Changed crystallinity of mebendazole solid dispersion: Improved anthelmintic activity

https://doi.org/10.1016/j.ijpharm.2010.10.002Get rights and content

Abstract

To improve the efficacy of mebendazole (MBZ), a poorly water-soluble drug, MBZ solid dispersions containing different proportions of low-substituted hydroxypropylcellulose (L-HPC) were prepared by lyophilization process. The physical characteristics of recrystallized MBZ, and solid dispersions (SD) at different MBZ:L-HPC proportions were investigated in terms of morphology (scanning electron microscopy, SEM), powder X-ray diffraction (XRD), differential scanning calorimetry (DSC) and dissolution rate. The in vivo performance was assessed by anthelmintic activity studies against enteral (pre-adult) stage of Trichinella spiralis in mice. The XRD, DSC and SEM revealed a characteristic decrease in crystallinity when increasing the L-HPC proportions in the solid dispersions. The dissolution studies demonstrated a marked increase in the dissolution rate in comparison with recrystallized drug. The considerable improvement in the dissolution rate of MBZ from solid dispersions was attributed to decreased drug crystallinity and altered surface morphology (major) and to the wetting effect of L-HPC (minor). The in vivo studies revealed that the anthelmintic effects of solid dispersions in mice were significantly increased in comparison with recrystallized MBZ (1.74-fold for SD-1:1, 3.20-fold for SD-1:2.5 and 3.80-fold for SD-1:5). These results have shown the suitability of MBZ:L-HPC solid dispersions for the treatment of enteral helmintic diseases at low doses.

Introduction

Mebendazole (MBZ), methyl-5-benzoyl benzimidazole-2-carbamate, a broad-spectrum anthelmintic drug of the benzimidazole class, effective against a number of nematodal and cestodal species under oral administration as tablets or suspension, is recommended for the treatment of non-surgical cases and as a supplementary treatment prior to and post-surgery (Agatonovic-Kustrin et al., 2008). However, it has been observed that in vivo results are far from being as effective as those demonstrated in vitro due to its low absorption at the gastrointestinal level. The possible reason for variable low efficiency of benzimidazole derivatives may be attributed to the low water solubility of the drugs which limits their absorption resulting in low bioavailability (Daniel-Mwambete et al., 2004). Therefore a high dose of MBZ is required for helminthic infections causing many adverse effects. Furthermore the information available concerning the effectiveness of various benzimidazole derivatives (e.g., flubendazole, albendazole, mebendazole) is somewhat inconsistent (Maki and Yanagisawa, 1988, Chung et al., 2001, Siriyasatien et al., 2003). Thus the observation of different therapeutic outcomes have been to some extend attributed to the different polymorphs with different dissolution rates and anthelmintic activities (Rodriguez-Caabeiro et al., 1987, Swaneppoel et al., 2003a, De Villiers et al., 2005).

A possible way of overcoming the MBZ low aqueous solubility is to alter the physical properties of the drug by preparing a solid dispersion (SD). The solid state forms (i.e., crystalline polymorphs, solvates, amorphous solids) of a drug substance can have a significant impact on the drug's solubility, dissolution rate, activity and bioavailability. Low-substituted hydroxypropylcellulose (L-HPC), as an inert carrier, has been used by many authors for obtaining solid dispersions of poorly soluble drugs (Leuner and Dressman, 2000, Ambike et al., 2004, DiNunzio et al., 2010). It is well known that the solid dispersion system increases the solubility and the dissolution rate of the drug by simultaneously reducing drug particle size and altering the drug crystal form, usually to an amorphous state, therefore they have shown an increase in drug bioavailability (Daniel-Mwambete et al., 2004, Mutalik et al., 2008, Onoue et al., 2009, Kawabata et al., 2010). The objectives of present study were: (i) to evaluate the feasibility of L-HPC in altering the crystalline property of MBZ and enhancing its dissolution rate by preparing solid dispersions using a freeze-drying method and (ii) to determine the in vivo anthelmintic efficacy of formulations with high MBZ solubility at a low dose of 1 mg/kg.

Section snippets

Materials

The materials used were as follows: MBZ (Sigma®, St. Louis, MO, USA) and L-HPC (LH-31, hydroxypropoxy content: 11%, Shin-Etsu®, Tokyo, Japan). All other chemicals reagents were of pharmaceutical grade or better.

Preparation of formulations

MBZ solid dispersions were prepared by conventional solvent method using L-HPC as a carrier. The solid dispersions of 1:1; 1:2.5; 1:5; and 1:10 (w/w) of drug to carrier were prepared. The required amounts of MBZ and L-HPC were co-dissolved in a minimal volume of a water:formic acid

SEM characterization

SEM was used to clarify the surface and shape characteristics of different samples (MBZ raw material; recrystallizated MBZ; PM-1:10; SD-1:1; SD-1:5 and SD-1:10). The MBZ raw material presented an acicular form (Fig. 1a). While the recrystallized MBZ observed at the same magnification (2000×) showed similar acicular forms to the pure drug (Fig. 1b). This recrystallized form sample presented fine crystals covering their surface, which may be generated due to the lyophilization process. Therefore,

Conclusions

MBZ:L-HPC solid dispersions are significantly (P < 0.05) more active than the conventional MBZ suspension at a low dose of 1 mg/kg against the enteral stages of a murine T. spiralis infection. The mixed use of SEM, XRD and DSC techniques let us know the reasons for an enhancement of the MBZ dissolution rate when formulated as L-HPC solid dispersions, attributed to reduced drug crystallinity and altered surface morphology (major) and to the wetting effect of L-HPC (minor). SEM was an especially

Acknowledgements

This work has been supported by a project from University Complutense of Madrid (project number: 910939). CIBEREHD is funded by the Instituto de Salud Carlos III.

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    AHCC® was used as pre-treatment during the fourteen days before the infection until the experiment was over. To evaluate the anthelmintic efficacy, the whole groups were orally infected with 300 ± 50 Trichinella spiralis L1, isolated from infected mouse carcasses, following an artificial digestion [21]. ABZ treatment was administered 24 h post infection (p.i.).

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