, Volume 4, Issue 2, pp 65-77
Date: 20 Aug 2012

Oral delivery of hematopoietic factors

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Abstract

As a second wave of biopharmaceuticals, oral protein/peptide delivery systems have been studied and applied to hematopoietic factors such as erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF). Many conventional oral drug-delivery systems such as absorption enhancers, emulsions, liposomes, microcapsules and nanocapsules, protein-unfolding technology, protein conjugates, and colon delivery technology have been challenged for the development of oral hematopoietic factor preparations. Those drug-delivery systems were designed to solve two hurdles: hydrolytic degradation by the digestive enzymes and poor membrane permeability of hematopoietic factors due to their three-dimensional structures. Furthermore, all of the trials have faced a hurdle of low bioavailability, because the dilution and spreading of an absorption enhancer in the gastrointestinal tract reduces the effect of the absorption enhancer on hematopoietic factors. To solve these problems, the gastrointestinal mucoadhesive patch system (GI-MAPS) was designed.

The GI-MAPS is based on a patch formulation composed of three layers: (i) a water-insoluble basement membrane; (ii) a drug-carrying layer; and (iii) a pH-sensitive bioadhesive surface membrane. After oral administration, the surface layer dissolves at the targeted intestinal site and adheres to the small intestinal wall, where a closed space is created on the target site of the gastrointestinal mucosa by adhering to the mucosal membrane. As a result, both the drug and the absorption enhancer coexist in the closed space and a high-concentration gradient is formed between inside the system and the enterocytes, which contributes to the enhanced absorption of hematopoietic factors because most drugs are absorbed by a passive-diffusion mechanism. As a result, the absorption enhancer makes full use of its capacity.

The GI-MAPS was applied to both G-CSF and EPO and feasibility studies were performed in rats and dogs. The Eudragit™ L100 GI-MAPS containing both G-CSF and HCO-60™ as an absorption enhancer showed a physiologic availability of 23% in dogs and the total white blood cell count peaked at 170% after administration. The GI-MAPS containing EPO and Labrasol™ as an absorption enhancer showed a bioavailability of 12.1% in rats. Thus, the GI-MAPS proof of concept has been clarified.

As the GI-MAPS is a novel drug-delivery system preparation, the fabrication method is the second hurdle to overcome in the launch of an oral preparation of hematopoietic factors. However, recent advances in microfabrication technology in the semiconductor industry have made it possible to produce many micron-size GI-MAPS. Several approaches to produce the micron-size GI-MAPS are described and the future of these technologies is discussed.