Stability characterization, kinetics and mechanism of tacrolimus degradation in cyclodextrin solutions

Abstract

Tacrolimus is a macrolide lactone and potent immunosuppressant. It is highly lipophilic and has very limited aqueous solubility. Tacrolimus is highly susceptible to hydrolysis which results in very limited stability in aqueous solutions. Besides this, tacrolimus also undergoes dehydration and epimerization. Cyclodextrin (CD) complexation can increase the solubility and stability of hydrophobic drugs in aqueous solutions through the formation of drug/CD complexes. The aim of this study was to investigate degradation kinetics, mechanism and stability of tacrolimus in aqueous CD solutions, with the ultimate goal of developing an aqueous vehicle for ophthalmic delivery. For this, phase-solubility and kinetic studies in aqueous solutions containing different CDs at different pH values were performed. Mass spectrometry studies were also performed to elucidate the degradation mechanism of the drug in aqueous CD solution. The study showed that the drug has maximum stability between pH 4 and 6 and hydrolysis was the main cause of tacrolimus degradation in aqueous 2-hydroxypropyl-βCD (HPβCD) solutions. βCD and its derivatives were the better CD solubilizers for tacrolimus. The solubility and stability studies were further conducted with CD and surfactants, which is tyloxapol, tween 80 and poloxamer 407, where the combination provided better results compared to individual components.

Development and Characterization of a Tacrolimus/Hydroxypropyl-β-Cyclodextrin Eye Drop

“…The phase solubility diagram of tacrolimus in aqueous HPβCD solutions at 25 • C is shown in Figure 3. The resulting profile indicates an A P -type diagram that shows a positive deviation from characteristic linearity, this being supported by previous studies [27,37]. Thus, the formation of a soluble complex in the aqueous media with the formation of high-order drug/CD complexes at high cyclodextrin concentrations is assumed.…”

“…Stability studies of pharmaceutical compounds are essential to ensure drug efficacy [79,80] as well as to know if degradation products can cause toxic side effects and other undesired effects [27]. In this assay, only TBS 40 and TLI 40 were studied due to all formulations containing the exact same qualitative composition; thus, the formulations with the highest tacrolimus concentrations were tested as representative; these formulations were chosen based on the clinical common usability and the drug concentration similarity at present.…”

“…Nowadays, tacrolimus eye drops are not marketed and all its use rests in the elaboration in hospital pharmacy departments (HPDs). The preparation of ophthalmic tacrolimus formulations is limited by its poor water solubility (1-12 µg/mL) [27,28] due to the hydrolytic mechanism [29]. For this reason, 0.03% (w/v) tacrolimus eye drops are being obtained by reformulation from intravenous drug presentation (Prograf ® ) [15].…”

“…There are several types of β-cyclodextrin (βCD) derivatives, although most of them have not been authorized or there are not enough preclinical studies to support their use at the topical ophthalmic level [36]. Some β-cyclodextrins have been used by other authors as complexing agents with several drugs [27,37,38]. The oligosaccharide 2-hydroxypropyl-β-cyclodextrin (HPβCD) is a cyclic oligosaccharide formed by seven units of α-1,4-linked glucose and a hydroxypropylated group, with a lipophilic central cavity and a hydrophilic outer surface.…”

“…Hence, there is already a commercialized formulation (Indocollyre ® 0.1% ophthalmic solution) complexing HPβCD and indomethacin [41]. The improvement of aqueous tacrolimus eye drops is still a challenge because of its low chemical stability and solubility in particular [27].…”