Preparation of tacrolimus ophthalmic solution using cyclodextrins

Abstract

Background and Aim: 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. Materials and Methods: 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. Results: 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. Conclusion: It is possible to prepare tacrolimus eye drop (0.05%) using cyclodextrins.

Keywords

• Tacrolimus
• Cyclodextrin
• Aqueous solubility
• Eye drop.