Nepafanec is a prodrug NSAID (non- steroidal anti-inflammatory drug) used to treat post-operative pain and inflammation in the cornea. Currently, the only commercially available dosage form of nepafenac is a suspension, due to the low water solubility of the drug. Suspensions are an unacceptable standard because they cause blurred vision and irritation of the eye, leading to increased lacrimation causing the drug to be removed from the eye by either drainage or spillage. This rapid removal of the formulation limits the residence time of the drug, thereby decreasing the ability of the drug to penetrate the cornea. By using hydroxypropyl-β- cyclodextrin (HPBCD), the drug can be encapsulated within the hydrophobic cyclodextrin core, thereby increasing the water solubility and bioavailability of the drug. Methods Conclusions Physicochemical Characterization of Nepafenac by Hydroxypropyl-Beta-Cyclodextrin Complex for Ocular Delivery Haley R. Porter, Forrest T. Smith, R. Jayachandra Babu Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL Purpose HeatFlow (W /g) 0 100 200 300 Tem perature N epafenac HPBCD D ry M ix K neaded M ix Freeze-D ried R otovap Intensity 0 10 20 30 A ngle N epafenac HPBCD D ry M ix K neaded M ix Freeze-D ried R otovap Results Solid-State Characterization confirmed liquid state results DSC NMR confirmed the structure of the complex XRD Phase Solubility Studies We used the techniques described by Higutchi and Connors, increasing molar amounts of HPBCD were dissolved in water (10, 20 , 50, 100, 150, 200, 250 mM) and excess amounts of nepafenac was added and agitated until equilibrium was reached. After 24 hours, excess nepafenac was filtered off and the supernatant was analyzed by HPLC to determine concentration. Solid-State Preparation Equimolar amounts of HPBCD and nepafenac were dissolved in methanol. The solution was subjected to rotary evaporation or freeze-drying to producesolid-state complexes. A physical mixture and a kneaded mixture were also prepared by adding equimolar amounts of drug and nepafenac and grinding until a homogenous mixture was Rotary Evaporation Mixture Nepafenac 2 hour Ex-Vivo Perfusion Studies proved the HPBCD solution had a significantly higher perfusion in cornea, aqueous humour and ciliary body Objective To characterize the inclusion complex formation of Nepafenac with HPBCD and to develop the formulation of an ophthalmic solution. Solid State Characterization The solid-state complexes were analyzed by differential scanning calorimetry (DSC), x-ray diffraction (XRD), nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FT- IR). Corneal Perfusion and Permeation Studies Perfusion studies were conducted on whole porcine eyes. Trans-corneal permeation of the HPBCD based ocular formulation was compared to that of nepafenac suspension using dialysis membranes or pig corneas and Franz diffusion cell apparatus. Methods Continued The phase solubility studies indicate an A L type of phase diagram and 1:1 complex with stability rate constants 3665 M -1 and 4296M -1 , respectively, for water and PBS buffer, indicative of strong association between Nepafenac and HPBCD. For DSC, the Nepafenac melting peak has almost disappeared in the freeze-dried complex and is completely absent in the rotovap complex indicating existence of new solid phase due to complexation of nepafenac and HPBCD. This is also portrayed in the XRD results. For the ex-vivo experiments, the HPBCD formulation permeated the cornea 18 times and 5 times more than the commercial formulation and suspension formulation. Additionally, the amount of nepafenac retained in the cornea (µg /g) was 11 times and 4 times higher than the commercial formulation and suspension formulation. The cornea, aqueous humour and ciliary body retained significantly higher amounts of nepafenac when treated with the HPBCD Ex-Vivo Corneal Retention discovered the solution had ~4 and 11 times higher retention of drug in cornea than the suspension and commercial formulation ***: P<0.0001) Solution Nevanac 0.1% Suspension 0 100 200 300 400 *** A m o u n t R e tain ed ( g /g) Ex-Vivo Permeation Studies revealed the solution had a permeation rate 18 and 5 times higher than the commercial and suspension formulation *** = (P<0.0001) 0 2 4 6 8 10 12 14 16 18 20 22 24 0 50 100 150 200 250 300 Solution Nevanac 0.1% (C ontrol) Suspension Tim e (hour) A m o u n t P e rm ea te d ( g /cm 2 ) Solution N evanac 0.1% Suspension 0.0 2.5 5.0 7.5 10.0 12.5 15.0 *** P e rm ea tion R a te ( g /cm 2 /hr) FT-IR defined the functional groups involved in complex N epafenac HPBCD D ry M ix K neaded M ix Freeze-D ried R otovap 0 1000 2000 3000 4000 1/cm %T Poster Number: 05M0430 Phase Solubility Studies revealed a linear relationship between HPBCD and nepafenac