Improved intraocular bioavailability of ganciclovir by mucoadhesive polymer based ocular microspheres: development and simulation process in Wistar rats.
BACKGROUND
The poor ocular bioavailability of the conventional eye drops is due to lack of corneal permeability, nasolacrimal drainage and metabolic degradation. To overcome this issue, drug encapsulated in mucoadhesive polymer based ocular microspheres have the advantages of improved drug stability, easy administration in liquid form, diffuse rapidly and better ocular tissue internalization.


METHODS
The ganciclovir chitosan microspheres (GCM) were prepared by modified water-in-oil emulsification method. The formulation was optimized and characterized by investigating in vitro release study, release kinetics, XRD and microspheres stability. Ocular irritancy, in vivo ocular pharmacokinetic parameters and histopathology study was evaluated in Wistar rats. The use of pharmacokinetic/pharmacodynamic indices and simulation process was carried out to further ensure clinical applicability of the formulation.


RESULTS
The in vitro release study showed initial burst (nearly 50 %) in first few minutes and followed Fickian (R(2) = 0.9234, n-value = 0.2329) type of diffusion release mechanism. The XRD and stability studies showed favorable results. The Wistar rat eyes treated with GCM showed significant increase in ganciclovir AUC (~4.99-fold) and Cmax (2.69-fold) in aqueous humor compared to ganciclovir solution and delay in Tmax. The Cmax/MIC90, AUC0-24/MIC90, AUC above MIC90 and T above MIC90 were significantly higher in GCM group. The aqueous humor concentration-time profile of ganciclovir in GCM and ganciclovir solution was simulated with every 28.1 and 12.8 h, respectively. The simulated concentration-time profile shows that in duration of 75 h, the ganciclovir solution require six ocular instillations compared to three ocular instillations of the GCM formulation. The photomicrograph of GCM and ganciclovir solution treated rat retina showed normal organization and cytoarchitecture.


CONCLUSIONS
Correlating with in vitro data, the formulation showed sustained drug release along with improved intraocular bioavailability of ganciclovir in Wistar rats.
Department of Pharmaceutical Technology, Karnataka College of Pharmacy, #33/2, Tirumenahalli, Hegde Nagar Main Road, Bengaluru, 560064, , Karnataka, India.
Usha Ganganahalli
UG
Kapanigowda
Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, 31982, Saudi Arabia.
Sree Harsha
SH
Nagaraja
Department of Pharmaceutics, Karnataka College of Pharmacy, #33/2, Tirumenahalli, Hegde Nagar Main Road, Bengaluru, 560064, , Karnataka, India. balupharmacy@gmail.com.
Balakeshwa
B
Ramaiah
Department of Pharmaceutical Technology, Karnataka College of Pharmacy, #33/2, Tirumenahalli, Hegde Nagar Main Road, Bengaluru, 560064, , Karnataka, India.
Prakash Rao
PR
Boggarapu
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D048271:Chitosan / Q000737:chemistry; D003692:Delayed-Action Preparations; D004355:Drug Stability; D005260:Female; D015774:Ganciclovir / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008863:Microspheres; D009883:Ophthalmic Solutions / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
D000998:Antiviral Agents; D003692:Delayed-Action Preparations; D009883:Ophthalmic Solutions; D048271:Chitosan; D015774:Ganciclovir