Effect of dissolution media and additives on the drug release from cubic phase delivery systems

Abstract

Unsaturated monoglycerides such as monooleate or monolinoleate form a physically stable, highly viscous cubic phase in contact with excess aqueous medium. The swelling and release properties of drug-loaded monoglyceride matrices were evaluated with regard to the development of an oral sustained release delivery system. The swelling capacity of the amphiphilic monoglyceride matrix was higher in 0.1 M pH 7.4 phosphate buffer than in 0.1 N HCl. However, the drug release was opposite in trend, with propranolol HCl being released at a slower rate in pH 7.4 buffer. This was attributed to the presence of free fatty acids in the monoglyceride matrix, which were ionized at pH 7.4, but unionized in 0.1 N HCl. The formation of insoluble complexes with the cationic drug, propranolol HCl, at the higher pH explained the slower release. The incorporation of oleic acid in the monoglyceride matrices further confirmed the influence of fatty acids and was a tool to manipulate the release of cationic drugs. The inclusion of oleic acid and propranolol HCl resulted in the concentration- and pH-dependent formation of other mesophases besides the cubic phase. Varying the ionic strength of the dissolution medium had a minor effect on both swelling and drug release from the nonionic, amphiphilic monoglycerides. While the cubic phase stayed physically intact in enzyme-free simulated gastrointestinal fluids, the addition of bile salts to the pH 7.4 buffer resulted in the dispersion and disappearance of the swollen monoglyceride phase.

Introduction

Lipids have received considerable attention as alternatives to polymeric carrier or coating materials in the development of drug delivery systems. The major advantages of lipids versus polymers include their low melt viscosity — thus obviating the need of organic solvents for solubilization, the absence of toxic impurities such as residual monomers, catalysts and initiators, and the potential biocompatibility and biodegradability.

Amphiphilic lipids form various lyotropic crystalline phases in contact with water, depending on the structural properties of the lipid, the water content and the temperature. Unsaturated monoglycerides such as monoolein or monolinolein form a cubic phase in contact with water 1, 2, 3. The structure of the cubic phase can be described as a lipid bilayer extending in three dimensions separated by water channels. This cubic phase is transparent with gel-like structure of high viscosity. It is physically stable in contact with excess water. These properties have made the cubic phase an interesting sustained drug delivery system 4, 5, 6, 7, 8, 9. Because of its amphiphilic nature, both hydrophilic or lipophilic drugs can be incorporated. In a series of papers, the suitability of this phase as a delivery system for peptide drugs was investigated [10]. For oral drug delivery, the drug-loaded semisolid monoglyceride could be melt-filled into a gelatin capsule and then transformed in vivo in contact with gastrointestinal fluids into the cubic phase [11]. Sustained release has been shown with various water-soluble drugs.

It is well known that variations in the dissolution medium such as pH or ionic strength can significantly affect the drug release from polymeric drug delivery systems. With lipid drug delivery systems intended for oral use, the effect of bile salts also has to be investigated. The objective of this study was to investigate the effect of dissolution media and additives in the monoglyceride phase (e.g. oleic acid) on the water uptake and drug release from unsaturated monoglycerides intended as carriers for oral sustained release.