Abstract
Tacrolimus is an immunosuppressant used to treat a large variety of inflammatory or immunity-mediated ophthalmic diseases. However, there are currently no commercial industrial forms available that can provide relief to patients. Various ophthalmic formulations have been reported in the literature, but their stability has only been tested over short periods. The objective of this study was to evaluate the physicochemical stability of a preservative-free tacrolimus formulation (0.2 and 1 mg/mL) at three storage temperatures (5 °C, 25 °C and 35 °C) for up to nine months in a multidose eyedropper. Analyses performed were the following: visual inspection and chromaticity, turbidity, viscosity, size of micelles, osmolality and pH measurements, tacrolimus quantification by a stability-indicating liquid chromatography method, breakdown product research, and sterility assay. In an in-use study, tacrolimus quantification was also performed on the drops emitted from the eyedroppers. All tested parameters remained stable during the nine month period when the eyedrops were stored at 5 °C. However, during storage at 25 °C and 35 °C, several signs of chemical instability were detected. Furthermore, a leachable compound originating from a silicone part of the eyedropper was detected during the in-use assay. Overall, the 0.2 mg/mL and 1 mg/mL tacrolimus ophthalmic solutions were physicochemically stable for up to nine months when stored at 5 °C.
Highlights
Tacrolimus (TAC), named FK-506, is a macrolide immunosuppressant of the calcineurin inhibitor pharmacological class that binds to a specific cytosolic protein FKBP12 immunophilin [1,2], forming a complex that binds to calcineurin and inhibits it
We investigated the physicochemical stability of a novel formulation of tacrolimus, at two concentrations (0.2 and 1 mg/mL) at three different storage conditions for nine months
The results showed that the tacrolimus formulation remained stable throughout the study when stored at 5 ◦ C, but tacrolimus degradation occurred when the formulations were stored at 25 ◦ C and 35 ◦ C
Summary
Tacrolimus (TAC), named FK-506, is a macrolide immunosuppressant of the calcineurin inhibitor pharmacological class that binds to a specific cytosolic protein FKBP12 immunophilin ( named FK506 binding protein) [1,2], forming a complex that binds to calcineurin and inhibits it. Inhibiting calcineurin blocks the dephosphorylation of NFAT (nuclear factor of activated T cells), preventing it from crossing the nuclear envelope and entering the nucleus. Pharmaceutics 2022, 14, 118 power, tacrolimus is a good candidate to manage ophthalmic pathologies [6] for which cyclosporine is not tolerated or no longer effective. It expands the therapeutic arsenal, for vernal keratoconjunctivitis (VKC) and allergic eye diseases, the management of which is complex. Ophthalmic TAC is used at various concentrations, depending on the disease, varying from 0.003% to 0.1% (m/v)
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