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.
Highlights
Tacrolimus (FK506) is a 23-membered macrolide lactone produced by the bacterium Streptomyces tsukubaensis
Chromatographic conditions Quantitative determination of tacrolimus was performed on a reversed-phase ultrahigh-performance liquid chromatographic (UHPLC) component system from Thermo Fisher Scientific Vanquish HPLC system consisting of VF-P10-A pump, a VF-A10-A autosampler, VH-C10-A column compartment, VWD-3100 UV–Vis detector operated at 205 nm and a Phenomenex Kinetex C18 1.7 μm 100 × 2.1 mm with a security guard ULTRA HOLDER
The rate decreases fast when the HPβCD concentration is increased from 2.5% to 5% but levels off at 7.5%
Summary
Tacrolimus (FK506) is a 23-membered macrolide lactone produced by the bacterium Streptomyces tsukubaensis. It is a potent immunosuppressant used to prevent graft rejection after organ transplants (Akashi, 1996). Recent studies have found that immunomodulators like tacrolimus are especially effective for the treatment of anterior inflammatory ocular disorders and can replace corticosteroids that frequently cause cataract and induce glaucoma (Siegl, 2019). In diseases like atopic dermatitis and dry eyes, topical tacrolimus formulations have been noted to have significant therapeutic efficacy (Arima, 2001). Tacrolimus is a highly lipophilic compound and has water solubility of only about 1 μg/ml. The drug is susceptible to hydrolysis resulting in very low stability in aqueous solutions (Siegl, 2019)
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