Oral-Absorption-Enhancing Drug-Delivery Technology - Pharmaceutical Technology

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Oral-Absorption-Enhancing Drug-Delivery Technology
The authors examine an oral-absorption-enhancement technology based on surface-active materials to increase apical membrane fluidity in vitro.

Pharmaceutical Technology
Volume 35, pp. s12-s14

GIPET technology platform

Product-development process. The in vitro/in situ studies on absorption enhancers typically are performed using cell monolayers, isolated tissue, or perfused rodent-intestinal segments using mixed solutions of the enhancer and test compound. Although such studies may produce useful data to compare compounds, they are not helpful in developing effective clinical dosage forms. Thus, in vivo studies in an appropriate species are needed to confirm the effects of enhancers in a drug-product formulation.

In working with the GIPET platform, Merrion Pharmaceuticals uses a preclinical animal model to produce reliable and predictive data to evaluate candidate compounds and suitable enhancers to take into the clinic. In the product-development pathway, cannulated beagle dogs are used for duodenal instillation to evaluate the effectiveness of GIPET systems to enhance specific drug products and GIPET enhancers. The specific steps are as follows:

  • Proof of concept: The active pharmaceutical ingredient (API) is evaluated in solution versus various formulations of the API and enhancer in solution
  • Formulation development: The emphasis is on optimizing dissolution and confirming stability
  • Phase I/II trials: Human PK and pharmacodynamic (PD) data are generated to match oral availability, biomarker, or clinical endpoints
  • Phase III development: The focus of the Phase III program is to develop an appropriate abbreviated new drug application package to be filed under Sec. 505 (b)(2).

Figure 1: Barriers to the intestinal absorption of hydrophilic and/or macromolecular compounds.
This model is designed to mimic human intestinal handling of the enteric-coated GIPET dosage form and the co-release of the drug and permeation enhancer in the duodenum and jejunum (see Figure 1). Delivery to the same site via the duodenal cannula decreases variability, thus increasing the sensitivity of the model and enabling accurate projections of drug/enhancer combinations and dose ranges for evaluation in clinical studies. Use of a larger species enables multiple PK samples to be taken from the same animal for each test formulation and for multiple test formulations for evaluation in the same group of animals, which also increases the power of discrimination between systems.

Figure 2: GIPET (Merrion Pharmaceuticals) manufacturing process.
The GIPET technology platform uses conventional solid oral dosage manufacturing equipment to allow for efficient technology transfer, scale-up, and use of high throughput equipment. The GIPET I technology produces a compressible powder form (see Figure 2), which can be blended, compressed, and coated as per conventional tablet excipients, thereby allowing for many formulation-development options with various molecule types.

The GIPET II and III platforms are based on liquid or semisolid fill of hard or soft gelatin capsules, a technology that is widely available. The emulsion systems are especially useful for the delivery of large lipophilic molecules (e.g., vitamin B12), and molecules that are more susceptible to primary metabolism because the intimate association with glyceride micelles may offer protection from enzymatic degradation. The micelle structures may also impart increased lipophilic characteristics to a compound, further aiding transcellular passage through the gut wall.

Mechanism of action. GIPET enhancers are surface-active materials and can act as mild surfactants, thereby increasing apical membrane fluidity in vitro and increasing the transcellular transport of normally excluded molecules. In vitro, they also have been shown to increase the paracellular transport route by contracting cytoskeletal actin filaments, which results in the opening of the TJ, thereby allowing for increased permeation of hydrophilic compounds (2, 3). GIPET materials form mixed micelle vesicular structures above their critical micelle concentration. At higher concentrations (i.e., their critical vesicle concentration), they form multilamellar micelle structures, also known as liquid crystals (4). Micelles and vesicles are dynamic structures, constantly forming and reforming under the influence of the changing environment of the intestine. It is probable that the active compound is entrapped within these mixed micelle structures via physical or electrochemical interaction. As a result of the intimate mix and co-release of the enhancer and drug from these systems, the latter may exhibit more lipophilic properties, thereby enabling larger or more highly charged molecules to cross the membrane. Incorporation into such structures also protects drug molecules prone to enzymatic degradation. GIPET enhancers also may inhibit efflux pumps (5).

Irrespective of the route of transport across the epithelial monolayer, maintaining concentrations of GIPET at the gut wall above the critical micelle concentration for longer time periods results in greater drug absorption. As a result, the drug payload and enhancer must be co-released at the target region of absorption in sufficient quantities to achieve therapeutically relevant systemic availability. GIPET achieves this condition by using enteric-coated tablets (GIPET I) or gelatin capsules (GIPET II and III) to synchronize release of drug and enhancer.


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