Study Of Thermosensitive In Situ Gel Containing Bovine Serum Albumin Nanoparticles For Ophthalmic Drug Delivery

Albumin nanoparticles (BSA-NPs) are nanoscale particles prepared bybovine serum albumin. BSA-NPs have gained considerable researchattention because of their excellent capacity for targeting deliver, controlledrelease and their property of being well tolerated without seriousside-effects. A liquid formulation based on in situ gels consisting ofpolymer solutions that may be administered as a liquid was recentlydeveloped, this formulation undergoes sol-gel phase transition into asemisolid gel upon exposure to a change in temperature. Hence, in thiswork, BSA-NPs and in situ gels were combined to prolong the drugresidence time and improve the ocular bioavailability of the drug.In this study, we prepared the in situ gels containing berberine andcurcumin loaded BSA-NPs, and preliminarily investigated theirproperties. Part Ⅰ：Preparation and characterization of thermosensitive insitu gel containing berberine bovine serum albumin nanoparticlesfor ophthalmic drug deliveryThis work was performed to prepare a thermosensitive in situ gelcontaining berberine bovine serum albumin nanoparticles (Ber-BSA-NPs-Gel) for ophthalmic drug delivery and preliminarily investigate itsphysicochemical properties. Poloxamer407(F127) and Poloxamer188(F68) were used as gel matrix, and gelatinization temperature was appliedas a target to optimize the prescription. The Ber-BSA-NPs were preparedby desolvation method, and the in situ gel system of Ber-BSA-NPs-Gelwas obtained by cold-dissolving method. NDJ-1viscometer was used todetermine the viscosity of the system, and simulated tear fluid (STF) wasapplied as release medium, ultraviolet spectrophotometry was employed asthe assay method to inspect its in vitro characteristics. After optimization,the gel prescription was finally confirmed as26%F127and4%F68. Theoptimized formulation was freely flowing liquid below30.9℃andconverted to a firm gel above34.2℃after STF diluted. The viscosities ofthe Ber-BSA-NPs-Gel before and after dilution with STF at roomtemperature were (0.2630±0.0283） Pa·s and （0.2432±0.0215） Pa·s,respectively. The viscosities above34.5℃were（0.5100±0.0184）Pa·s and(0.4900±0.0215）Pa·s, respectively. The in vitro study indicated that Ber-BSA-NPs-Gel possessed a superior sustained-release effect. The in situthermosensitve gel system meets the requirements for ophthalmicapplication and shows great potential in ocular application. Part Ⅱ：Optimization and evaluation of a thermo-responsiveophthalmic in situ gel containing curcumin-loaded albuminnanoparticlesThis study aimed to optimize and evaluate a thermo-responsiveophthalmic in situ gel containing curcumin-loaded albumin nanoparticles(Cur-BSA-NPs-Gel). Albumin nanoparticles were prepared via adesolvation method, and the gels were prepared via a cold method. Thecentral composite design and response surface method was used to evaluatethe effects of varying Pluronic F127and Pluronic F68concentrations onthe sol-gel transition temperature, which is an indicator of optimumformulations. The optimized formulation was finally confirmed as26%F127and4%F68，and the formulation was a free-flowing liquid below30.7°C that transforms into a semi-solid gel above34.4°C after dilutionwith simulated tear fluid. Results of the in vitro release and erosionbehavior study indicated that Cur-BSA-NPs-Gel achieved superiorsustained-release effects and that incorporation of albumin nanoparticles exerted minimal effects on the gel structure. In addition, in vivo ophthalmicexperiments employing Cur-BSA-NPs-Gel were subsequently performed inrabbits. In vivo eye irritation results showed that Cur-BSA-NPs-Gel mightbe considered safe for ophthalmic drug delivery. The in vivo study alsorevealed that the formulation could significantly increase curcuminbioavailability in the aqueous humor. In conclusion, the optimized in situgel formulation developed in this work has significant potential for ocularapplication.