Purpose: Valacyclovir Hydrochloride, a prodrug of Acyclovir is an anti-viral agent used in the treatment of ocular infections. It is effective against human herpes virus and has 40-50% more bioavailability than acyclovir. Ophthalmic solutions and ointments provide less bioavailability and require repeated administration, which leads to poor patient compliance. Thus, this study was aimed at preparing Valacyclovir Hydrochloride ocular inserts by hot melt extrusion techniques which will reduce frequency of administration and provide site specific drug delivery for treatment of corneal keratitis.
Methods: Klucel® Pharm MF and JF were studied as the matrix for the ocular inserts. Valacyclovir Hydrochloride and polymer were sieved through mesh #60 and mixed with the plasticizer in a mortar and pestle, then blended in a Maxiblend Globe Pharma at 25 rpm for 10 minutes. The blend was fed through the hopper on the rotating twin screws of Haake MiniLab ThermoFisher® Scientific Extruder with a constant feeding rate and a screw speed of 50 rpm. The extrudates obtained were cut into desired size (4mm × 2mm × 1mm), sterilized by UV radiation and packed individually into aluminum foil. Each insert contained 1mg of Valacyclovir Hydrochloride. The ocular inserts were evaluated for physical characterization, drug content, swelling index and in vitro drug release. The ex vivo trans-corneal permeation studies were carried out on Valia-chein®(Permigear) cells using fresh rabbit cornea as the membrane. The in vivo drug bioavailability was evaluated on New Zealand Male Albino Rabbits. The protocol on the use of animals was approved by The Institutional Animal Care and Use Committee (IACUC). The surface morphology was observed using Scanning Electron Microscope.
Results: Each ocular insert weighed 5.29±0.72 mg with uniform thickness, exhibited a smooth surface and pH of 7.02. The drug content of the ocular inserts before and after 30 days of stability was observed to be 99.5% ± 0.09. The swelling index demonstrated that the ocular inserts can retain the matrix for 20 minutes before dissolving. The formulation was able to release 98% of drug in 8 hours when Klucel® Pharm MF was used as the matrix of the ocular inserts. The trans-corneal permeation and flux through the rabbit cornea was observed to be more in the ocular inserts having Klucel® Pharm MF as the matrix than the Pharm JF. After instillation in the rabbit eye, acyclovir was detected in the aqueous humor (Figure: 1) and cornea (Figure: 2) at two and six hour timepoints.
Conclusion: It was observed that the ocular inserts dissolved completely in 9 hours proving the biodegradable nature of the ocular inserts. The drug was released over a period of 8 hours, demonstrating the high potential to improve patient compliance in comparison to eyedrops and eye ointment. The ocular inserts were soft in texture and turn into gel like consistency in the eye. The polymer and plasticizer used in the formulation were non-irritating and non-greasy and hence improve the therapy and acceptability of the formulation.
Akash Patil– PhD Candidate, University of Mississippi, Oxford, Mississippi
Suresh Bandari– Post-doc, University of Mississippi, OXFORD, Mississippi
Soumyajit Majumdar– Professor and Associate Dean, Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi. Oxford, MS, Mississippi
Michael Repka– Professor, University of Mississippi, Mississippi