Bioavailability and efficacy characteristics of two different oral liquid formulations of albendazole

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Abstract

The oral bioavailability and anthelmintic efficacy in mice of a new formulation of albendazole (ABZ) dissolved in a solution of hydroxypropyl-β-cyclodextrin (HPCD) are compared with a conventional ABZ suspension of carboxymethylcellulose. Plasma concentrations of ABZ and albendazole sulphoxide (ABZ-SO), its active and main metabolite, were assayed by HPLC. The AUC0–∞ and Cmax values obtained for both ABZ and ABZ-SO, after administration of the ABZ–HPCD solution were significantly higher (P<0.01) than those obtained from the ABZ suspension. Although, the differences between the ABZ and ABZ-SO-Tmax values were found not to be significant, regardless of the formulation. The anthelmintic activities against enteral (pre-adult) and parenteral (migrating and encysted larvae) stages of Trichinella spiralis were studied in mice. The ABZ solution was more efficient against pre-adult and encysted larvae than the ABZ suspension. The efficacy differences between both formulations against the migrating larvae, were found to be not significant (P<0.05). For the migrating parasite stage, there was a linear correlation between the anthelmintic activity and pharmacokinetical parameters with respect to the ABZ-AUC0–∞ value. Meanwhile, for the muscular encysted parasite stage, better relationships were obtained for AUC0–∞ and Cmax values from ABZ-SO, which had correlation coefficients of 0.996 and 0.987, respectively.

Introduction

Albendazole (ABZ), methyl [5-(propyl-thio)-1-H-benzimidazole-2yl] carbamate, is a broad spectrum antihelmintic drug with low aqueous solubility, which may limit its oral absorption (Jung et al., 1998). In order to prepare ABZ solutions, different formulation approaches have been experimented in the last years. For instance, since ABZ is basic in nature, its solubility could be increased by ionisation in an acid medium, although this increase in solubility is not enough for the preparation of high ABZ concentration doses. Another way of increasing its solubility is by addition of surfactant agents, such as polysorbate and bile salts, or cosolvent agents, like Transcutol® (Torrado et al., 1996a, Torrado et al., 1997, Redondo et al., 1998). Some of these excipients may also have some absorption enhancer effects, which can be useful on increasing the oral bioavailability of ABZ formulations. Unfortunately, many of these agents can also be irritant to the digestive system linings and so its use must be restricted whenever possible. Alternatively, the ABZ solubility can be improved by elaboration of solid dispersions with polyvinylpyrrolidone (Torrado et al., 1996b, Lopez et al., 1997); although the elaboration method, rotatory evaporator and the use of organic co-solvents, and the high quantity/concentrations of the complexing agent are the application limiting factors for these products. Recently, the use of hydroxypropyl-β-cyclodextrin (HPCD), has facilitated the formulation of high concentration of ABZ solutions (Castillo et al., 1999, Piel et al., 1999).

The aim of this paper, is to compare the bioavailability and anthelmintic activities/characteristics of HPCD–ABZ solution-formulation to a conventional reference ABZ suspension in sodium carboxymethylcellulose. Moreover, the correlation between the bioavailability and anthelmintic efficacy was studied. Thus, different doses of ABZ (50–100 mg/kg) were orally administered to mice and blood samples were taken for analysis of ABZ concentration and its main metabolites by HPLC (Garcia et al., 1999). Furthermore, the anthelmintic activity of ABZ formulations was studied in the Trichinella spiralis model in mice at three different stages (pre-adult, migrating and encysted larvae) of the parasite infection. This in vivo model allows us to study the efficacy at both the enteral stage (pre-adult) and at the parenteral stage (migrating and encysted larvae). Therefore, the model can be used to verify whether a certain formulation might be indicated for various stages of helminthic infections or not (López-Garcı́a et al., 1997, López-Garcı́a et al., 1998).

Section snippets

Chemicals

ABZ and albendazole sulphone (ABZ-SO2) were kindly supplied by Glaxo-Smithkline (England). Albendazole sulphoxide (ABZ-SO) was a gift from Chemo Ibérica (Madrid, Spain). HPCD was supplied by Cerestar Ibérica (Barcelona, Spain). All the products and materials used in this study comply with the pharmaceutical and analytical standards, respectively.

ABZ formulations (8 mg/ml) and determination of dispensing error

  • ABZ solution was prepared by dissolution of ABZ in a solution of 20% (w/v) HPCD in 0.2 M HCl. The final pH of the solution was 0.92.

  • ABZ suspension was

Results and discussion

Fig. 1 shows the mean ABZ drug concentrations after the oral administration of the two different liquid formulations at doses of 50 and 100 mg/kg. It is clear from this figure that the cyclodextrin solution improves ABZ oral bioavailability in relation to the conventional oral suspensions. Due to fast ABZ degradation rate, its plasma concentrations are very low. Under our experimental conditions, its apparent elimination constant was 0.33±0.1 per h. For this reason, in our previous studies, the

Acknowledgements

We thank Dr Torrellas (Glaxo-Smithkline), C. Picornell (Chemo Ibérica) and J. Guerrero (Cerestar Ibérica) for kindly supplied us with different materials.

References (21)

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