Microemulsion formulation for enhanced absorption of poorly soluble drugs: II. In vivo study

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Abstract

Oral administration study of microemulsion formulations, which are known to improve the bioavailability of poorly soluble drugs, was performed using rats. Nitrendipine was used as a poorly soluble model drug, and its absorption was enhanced significantly by employing the microemulsion formulations compared to a suspension or an oil solution. The effect of the fed state on the oral absorption of nitrendipine became insignificant with the microemulsion formulations, although it affected the absorption from the suspension formulation significantly. The absorption behavior also varied with the type of surfactant. The absorption from Tween 80-based formulation was very rapid, while HCO-60-based formulation showed prolonged plasma concentration profile. However, the absorption from BL-9EX (polyoxyethylene alkyl ether)-based formulation was hardly observed. Damage to the gastrointestinal mucosa, which seems to be a serious problem of surfactant-based formulations, also differed with the type of surfactant employed. HCO-60 and Tween 80-based formulations were mild to the organs, while BL-9EX-based formulation caused serious damage. The behavior and absorption mechanism of the microemulsion formulations are discussed.

Introduction

Recent progress in combinatorial chemistry has made possible automatic production of a great member of new compounds. Today, a good chemist may synthesize thousands or tens of thousands compounds per year, while only 50 to 100 compounds could have been produced by the same chemist 10 years ago [1]. However, these automatically produced compounds often show poorly-soluble behavior against water and their bioavailability is usually low. Techniques to enhance their absorption after oral administration is very important.

Many techniques have been developed to enhance the absorption of poorly-soluble drugs [2], [3], [4], [5]. Most of them increase surface area of drugs to improve solubilization behavior. One promising technology is the self-emulsifying drug delivery system (SEDDS) [6], [7]. The SEDDS is a mixture of an oil and a surfactant which contains drugs, and it forms oil-in-water emulsion spontaneously in aqueous media under mild agitation. When it is administered to men, emulsion droplets should be smaller than those in vitro, because bile salts would be incorporated into the surfactant layers of the emulsion droplets. The great increase in the interfacial area promotes release of the drug molecules from the droplets and their absorption. The SEDDS is reported to improve the reproducibility of the plasma profile [6] and bioavailability [7].

Recently, various efforts have been made to utilize microemulsion (ME) [8], [9] as a formulation technique [10], [11], [12], [13], [14], [15], and it has been applied to a formulation of a poorly-soluble immunosuppressant for oral administration [12], [13], [14]. The enhancing mechanism of ME formulation is very similar to that of an SEDDS. However, it is less affected by bile salts, because it can form very small droplets ranging from ca. 1 to 100 nm without their participation. This suggests that the absorption behavior of drugs would be less affected by the amount of the bile salts compared to an SEDDS. It has been reported to make the plasma concentration profiles and bioavailability of drugs more reproducible than an SEDDS [12], [13], [14].

The administration of the oral ME formulation is achieved by a soft capsule which contains an oil solution of drug and surfactants. In the previous paper [10], we proposed various types of ME formulation prescriptions. The most suitable surfactants among those tested were HCO-40, HCO-60, Tween 80, BL-9EX, and Pluronic P84. Notably, Tween 80 and BL-9EX could form ME without the aid of cosurfactants. Propyleneglycol monoalkyl ester and glycerol monoalkyl ester were the most suitable oils for solubilization into the surfactant solutions, and enhanced solubility was observed by mixing different types of oils. This study investigated the effectiveness of these ME formulations in vivo.

Section snippets

Materials

The oils and surfactants used in this study were the same as those of the previous paper [10]. Nitrendipine was obtained from Wako Pure Chemical (Osaka, Japan). All the reagents were of the highest purity available and used as supplied.

Preparation of formulations

The prescription of each formulation is listed in Table 1. The compositions of the ME formulations were based on the solubilization study of oil into 10 wt% surfactant solutions as shown in Fig. 1 (see Results). The detailed procedure of this experiment was

Prescription of ME formulations

We found several types of ME formulations in the previous study [10]. Some were formed with only nonionic surfactants, while others needed highly surface-active charged surfactants. Fig. 1 shows examples of the screening study. When a small amount of MCG/DCPG mixture was added periodically to the 10 wt% C12E9 solution at 37 °C, it solubilized 10 wt% oil independent of the presence of SDS as a cosurfactant. Tw80 solution solubilized 20 wt% of oil in the absence of SDS, but the solubilization

Discussion

ME formulations are considered to be a promising formulation technique, because the enhanced absorption of poorly-soluble drug becomes more and more important problem to overcome recently. The reality of this type of formulation was proved by the launch of the immunosuppressant formulation. However, much remains unknown about ME formulations. For example, we hardly know what kind of ME formulation is effective. Our in vivo study showed that three ME formulations exhibited different absorption

Conclusions

Oral administration study of three types of ME formulations was performed using rats. The effect of the fed state was reduced for all the ME formulations compared to the suspension and the solution. This is likely to be due to the ME droplets mimicking bile salt micelles. Enhanced and prompt absorption were also observed but depended on the type of surfactant used. It was suggested that too stable ME, that is, one which formed very quickly and has sterically protected interfacial structure, is

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