1. 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
Temperature
Nepafenac
HPBCD
Dry Mix
Kneaded Mix
Freeze-Dried
Rotovap
Intensity
0 10 20 30
Angle
Nepafenac
HPBCD
Dry Mix
Kneaded Mix
Freeze-Dried
Rotovap
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 obtained.
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 AL 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 solution compared to the suspension.
The HPBCD formulation indicative of higher permeation
rate and higher drug delivery.
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
***
AmountRetained(µg/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% (Control)
Suspension
Time (hour)
AmountPermeated(µg/cm
2
)
Solution Nevanac 0.1% Suspension
0.0
2.5
5.0
7.5
10.0
12.5
15.0
***
PermeationRate(µg/cm
2
/hr)
FT-IR defined the functional groups
involved in complex
Nepafenac
HPBCD
Dry Mix
Kneaded Mix
Freeze-Dried
Rotovap
01000200030004000
1/cm
%T
Poster
Number:
05M0430
Phase Solubility Studies revealed a linear
relationship between HPBCD and nepafenac