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.

MethodsConclusions

Physicochemical Characterization of Nepafenac by Hydroxypropyl-Beta-Cyclodextrin Complex for Ocular Delivery

Haley R. Porter, Forrest T. Smith, R. Jayachandra BabuDrug Discovery and Development, Harrison School of Pharmacy, Auburn University , AL

Purpose

Hea

t Flo

w (W

/g)

0 100 200 300

Temperature

Nepafenac

HPBCD

Dry Mix

Kneaded Mix

Freeze-Dried

Rotovap

Inte

nsity

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 StudiesWe 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 PreparationEquimolar 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

ObjectiveTo characterize the inclusion complex formation of Nepafenac with HPBCD and to develop the formulation of an ophthalmic solution.

Solid State CharacterizationThe 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 StudiesPerfusion 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% Suspension0

100

200

300

400

***

Amou

nt R

etai

ned

( 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 22 240

50

100

150

200

250

300

SolutionNevanac 0.1% (Control)Suspension

Time (hour)

Am

ount

Per

mea

ted

( g

/cm2 )

Solution Nevanac 0.1% Suspension0.0

2.5

5.0

7.5

10.0

12.5

15.0

***

Perm

eatio

n R

ate

( g

/cm2 /h

r)

FT-IR defined the functional groups involved in complex

Nepafenac

HPBCD

Dry Mix

Kneaded Mix

Freeze-Dried

Rotovap

010002000300040001/cm

%T

Poster Number: 05M0430

Phase Solubility Studies revealed a linear relationship between HPBCD and nepafenac