed says. “This approach provides statistically reliable results with fewer experimental runs.”

With a two-factor response surface design, amounts of alginate and KGM were tested at three levels using eleven experimental runs.

Dr. Mohamed then used Minitab to create 3D surface plots of the experiment data to visualize the effects of alginate and KGM on overall protein encapsulation efficiency, protein release percentage at 2 hours after ingestion, and the time for the ingested protein to be fully released into a person’s bloodstream.

response surface plot

Surface plots, like the one shown above, helped Dr. Mohamed understand the effects of the factors on each response, and she learned that the percentage of protein encapsulation efficiency increases as both alginate and KGM increase.

Also using Minitab, Dr. Mohamed created 2D contour plots to provide a visual illustration of response values, which allowed her to further analyze how varying amounts of the factors affected the response variables.

contour surface plot

Finally, Dr. Mohamed used Minitab’s Response Optimizer to determine the optimum levels of alginate and KGM across all three responses. “The optimal response was obtained at 4 percent alginate and 0.6 percent KGM,” she says. “This formulation effectively enhanced the stability of the encapsulated protein in an acidic environment simulating the human gastrointestinal tract and showed suitable gradual protein release after the fact.”

While this study can’t exactly mimic how encapsulated proteins will perform when ingested by real humans, its results can be used to further research on this topic.

“The findings of this study show that optimal levels of alginate and KGM have the potential to be used as a delivery vehicle for protein drugs, thus moving away from frequent painful injections of protein drugs as we do today,” Mohamed says. “Next, I would like to focus my research specifically on encapsulating insulin, and the same optimization techniques I performed using Minitab for this research will be invaluable in future studies.”

This research was published in an article in Volume 5, Issue 2 of the International Journal of Current Pharmaceutical and Clinical Research.

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