Fig. 6.12  HRA images showing the distribution kinetics of intravitreally injected 1 mm particle suspension 1 h until day 30 after injection. The upper part of the image represents the superior area of the rabbit vitreous. Microparticles remained relatively in place at the injection site (superiortemporal) in both models for at least 5 h post-injection, however, particle sedimentation occurred at a faster rate in the liquefied vitreous model (adapted from Tan et al. 2011, with permission)

choroidal neovascularisation required more frequent dosing, with an average of 3.75 injections as compared to 1.75 injections in the younger aged patients (mean age: 39.5 years), for a similar degree of visual improvement (Spielberg and Leys 2009). The more frequent dosing observed in the elderly could be attributed to the faster rate of drug clearance associated with the liquefied vitreous humour. More importantly, the clinical study has the crucial implication that treating patients of all age groups with a standard dosing regimen is inappropriate and might result in subtherapeutic efficacy.

6.7.3  Vitrectomised Eyes

Vitrectomy is a commonly used technique for conditions such as rhegmatogeneous retinal detachment (Lai et al. 2008; Nakin et al. 1992), macular hole (Shimada et al. 2009) and vitreoretinopathies (Park et al. 2010). The primary aim of the surgical procedure is to relieve the tractional forces exerted by the degenerating vitreous on the retina, before cellular remodelling occurs (Mura et al. 2009). In some cases, post-operative endophthalmitis and hypotony may develop depending on the surgical

techniques used, with higher risks reported with smaller gauge (25G) vitrectors (Kunimoto et al. 2007; Shimada et al. 2008) and sutureless vitrectomy (Acar et al. 2008), respectively. When the vitreous is removed, it is replaced by intravitreal gas (Ruby et al. 1999), silicone oil (Tognetto et al. 2005) or air (Poliner and Schoch 1987; Itakura et al. 2009), and the decision will be based on treatment modalities. Itakura and colleagues examined the concentration of hyaluronan in the fluid samples during fluid–air exchange from patients with macular hole and diabetic retinopathy after vitrectomy and discovered a significant lower amount of high molecular weight hyaluronan in the replacement fluid, which led the authors to the conclusion that hyaluronan is no longer produced in the vitreous after surgery. This observation is due to two possible reasons: (1) loss of hyalocytes to secrete vitreous hyaluronan and (2) loss of vitreous collagen meshwork serving as a scaffold for the assembly of high molecular weight hyaluronan. Therefore, the vitreous can no longer be reformed once it is removed. This will have a considerable impact on the overall functions of the surrounding tissues, which have been discussed in the recent reviews by Stefánsson (2009) and Holekamp (2010).

6.7.3.1  Intravitreal Drug Distribution and Clearance in Silicone Oil

Silicone oil used in surgical vitrectomy stays within the vitreous cavity a few months as a tamponade to facilitate retinal reattachment using the physicochemical properties – low density and interfacial tension – to work against the subretinal fluid (Giordano and Refojo 1998). The duration for which silicone oil is left in the eye depends on individual patient prognosis; however, prolonged residence is not recommended as it can result in long-term ocular complications including glaucoma, cataracts and post-operative keratopathy (Falkner et al. 2001; Tiedel et al. 1990). Nevertheless, silicone oil is increasingly utilised as a drug vehicle during the tamponade period, mainly for antiproliferative agents to simultaneously treat underlying problems such as iris neovascularisation (Singh and Stewart 2008) and proliferative vitreoretinopathy (Ahmadieh et al. 2008). This clinical application has led to considerable interest in understanding drug kinetics, safety and other pharmaceutical issues such as the solubility of the agent in silicone oil.

An early clinical study in 1980s observed patients with silicone-fluid filled eyes presenting with lower incidence of sight-threatening neovascular glaucoma. This led to an experimental hypothesis that silicone oil behaves as a diffusional or convective barrier to oxygen transport from the anterior chamber (de Juan et al. 1986). In order to test the hypothesis, de Juan and coworkers compared the oxygen pressure (PO2) at the anterior chamber between one eye with lensectomy-vitrectomy and the contra-lateral eye that went through the same surgical procedures but had replacement with silicone oil. The result showed significantly higher anterior chamber PO2 in silicone oil treated eyes as compared to the fellow eye leading the authors to confirm their earlier hypothesis which suggested that silicon oil may protect the anterior segment from the occurrence of neovascularisation. Coincident with this observation, McLeod reported in another study where patients with complete silicone

oil filling eyes were protected from rubeotic glaucoma induced by retina hypoxia first reported by Smith (McLeod 1986; Smith 1981). The author attributed this observation to decreased movements of vasoproliferative factors from ischaemic retina to the anterior segment, thereby reducing anterior segment exposure. The conclusions from both studies are that silicone oil is capable of reducing transport of significantly.

Kathawate and Achaya have developed a 3D mathematical model of human eye to simulate flow distribution and transport processes in silicone oil and results were compared to water (Kathawate and Acharya 2008). A Navier Stokes model was adopted where velocity, pressure and concentration fields were mathematically calculated by solving the conservation equations for mass, momentum and drug concentrations. The simulation data revealed that fluid velocity in silicone oil was significantly lower than water when silicone oil was modelled as a highly viscous fluid with a viscosity of 1.067 kg/ms, 1,000 folds higher than water (0.001 kg/ms). The slower fluid motion in silicone oil may explain the decrease in oxygen and vasoproliferative factors transport seen in the clinical and experimental studies aforementioned. In addition, the lower velocities in the silicone oil resulted in the slower transport of small (D = 6e−10 m2/s) molecules across the retinal layer. A similar observation was demonstrated when very large (1e−11 m2/s) molecules were modelled, suggesting that retinal-directed convective forces play a weaker role in this instance and a diffusion mechanism is more important.

Consistent with the simulation data, the vitreal clearance of ganciclovir released from an implant was found to be lower in the silicone oil as compared to salinefilled eyes following intravitreal placement (Perkins et al. 2001), suggesting that highly viscous silicone oil will behave as a slow-release drug reservoir. When silicone oil fills of 0.5 and 1.0 mL volumes were tested to represent cases of suboptimal filling, no variations in concentrations were observed, suggesting drug clearance is independent of the filling volume. Other therapeutic agents used in conjunction to silicone oil tamponade include retinoic acid (Nakagawa et al. 1995; Araiz et al. 1993) and bevacizumab (Falavarjani et al. 2010; Singh and Stewart 2008) which have demonstrated therapeutic efficacy as an adjunctive treatment option to proliferative vitreoretinopathy, iris neovascularisation and neovascular glaucoma with considerable degree of ocular tolerance. High drug levels in the posterior ocular tissues for longer than 1 week were achieved with an optically clear formulation of acetylsalicylic acid in silicone oil (Kralinger et al. 2001a). The safety of this drug formulation in rabbit was confirmed by assessing the retina health by ERG and histological studies (Kralinger et al. 2001b). A retrospective study has demonstrated that methotrexate administered at doses range from 200 to 1,200 mg was tolerable in silicone oil-filled eyes and patient best-corrected visual acuity was either stable or improved from pre-treatment (Hardwig et al. 2008).

In view of the lack of knowledge describing drug solubilities in silicone oil, Pastor et al. performed a series of solubility studies with commonly used antiinflammatory agents (Pastor et al. 2008). The drug molecules were first dissolved in organic solvent at therapeutic doses, followed by injection into purified silicone oil of viscosity 1,000 cP where drug solubility was assessed by the transparency of the