Preparation of tacrolimus ophthalmic solution using cyclodextrins

Application of topical tacrolimus in Vernal Keratoconjunctivitis is considered as an alternative to steroids. Due to the low aqueous solubility of the drug, preparing a solution of the drug has got particular importance. In the present study, tacrolimus eye drop was prepared using cyclodextrin, as a drug solubility enhancer.
To improve the aqueous solubility of tacrolimus, 5 types of cyclodextrins called α, γ, hydroxypropyl (HP)-β, HP-γ, and sulfobutyl ether (SBE)-β-cyclodextrin (CD), were used. After phase solubility studies, the most appropriate cyclodextrin was selected to prepare tacrolimus eye drop. For eye drop preparation, phosphate buffer (pH=7.4), hydroxypropyl methylcellulose (HPMC) and polyvinyl alcohol (PVA) polymers (viscosity increasing agent), methyl paraben and benzalkonium chloride (preservative agent) were used together with cyclodextrin-tacrolimus complex.
α, HP-β, and γ-CD had the most effect on aqueous solubility, respectively. These 3 types of CDs, respectively increased the intrinsic solubility of tacrolimus174, 160, and 102 times. Taking this into account, α and HP-β-CD were chosen to prepare a soluble form of tacrolimus. In the eye drop formulation containing CD-tacrolimus complex, methyl paraben and HPMC, remarkably reduced the drug solubility while there was not a critical change in the solubility of tacrolimus in the case of CD-tacrolimus complex, buffer, HPMC or PVA and benzalkonium chloride.
It is possible to prepare tacrolimus eye drop (0.05%) using cyclodextrins.