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

Abstract

Uveitis is a vision inflammatory disorder with a high prevalence in developing countries. Currently, marketed treatments remain limited and reformulation is usually performed to obtain a tacrolimus eye drop as a therapeutic alternative in corticosteroid-refractory eye disease. The aim of this work was to develop a mucoadhesive, non-toxic and stable topical ophthalmic formulation that can be safely prepared in hospital pharmacy departments. Four different ophthalmic formulations were prepared based on the tacrolimus/hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complexes’ formation. Phase solubility diagrams, Nuclear Magnetic Resonance (NMR) and molecular modeling studies showed the formation of 1:1 and 1:2 tacrolimus/HPβCD inclusion complexes, being possible to obtain a 0.02% (w/v) tacrolimus concentration by using 40% (w/v) HPβCD aqueous solutions. Formulations also showed good ophthalmic properties in terms of pH, osmolality and safety. Stability studies proved these formulations to be stable for at least 3 months in refrigeration. Ex vivo bioadhesion and in vivo ocular permanence showed good mucoadhesive properties with higher ocular permanence compared to the reference pharmacy compounding used in clinical settings (t1/2 of 86.2 min for the eyedrop elaborated with 40% (w/v) HPβCD and Liquifilm® versus 46.3 min for the reference formulation). Thus, these novel eye drops present high potential as a safe alternative for uveitis treatment, as well as a versatile composition to include new drugs intended for topical ophthalmic administration.

Enhanced oral bioavailability of koumine by complexation with hydroxypropyl-β-cyclodextrin: preparation, optimization, ex vivo and in vivo characterization

“…(Garcia-Otero et al. 2021 ). Among these, inclusion complexes with CD have been generally used to increase the oral bioavailability of poorly aqueous solubility drugs (Hu et al.…”

Anti-Inflammatory Effect of Tacrolimus/Hydroxypropyl-β-Cyclodextrin Eye Drops in an Endotoxin-Induced Uveitis Model

“…Our group has previously developed a formulation of TAC-HPβCD eye drops containing a 0.02% ( w / v ) of TAC and a 40% ( w / v ) of HPβCD in Liquifilm ® , which can be safely prepared in HPDs and showed to be stable for at least 3 months under refrigeration [ 40 ]. The major advantage of TAC-HβCD eye drops is that there is no need of using irritating excipients since our formulation strategy increases the solubilization of poorly soluble active ingredients and reduces the use of toxic products.…”

“…First, the indicated proportion of hydroxypropyl-β-cyclodextrin (40% w / v ) is dissolved in Liquifilm ® by stirring, when it was completely solubilized tacrolimus powder was added at a proportion of 0.02% ( w / v ) and left for 72 h under agitation (>750 rpm). Once this time has elapsed, the formulation is filtered through a 0.2 µm polyether sulfone (PES) filter (Stericup filtration system), and then packaged in sterilized polypropylene eyedropper bottles, showing to be stable for at least 3 months under refrigeration [ 40 ].…”

“…In this sense, our group has previously developed and characterized a topical ophthalmic formulation of tacrolimus-hydroxypropyl-β-cyclodextrin (TAC-HPβCD) eye drops containing a 0.02% ( w / v ) of tacrolimus and a 40% ( w / v ) of HPβCD in Liquifilm ® , demonstrating positive effects in terms of drug solubility, stability in aqueous solution and retention time on the ocular surface [ 40 ]. This formulation improves the currently prepared eyedrops in HPDs by replacing the irritating compounds of the intravenous drug presentation for HPβCD, which is the most appropriated cyclodextrin for topical ophthalmic administration according to the European Medicines Agency (EMA) [ 40 , 41 ].…”

New insights into the use of hydroxypropyl cellulose for drug solubility enhancement: An analytical study of sub‐molecular interactions with fenofibrate in solid state and aqueous solutions

“…Hence, the study of these excipients is valuable in terms of product quality control and evaluation of long‐term stability. Furthermore, the precise method of their preparation serves to modulate specific aspects at the molecular level, including the miscibility of the components, [ 1 ] and the strength of interactions between components, either in the solid [ 2 ] or aqueous [ 3 ] states, thereby enhancing various properties, such as drug solubility in water, which can impact the performance of the drug formulation.…”