Cubic phase gels as drug delivery systems

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Abstract

Lipids have been used extensively for drug delivery in various forms such as liposomes, and solid-matrices. The focus of this review is evaluation of liquid crystalline cubic phases, spontaneously formed when amphiphilic lipids are placed in aqueous environment, for drug delivery. Cubic phases have an interesting thermodynamically stable structure consisting of curved bicontinuous lipid bilayer in three dimensions, separating two congruent networks of water channels. The unique structure of cubic phase has been extensively studied using various spectroscopic techniques and their resemblance to biomembranes has prompted many scientists to study behavior of proteins in cubic phases. The ability of cubic phase to incorporate and control release of drugs of varying size and polar characteristics, and biodegradability of lipids make it an interesting drug delivery system for various routes of administration. Cubic phases have been shown to deliver small molecule drugs and large proteins by oral and parenteral routes in addition to local delivery in vaginal and periodontal cavity. A number of different proteins in cubic phase appear to retain their native conformation and bioactivity, and are protected from chemical and physical inactivation perhaps due to the reduced activity of water and biomembrane-like structure of cubic phase. Release of drugs from cubic phase typically show diffusion controlled release from a matrix as indicated by Higuchi’s square root of time release kinetics. Incorporation of drug in cubic phase can cause phase transformation to lamellar or reversed hexagonal phase depending on the polarity and concentration of the drug, which may affect the release profile. Biodegradability, phase behavior, ability to deliver drugs of varying sizes and polarity and the ability to enhance the chemical and/or physical stability of incorporated drugs and proteins make the cubic phase gel an excellent candidate for use as a drug delivery matrix. However, shorter release duration and the extremely high viscosity may limit its use to specific applications such as periodontal, mucosal, vaginal and short acting oral and parenteral drug delivery.

Introduction

Lipids of various types have been extensively studied for drug delivery by different routes of administration. Relatively hydrophobic lipids in the solid state have been used primarily as matrix material as carriers of hydrophilic drugs to provide sustained release orally and as a drug delivery carrier in solid implants. Amphiphilic polar lipids such as phospholipids when placed in water spontaneously forms thermodynamically stable lipid bilayers, which can assume various geometric shapes and structures. Liposome is one such example in which, amphiphilic lipids reorganize into closed circular lipid bilayers enclosing an aqueous phase, and they have been extensively studied for drug, protein and gene delivery. However, the spontaneous reorganization of amphiphilic lipids in aqueous environment can result in other three-dimensional structures such as the lamellar phase, the cubic phase, and transferosomes, which can be used for, drug delivery [1], [2], [3]. The structure of cubic phase has generated a lot of interest and is yet another exciting lipid-based system beginning to be explored for drug, protein and vaccine delivery [1], [2], [3], [4]. We will attempt to briefly review the origin, structure and phase behavior of cubic phase, followed by common techniques used to study cubic phases. The introduction to cubic phase will be followed by examining studies on drug delivery attempts using cubic phases and critically evaluate the potential of cubic phase as delivery system.

Section snippets

Phase behavior of amphiphilic lipids forming cubic phase

Polar amphiphilic lipids such as glyceryl monooleate (GMO) when placed in water reorganize into lipid bilayers forming a reversed micellar phase (L2) and three types of liquid crystalline phases (lamellar, reversed hexagonal and the cubic phase) depending upon the temperature and water content as shown in the phase diagram shown in Fig. 1 [1], [2], [4], [5]. The lamellar (Lα) phase has a long-range order in one dimension. Its structure consists of a linear arrangement of alternating lipid

Structure of cubic phases

The schematic structure of the cubic phase mentioned in the phase diagram is shown in Fig. 2 [1], [2], [4], [5]. Structure of the cubic phase is unique and consists of a curved bicontinuous lipid bilayer extending in three dimensions, separating two congruent networks of water channels. The water pore diameter of the fully swelled phase is about 5 nm and the phase is very viscous. The unique curvature of the bilayer as in the cubic phase is associated with an energy known as the curvature

Cubic phase as drug delivery system

As seen from above novel applications of cubic phase in recent articles, its unique structure has generated a lot of interest and is being studied as a model for physiological lipid membrane and how that influences the structure and activity of incorporated proteins. In contrast, very few researchers have shown interest in cubic phase gel for drug delivery, in spite of cubic phase possessing desirable physico-chemical properties for drug delivery [4], [29], [38], [39]. Almost all of the reports

Chemical stability enhancement in cubic phase gel

Ericsson et al. [4] in their first article on delivery of oligopeptides from cubic phase gel observed that the cubic phase protected the peptides from enzymatic degradation. The rate of enzymatic degradation of the renin inhibitor H214/03 in the cubic phase was 5.7% of that in a homogeneous solution representing intestinal fluids. The degradation rates were mainly dependent on the release rate of the peptide from the cubic phase to the surface during the experiment. H214/03, being a hydrophobic

Phase behavior and release characteristics of cubic phase gel

Very little is known about the degrees of freedom in cubic phase systems with respect to release duration, phase transformations, drug–bilayer interactions and rheological property and its impact on practical issues such as injectability. For the cubic phase system to be developed as an effective arsenal in drug delivery field, more research on the physical chemistry of cubic phase, and a basic understanding of the phase diagram and release kinetics and mechanism is required. Furthermore,

Potential of cubic phases as delivery systems and future direction

The unique structure and physicochemical properties of liquid crystalline cubic phase gel makes it suitable as a drug delivery matrix. The ability to incorporate and slowly release a variety of drugs with different physicochemical properties by a variety of routes of administration has been demonstrated. The similarity of cubic phase to physiological lipid membranes and its ability to incorporate and maintain protein in their native bioactive conformation is a unique attribute, extremely

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    1

    Present address: Pentech Pharmaceuticals, 417 Harvester Court, Wheeling, IL 60090, USA.

    2

    Present address: Genzyme Corporation, 45 New York Avenue, P.O. Box 9322, Framingham, MA 01701-9322, USA.

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