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

Oral absorption-enhancing technologies

Oral absorption-enhancing technologies are one way to address the problem of poor bioavailability encountered in biopharmaceutical drug delivery. Several specialty pharmaceutical companies have developed such technology platforms.

Passive transcellular transport through small-molecule carriers. One approach taken by the biopharmaceutical company Emisphere Technologies uses small-molecule carriers to enable the passive transcellular transport of drug molecules across cell membranes. The company has developed a library of about 4000 proprietary small-molecule compounds, including acylated amino acids. The compounds' molecular weights typically are less than 400 Da and are the basis of Emisphere's Eligen Technology.

The company uses a screening process to match the properties of its carriers (e.g., solubility) to those of the drug to be formulated. The goal is to find carriers that will help protect the drug and interact with it in the right way to deliver it into circulation.

The carriers and the protein are blended together in a conventional process, but manufacturers must control parameters such as heat to ensure that the protein is not damaged. "It's really, in most cases, blending the carriers and proceeding with the process as you would with any other oral drug," says Prateek Bhargava, Emisphere's manager of formulations. The carriers can be used in most processes (e.g., milling, blending, and compression) and require no special handling.

After blending, the carrier and protein engage in a weak, noncovalent interaction that does not alter the protein's form. The process is similar to that of physically mixing a small-molecule active ingredient and excipient. This interaction protects the protein from rapid degradation as it enters the acidic environment of the stomach and confronts enzymes in the small intestine. The carriers transport the therapeutic molecule through the gastrointestinal tract quickly, which also reduces the opportunity for protein degradation, says David Gschneidner, Emisphere's director of chemistry.

Unlike other carrier-based drug-delivery systems that typically use permeation enhancers, the Eligen Technology conveys its payload through passive transcellular transport. The carriers cause a transient fluidization of the membranes in the gastrointestinal tract, thus increasing their permeability. After the membrane absorbs the formulation, it closes again. "Typically, we start to see absorption in the stomach. It can also continue into the upper intestine, all the way through the small intestine, but we typically see a rapid uptake of the drug, says Gschneidner.

After the formulation enters the bloodstream, it is greatly diluted. The large volume of blood is enough to break the weak noncovalent bond between the carrier and the protein, thus causing the two to separate in a passive process. The carrier is eliminated through normal excretory processes.

The largest molecule that the Eligen Technology has delivered is human growth hormone, which has a molecular weight of about 22 kDa. The carriers also have been able to deliver heparin, which has a molecular weight of 12–15 kDa, and insulin, which has a molecular weight of almost 6 kDa.

Emisphere has not yet marketed an oral formulation of a large molecule, but has one product, salmon calcitonin, a 32-amino-acid linear polypeptide hormone, in Phase III clinical trials. The drug, a treatment for osteoporosis and osteoarthritis, is being developed jointly with Novartis. In addition, Emisphere is collaborating with Novo Nordisk on the oral delivery of glucagon-like peptide-1 (GLP-1) and insulin analogs. The GLP-1 analogs are in Phase I trials, and the oral insulin is in preclinical development.


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