Establishment of new preparation method for solid dispersion formulation of tacrolimus

Abstract

The aim of this study was to establish a new preparation method for solid dispersion formulation (SDF) of tacrolimus, a poorly water-soluble drug, without dichloromethane, because no use of dichloromethane is recommended by ICH harmonized tripartite guideline. To select the appropriate carrier, three different SDFs with polyethylene glycol 6000 (PEG 6000), polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) were prepared by the conventional solvent method, in which tacrolimus and the carrier were completely dissolved in the mixture of dichloromethane and ethanol. Powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC) patterns indicated that tacrolimus exists in an amorphous state in all three SDFs. The supersaturated dissolution profiles of tacrolimus were observed in all SDFs, and the highest level of supersaturation for tacrolimus was obtained and maintained for 24 h from SDF with HPMC. On the other hand, the supersaturated level from SDF with PEG 6000 or PVP decreased rapidly. The in vivo oral absorption study in dogs showed that bioavailability of tacrolimus from SDF with HPMC was remarkably improved compared with the crystalline powder. It was clarified that HPMC is the most appropriate carrier for SDF of tacrolimus. Then, SDF of tacrolimus was prepared by the new method, which allows us to make SDF of tacrolimus by swelling HPMC with ethanol, in which tacrolimus was completely dissolved. This new method does not need dichloromethane. The physicochemical properties of SDF with HPMC prepared by the new method were the same as those of SDF prepared by the conventional solvent method. Furthermore, SDF with HPMC prepared by the new method was still stable after stored at 40 °C for 3 months. The pharmacokinetic parameters after oral administration in monkeys showed no significant difference (P>0.01) between SDFs with HPMC prepared by the two methods. In conclusion, we have established the new preparation method for SDF of tacrolimus with HPMC and the new method makes it possible to prepare SDF of tacroliumus without dichloromethane.

Introduction

Tacrolimus (Fig. 1), which is a 23-member macrolide lactone with potent immunosuppressive activity, was isolated from Streptomyces tsukubaensis in 1984 (Kino et al., 1987a, Kino et al., 1987b). Tacrolimus is a poorly water-soluble compound, which has the low solubility in water, about 1–2 μg/ml (Hane et al., 1992) and showed relatively low bioavailability (Honbo et al., 1987). In order to enhance the oral absorption of tacrolimus, Honbo et al. (1987), reported that oily ethanol formulation and solid dispersion formulation (SDF) are most potent among many different formulations of tacrolimus examined.

SDF, which was developed by Chiou and Riegelman (1971), is the formulation that possibly enhances the dissolution rate, solubility and oral absorption of a poorly water-soluble drug. Swarbrick (1990), Shargel (1993) and Craig (2001) discussed the increase in drug dissolution rate from SDF and they concluded that the dissolution rate was increased by the following factors: (1) the reduction of the drug particle size to molecular level, (2) the solubilizing effect on the drug by the water-soluble carrier, and (3) the enhancement of the wettability and dispersibility of the drug by the carrier material. According to the definition of SDF, both a given drug and carrier should be completely dissolved with organic solvents (solvent method) or fused by the heating (melting method) in order to prepare SDF. With regard to carriers for SDF, many carriers such as polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, gelucires, eudragits and chitosans have been reported to improve the solubility and bioavailability of poorly water-soluble drugs (Okimoto et al., 1997, Portero et al., 1998, Jung et al., 1999, Kohri et al., 1999, Trapani et al., 1999, Damian et al., 2002, Tantishaiyakul et al., 1999, Yamada et al., 2000, Cilurzo et al., 2002, Kushida et al., 2002, Nakamichi et al., 2002), but among them HPMC is considered as one of the most suitable carriers for SDF (Kohri et al., 1999, Kushida et al., 2002). HPMC remarkably enhances the water-solubility of drugs compared with other water-soluble carriers and/or prevents drugs from re-crystallizing in the dissolution medium (Sugimoto et al., 1982, Suzuki and Sunada, 1998, Kohri et al., 1999, Kushida et al., 2002).

HPMC is a water-soluble polymer and cannot be dissolved in alcohol alone, while HPMC can be easily dissolved in water, and the mixtures such as water and alcohol or alcohol and chlorohydrocarbon. Any method, in which a single solvent such as ethanol alone is employed, has not been reported for the preparation of SDF with HPMC by the solvent method. Usually, the mixed solvents with dichloromethane have been utilized for the preparation of SDF with HPMC by the solvent method (Ho et al., 1996, Yano et al., 1997, Jung et al., 1999, Kobayashi et al., 2001, Kushida et al., 2002). SDF of tacrolimus with HPMC was also prepared using the mixture of ethanol and dichloromethane (Honbo et al., 1987). Dichloromethane, commonly used in the solvent method for HPMC, is classified in Class 2 solvents of ICH harmonized tripartite guideline. Therefore, it is really expected that a preparation method for SDF without dichloromethane is established from the environmental point of view.

In this study, physicochemical properties of SDFs prepared with different water-soluble carriers, PEG 6000, PVP and HPMC, were evaluated to select an appropriate carrier for SDF of tacrolimus. Then, to establish the new preparation method for SDF of tacrolimus with HPMC, we tried to use a single solvent, ethanol, and prepared SDF by swelling HPMC with ethanol solution of tacrolimus. Furthermore, SDF prepared by the new method was compared with that prepared by the conventional solvent method in terms of the physicochemical and biopharmaceutical properties.