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

Enterically coated tablets. To deliver biopharmaceuticals orally, Unigene Laboratories creates enterically coated tablets that include permeation enhancers and protease inhibitors, which prevent protein degradation. The protease inhibitor is citric acid, an organic acid that, when released from the tablet, creates a transient, localized, acidic microenvironment in which enzymes cannot readily break down the peptide.

The permeation enhancer is an acyl carnitine, L-lauroyl carnitine. By affecting calcium transport and levels of adenosine triphosphate within the epithelial cells of the intestine, the acyl carnitine temporarily loosens the tight junctions between these cells. This action frees the peptide to pass through these junctions by a mechanism called paracellular transport.

The tablet formulation is protected by a pH-sensitive, poly(meth)acrylate based enteric coat that remains stable in the acidic environment of the stomach. The coating, made from Evonik's Eudragit polymers, keeps the tablet intact and prevents the peptide from being absorbed in the stomach. When the tablet enters the duodenum, which is a neutral environment, the enteric coating dissolves. The location of drug release can be adjusted by using an Eudragit polymer of the appropriate pH. Altering the thickness of the enteric coating affects the timing of drug release and can help obtain the best bioavialability and consistency.

A water-soluble subcoat ensures that the enteric coating dissolves completely before the tablet releases its acid (i.e., the protease inhibitor) into the intestine. Otherwise, the release of the acid could prevent the rapid and complete dissolution of the enteric coat. The subcoat thus ensures that the formulation "is much more consistent in its release characteristics than it would have otherwise been," says Nozer Mehta, Unigene's vice-president of biological R&D.

Paracellular transport raises the risk that unwanted materials, such as other small, digested food-based peptides, may pass through the tight junctions after they have been opened. This risk is mitigated because the enteric coating is designed to remain intact until the tablet opens in a small area in the duodenum. The coating thus prevents acyl carnitine from opening tight junctions throughout the gastrointestinal tract. Unigene's studies also show that the tight-junction opening is a transient phenomenon (1). "If you gave the permeation enhancer 30 minutes in advance and then gave the peptide, you would not see any absorption, says Mehta.

Paracellular transport does limit the size of the molecules that can be delivered. Unigene has delivered insulin successfully, and it generally focuses on molecules made of fewer than 50–60 amino acids. "Large proteins probably would not work with our technology," says Mehta.

Peptides do not have to be derivatized or changed to be compatible with Unigene's oral technology. In addition, the method requires no special manufacturing equipment other than spray coaters to apply the subcoat and the enteric coat to the tablet.

Unigene and Tarsa Therapeutics recently completed a Phase III study of a calcitonin formulation made with Unigene's oral delivery technology. Unigene also is using the technology to develop a parathyroid hormone analog, currently in Phase II development, with GlaxoSmithKline.


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