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

Researchers' solutions

Researchers at universities also are looking for methods of delivering peptides and proteins orally. A research team at Kyoto Pharmaceutical University created a gastrointestinal mucoadhesive patch system (GI-MAPS) consisting of four layered films contained within an enteric capsule. The system's backing layer is made of ethyl cellulose (EC), a water-insoluble polymer. Its surface layer is made of an enteric pH-sensitive polymer (e.g., hydroxypropylmethylcellulose phthalate) coated with an adhesive layer. The middle layer, made of cellulose membrane, contains the drug and permeation enhancers (e.g., organic acids and surfactants), and is attached to the backing layer by a heating-press method. The surface layer is attached to the middle layer with an adhesive layer made of carboxyvinyl polymer.

After oral administration, the system's surface layer dissolves and adheres to the mucosal membrane of the small intestine. This result creates a closed space that contains the drug and the absorption enhancer. The high-concentration gradient in the closed space causes the small intestine to absorb the protein through passive diffusion.

The GI-MAPS enabled the researchers to deliver recombinant human granulocyte colony-stimulating factor orally to dogs and obtain bioavailability of 23%. By collabotaing with the semiconductor industry, drug-delivery company BioSerenTach developd a machine that produces GI-MAPS under GMP conditions (5, 6).

Particulate systems, including solid lipid nanoparticles (SLN), have been investigated as carriers for peptides, proteins, and antigens. Scientists have incorporated proteins and antigens into SLN and administered them orally. SLN formulations have improved protein stability, protected proteins from degradation, and achieved sustained drug release. Cyclosporine A, insulin, calcitonin, and somatostatin have been incorporated into solid lipid particles and are currently being studied (7).

Researchers at St. John's University in Queens, New York, formulated oral dosage forms of β-lactamase (BLM) within self-nanoemulsifying drug-delivery systems (SNEDDS). The scientists composed a SNEDDS of propylene glycol monolaurate, polyethoxylated castor oil, and 2-(2-ethoxyethoxy)ethanol. They loaded approximately 2200 mU of BLM into the oil phase of SNEDDS using a solid-dispersion technique (8, 9).

In vitro tests of transporting BLM across a cell monolayer showed that the SNEDDS resulted in 33% cumulative transport of BLM at 5 h while the BLM free solution achieved negligible transport. Oral delivery of 4500 mU/kg of BLM in a SNEDDS to rats achieved a bioavailability of 6.34%, which was 1.5 times greater than that achieved by BLM free solution. Delivery of BLM in the aqueous phase of the nanoemulsion resulted in a pharmacokinetic profile similar to that obtained by the free solution (10). The scientists currently are continuing these studies.


Scientists have made progress in developing tablet formulations that can protect proteins from the digestive system and deliver them into the bloodstream. The level of bioavailability that current formulations achieve may not be adequate for clinical or commercial purposes, however. Even if these problems were to be solved, manufacturers would still need to develop new manufacturing and analytical methods that safeguarded proteins' stability and ensured their biological activity.


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