Effects of synthetic lipids on solubilization and colloid stability of hydrophobic drugs

https://doi.org/10.1016/S0021-9797(02)00103-0Get rights and content

Abstract

Aqueous miconazole (MCZ) aggregates were solubilized and/or colloidally stabilized by bilayer-forming synthetic amphiphiles such as dioctadecyldimethylammonium bromide (DODAB) or sodium dihexadecylphosphate (DHP) dispersions. Particle sizing, light absorption and scattering from drug particles, zeta-potential determination, and drug aggregation kinetics from turbidity changes in the presence or absence of lipid dispersions were obtained over a range of drug and lipid concentrations. The very low solubility of MCZ in water made possible the determination of size distributions for drug particles in water and comparison to those in the presence of DODAB or DHP nanosized bilayer fragments or entire and closed bilayer vesicles. Large drug aggregates disappeared upon incubation with nanosized bilayer fragments produced by ultrasonic dispersion with tip. Light-absorption spectra for MCZ in a poor solvent (water), in a good organic solvent (methanol), and in different lipid dispersions showed that solubilization depended on the presence of bilayer fragments. MCZ was poorly soluble in dispersions formed of closed bilayers (vesicles) of DODAB or DHP in the gel state and in phosphatidylcholine (PC) vesicles in the liquid-crystalline state. Increased hydrophobicity at the borders of bilayer fragments explained MCZ solubilization. At [MCZ]>0.4 mM, kinetics of drug aggregation, zeta-potential measurements, and size minimization were obtained upon addition of minute amounts of oppositely charged bilayer fragments ([DHP]=0.05 mM), making possible determination of a remarkable stabilizing effect of drug particles by coverage with anionic bilayer fragments. High drug colloid stability in the presence of charged bilayer fragments was achieved by two different means: (1) at large drug concentrations and small concentrations of bilayer fragments, coverage of large drug particles with bilayer fragments; (2) at large amounts of bilayer fragments, drug solubilization in its monomeric form at the borders of bilayer fragments. Inexpensive, synthetic bilayer fragments offered a large area of hydrophobic nanosurfaces dispersed and electrostatically stabilized in water, opening new prospects for drug solubilization and colloid stabilization of insoluble drug particles.

Introduction

The extreme versatility of supramolecular assemblies [1], [2], among them bilayers [3], could be advantageously explored for the controlled construction of new materials [4], [5], [6], [7], [8], [9], [10], [11]. From the observation of biological wisdom in nature, it had been recognized that intermolecular interactions form the basis of highly specific recognition, reaction, transport, and regulation processes such as enzymatic reactions, substrate binding, transcription and translation of genes, and cellular recognition. Vesicles and other bilayer assemblies, though ephemeral, produced useful devices either by deposition onto polymeric, mineral, or biological surfaces [3], [4], [5], [6], [7] or by acting as templates for direction of inorganic matter deposition, redox processes, or polymerization reactions [8], [9], [10], [11]. In biology and medicine, they offered a suitable matrix to solubilize and/or carry drugs [12], [13], [14], [15], [16], [17], [18], [19] or biomolecules [20], [21], [22], [23], [24], either as entire entities or as complexes with the biomolecule or drug to be carried.

On the other hand, there were two clinically important classes of antifungal hydrophobic drugs: the polyenes (e.g., amphotericin B) and the azoles (e.g., miconazole). See Ref. [25] for a review. The self-assembly of amphotericin B (AB) [13], [14], [15], [16] at hydrophobic sites of synthetic bilayer fragments [26], [27], [28], [29], [30] was recently reported [31]. Some double-chained synthetic or natural lipids self-assemble, yielding closed bilayers (vesicles) or disrupted vesicles (bilayer fragments or disks), depending on the procedure used to disperse the lipid [26], [27], [28], [29], [30]. In the case of bilayer fragments, another important component of the interaction drug aggregate/bilayer had to be considered, the extraattractive interaction between the hydrophobic drug particulate and the hydrophobic borders of the bilayer fragment. In this work the low solubility of miconazole (MCZ) in water was explored to obtain a size distribution for the drug powder in pure water, both in the presence and in the absence of nanosized bilayer fragments or more traditional lipid dispersions composed of entire vesicles. Drug solubilization and colloid stability were followed from drug absorption spectra and turbidity kinetics of drug aggregation in the different aqueous media. The results showed that synthetic bilayer fragments offered extra solubilization sites useful as receptive hydrophobic surfaces at their hydrophobic borders. The hydrophobic interaction between drug and bilayer fragments possibly involved the hydrophobic moiety of the drug and exposed hydrocarbon regions at the border of the one-bilayer disk. Furthermore, upon addition of minute amounts of anionic DHP bilayer fragments, when large drug particles remained insoluble in water, low and steady turbidity values which did not change with time revealed remarkable colloid stability for negatively charged drug particles, possibly achieved due to coverage of drug particles with anionic bilayers.

Section snippets

Experimental

Dioctadecyldimethylammonium bromide (DODAB), sodium dihexadecylphosphate (DHP), and phosphatidylcholine (PC) were from Sigma with the highest purity available. Lipids were dispersed in water using procedures that yielded vesicles and/or bilayer fragments. Sonication with tip [32], [33] was the method employed for producing cationic DODAB or anionic DHP bilayer fragments in the rigid gel state at room temperature [3], [26], [27], [28], [29], [30]. This procedure dispersed the amphiphile powder

Miconazole solubilization in synthetic bilayer fragments

Light absorption spectra for MCZ in the presence of DODAB dispersions obtained by sonication with tip or by ethanolic injection in water were very similar to MCZ spectra in a good organic solvent such as methanol (Figs. 1A–C). In contrast, MCZ optical spectra in a DODAB lipid dispersion of entire, closed bilayer vesicles (Fig. 1E) were similar to those in water (Fig. 1D), a very poor solvent. The comparison of optical spectra for the drug in water (Fig. 1D), CH3OH as a good organic solvent (

Discussion

This work addresses two important issues which are essential for drug formulation: drug solubilization and drug particle colloidal stabilization. When solubilization was restricted by reducing bilayer fragments concentration, the results clearly showed that insoluble drug particles could be well stabilized against further aggregation by just minute amounts of oppositely charged synthetic bilayer fragments.

Although the liquid crystalline state of the PC bilayer at room temperature should have

Acknowledgments

FAPESP, CNPq, and CAPES are gratefully acknowledged for financial support. L.F.P. was the recipient of a CAPES Ph.D. fellowship.

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