Improved intraocular bioavailability of ganciclovir by mucoadhesive polymer based ocular microspheres: development and simulation process in Wistar rats

Abstract

BackgroundThe 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.MethodsThe 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.ResultsThe in vitro release study showed initial burst (nearly 50 %) in first few minutes and followed Fickian (R2 = 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.ConclusionsCorrelating with in vitro data, the formulation showed sustained drug release along with improved intraocular bioavailability of ganciclovir in Wistar rats.

Intra-cameral level of ganciclovir gel, 0.15% following topical application for cytomegalovirus anterior segment infection: A pilot study

“…At the end of week 6, the patients were reviewed in the clinic, 3.0 hours following the last application of the ganciclovir gel. As the half-life of ganciclovir is 3.5 to 4 hours [ 17 , 18 ], we sampled the aqueous humor 3.0 hours following the last application of the gel. At this study visit, the patients were asked to verbally confirm the gel application time and quantum before proceeding.…”

A comprehensive insight on ocular pharmacokinetics

“…Recently ganciclovir chitosan microspheres (GCM) were prepared and evaluated in Wistar rats (69). In vitro release study exhibited initial burst (nearly 50 %) in first few minutes.…”

“…C max of GCM was 2.69-fold higher than ganciclovir group (p < 0.0001) and the delay in T max inferred the sustained release of GCM. It was concluded that the incorporation of ganciclovir into microspheres significantly enhanced relative ocular bioavailability (70). …”

Self-Assembled chitosan/phospholipid nanoparticles: from fundamentals to preparation for advanced drug delivery

“…Moreover, chitosan also holds other special characteristics suitable for ocular drug delivery including nontoxic, low eye irritation, mucoadhesive, in situ gelling, transfection and permeation enhancing properties. All of these advantages contribute to the applications of SACPNs as suitable ocular deliver vehicles (Kapanigowda et al, 2015;Werle & Bernkop-Schn€ urch, 2008. Fox instance, amphotericin-B is encapsulated in SACPNs for prolonged ocular application (Chhonker et al, 2015).…”