Introduction and objectives: Noninfectious uveitis is a disease often caused by an autoimmune response, inflammatory cytokines promote the activation of T-cells and trigger recruitment of large numbers of circulation inflammatory leukocytes into the eye. This process may cause irreversible tissue damage and visual impairment. Since tacrolimus inhibits T-cell proliferation and suppresses the release of inflammatory cytokines, it can theoretically be used to reduce inflammatory activity in uveitis patients [1]. Hospital pharmacy prepares tacrolimus eye drops reformulating from parenteral drugs (Prograf®) as magistral formulations because there is not any commercial alternative. However, Prograf® (tacrolimus solubilized in ethanol) has some irritating compounds that cause discomfort and unpleasantness to the patient, so these excipients had to be removed. Due to tacrolimus poorly solubility, the purpose of this work was to improve the drug solubility complexing tacrolimus with HPßCD, evaluate the safety, and study the ocular permanence of the eye drops.
Materials and Methods: Initially, tacrolimus phase solubility diagram in water with HPßCD was performed. It was studied the tacrolimus solubilization comparing the interaction between tacrolimus-HPßCD complex using water (MilliQ®), BSS® (Balanced Salt Solution, Alcon) and Liquifilm® (Allergan) as vehicles. Irritation Ocular Assay (HET-CAM) and BCOP studies were performed in order to evaluate the safety of the formulations. In vivo PET/CT studies were carried out on anesthetized male Sprague-Dawley rats. 7.5 μL of each formulation labelled with 18F-fluorodeoxyglucose (18F-FDG) was instilled into the eye and PET/CT images were acquired at different times (0,30,75, 120, 240 and 300 min post-administration). Two animals (4 eyes) were tested for each formulation.
Results and Discussion: The solubility diagram in water was AP type and stability constant values of K1:1=148.2 mol-1 and K1:2=1.406 mol-1. It can be seen a better tacrolimus solubility when it is combined the HPßCD and Liquifilm® this may be because this vehicle incorporates polyvinyl alcohol (PVA), a polymer that has demonstrated a synergistic solubilization effect when it is combined with HPßCD [2]. HET-CAM assay and BCOP did not show blood vessels injury and any considerable change in the corneal surface. In vivo ocular permanence shows that formulations containing higher HPßCD concentrations give a better ocular surface permanence.
Conclusion: Results reveal tacrolimus solubility improvement, irritation absence on the ocular surface and a prolonged permanence time over the eye. These changes in the formulation compounds would enhance the patient’s adherence-to-treatment, reducing their eye discomfort.
Acknowledgements: X.G-O and R.V-F acknowledge the financial support of Health Research Institute Foundation of Santiago de Compostela (FIDIS).
References:
[1]. Zhai J, Gu J, Yuan J, Chen J. Tacrolimus in the treatment of ocular diseases. 2011;25:89–103.
[2]. Saokham, P.; Muankaew, C.; Jansook, P.; Loftsson, T. Solubility of Cyclodextrins and Drug/Cyclodextrin Complexes. Molecules2018, 23, 1161.
