Phase behavior of the microemulsions and the stability of the chloramphenicol in the microemulsion-based ocular drug delivery system

Abstract

Microemulsion systems composed of Span20/80 + Tween20/80 + n-butanol + H₂O + isopropyl palmitate (IPP)/isopropyl myristate (IPM) were investigated as model systems of drug carriers for eye drops. Effects of chloramphenicol, normal saline, sodium hyaluronate and various oils on the phase behavior were studied. The phase transition was investigated by the electrical conductivity measurements. The electrical conductivity of the microemulsion was affected by the encapsulation of the drug into the system, and the addition of normal saline and sodium hyaluronate. The chloramphenicol is used to treat the diseases such as trachoma and keratitis. However, this drug in the common eye drops hydrolyzes easily. The main product of the hydrolysis is glycols. Here, the chloramphenicol was trapped into the oil-in-water (o/w) microemulsions and its stability was investigated by the high performance liquid chromatography (HPLC) assays in the accelerated experiments of 3 months. Its location in the microemulsion formulations was determined by means of ¹H NMR spectroscopy. The results of HPLC revealed that the contents of the glycols in the microemulsion formulations were much lower than that in the commercial eye drops at the end of the accelerated experiments. It implied that the stability of the chloramphenicol in the microemulsion formulations was increased remarkably. The NMR experiments confirmed that the chloramphenicol molecules should be trapped into the hydrophilic shells of the microemulsion drops, which was composed of many oxyethylene groups. The nitro-groups of the chloramphenicol molecules were near the α2-CH₂ of the surfactant molecules and the benzene rings of the chloramphenicol molecules were near the oxyethylene groups of the surfactant molecules. It was this reason that enabled the chloramphenicol molecules in the microemulsions to be screened from the bulk water and its stability to be increased remarkably.

Introduction

The microemulsions are transparent, thermodynamically stable multi-component fluids (Eicke et al., 1994, Gradzielski and Hoffmann, 1994), normally composed of an aqueous component, an oily component, an amphiphile as emulsifying agent and frequently a co-surfactant (usually an alkanol of intermediate chain length). Basically, there are three different types of microemulsions: oil-in-water (o/w), water-in-oil (w/o) and finally, bicontinuous structures (B.C.).

Eye drops are the most used dosage form by ocular route and chloramphenicol (see Fig. 1) is the main effective drug in the common used eye drops. However, the eye drops have several disadvantages, such as a very low bioavailability (1–10%) of the drugs, which must be absorbed at this site and must be inserted several times a day (Jarvinen et al., 1995). Also, the effective component, that is chloramphenicol, has very low solubility in water and easily hydrolyzes (see Scheme 1). The main product of the hydrolysis is glycols. If the content of the glycols becomes higher than the authorized amount, it would cause the content of chloramphenicol to be lower than the standard (the content of chloramphenicol in the eye drops should not be less than 0.25%). Then, the chloramphenicol eye drops turn into unqualified (The Pharmacopoeia Committee of State, 2000).

For several years, microemulsions have been investigated as new drug delivery systems and their potential applications in ophthalmology have been studied by several research teams (Vandamme, 2002). Formulations based on microemulsions have several interesting characteristics such as the enhancement of the drug solubility, good thermodynamic stability and ease of preparation (Peira et al., 2001, Trotta et al., 2003). However, the points, which are needed to study, of the drug-loaded microemulsions are where the drug molecules are located and how the stability of the drug molecules are increased. The methods of ¹H NMR spectroscopy and HPLC assay have been proven to be particularly useful in this field (Kreilgaard et al., 2000, Soderman and Nyden, 1999).

As far as chloramphenicol eye drops are concerned, it is desirable that the chloramphenicol molecules could be incorporated into the oil core or palisade layer of the o/w microemulsion drops, so the hydrolysis is avoided and its stability could be increased. Furthermore, the release of the drug molecules from the drops of the microemulsion may be delayed, thus a delayed effect would be expected (Sarciaux et al., 1995). In the present work, the pseudo-ternary phase diagrams of various microemulsion systems were constructed and the phase transitions were investigated by the electrical conductivity measurements. Effects of chloramphenicol, normal saline, sodium hyaluronate and various oils on the phase behavior were studied. The stability of the chloramphenicol molecules was monitored in the accelerated experiments through HPLC assay and the locations of the chloramphenicol molecules in the microemulsions were determined by ¹H NMR spectroscopy.