In Vitro Characterization of Six Month Dosage Forms for a GnRH Antagonist

Susan D’Souza,Patrick P Deluca,Santos Murty,Jabar A Faraj

doi:10.1155/2014/435963

Abstract

The objective of this study was to develop long-acting injectable dosage forms of Orntide, a peptide GnRH antagonist, to provide tailored release for 6-month duration. Using a polylactide homopolymer and the solvent extraction/evaporation method, three microsphere formulations (Formulations A, B, and C) were prepared at various drug loadings (11.85–15.79%). The microspheres were characterized for particle size by laser diffractometry, surface morphology by scanning electron microscopy (SEM), and bulk density by tapping, as well as long-term in vitro drug release, mass loss and hydration at 37°C, and short-term in vitro drug release at elevated temperatures (51–59°C). Experiments at 37°C revealed that drug release was triphasic and occurred due to slow degradation of the polylactide polymer. Short-term in vitro release results indicated that drug release was diffusional. Application of the Higuchi equation to short-term release confirmed the temperature dependency of the diffusional rate constant. Using the rate constant and the Arrhenius equation, an Ea value of 45 kcal/mol (Formulation A) and approximately 25 kcal/mol (Formulations B and C) was obtained for diffusional release. Study results suggest that by selection of an appropriate biodegradable polymer, injectable dosing forms that release drug for 6 months or longer can be developed.

Highlights

Several reports document the challenges faced by pharmaceutical researchers in the area of drug delivery of large molecules [1,2,3,4,5]
Administration of large molecules like peptides and proteins in vivo is fraught with obstacles
Drug release continued slowly to reach approximately 10% in 15 days. This slow release behavior was maintained through day 60, where drug release was a modest 20–28%

Summary

Introduction

Several reports document the challenges faced by pharmaceutical researchers in the area of drug delivery of large molecules [1,2,3,4,5]. Choosing an alternate route of administration (e.g., parenteral, nasal) to deliver these types of large molecules does not provide significant advantages over oral administration due to the fact that they are rapidly degraded in body fluids, resulting in a short-half life in vivo [7]. Since proteins and peptides are generally considered to be highly potent molecules requiring administration of small therapeutic doses, a frequent dosing regimen is needed to maintain constant and continuous blood levels over a period of time. Such type of dosing is neither suitable nor ideal and often results in nonadherence to therapy, patient compliance issues, and increased costs [8]

Objectives

Methods

Results

Conclusion