10.9  Microparticles for the Treatment of Posterior Segment Diseases. Animal Models and Human Studies

Microparticles intended for the treatment of posterior segment diseases have been mainly injected by periocular or intravitreal injection. Although several studies have been conducted employing topical routes there is no evidence of effective concentrations in the vitreous with this administration.

PLGA microparticles have been prepared with different drugs, such as adriamycin, 5-fluorouracil (5-FU), and RA for proliferative retinopathy, dexamethasone and cyclosporine for uveitis, anti vascular endothelial growth factor (VEGF) for age macular degeneration (AMD), budesonide and celecoxib for diabetic retinopathy, TA for macular edema, acyclovir for herpes infection, ganciclovir for cytomegalovirus retinitis, neurotrophic factors for neuroprotection, an inhibitor of protein kinase C (PKC412) for choroidal neovascularization (CNV), triamcinolone for macular edema, neuroprotective agents for glaucoma and retinitis pigmentosa, and a combination of steroids (TA) and antibiotic agents (ciprofloxacin) to prevent ocular inflammation and infection after cataract surgery. Finally, co-transplantation of MMP2-microspheres and RPCs ha been reported as a practical and effective strategy for retinal repair.

10.9.1  Proliferative Vitreoretinopathy (PVR)

Antiproliferative drugs have demonstrated to be therapeutically active in the treatment of the PVR in which contractile cellular membranes are formed mainly by retinal pigment epithelium (RPE) cells (Pastor 1998). Microparticles employed for the treatment of PVR have been loaded with active agents with antiproliferative activity (Moritera et al. 1991, 1992). Adriamycine was encapsulated in PLA (3,400 Da). Microspheres (50 mm size) containing 1% of the active substance were injected in normal rabbit eyes and in a rabbit model of PVR and compared with the administration of the active substance alone. The authors found a significant decrease in the retinal toxicity of the single injection of 10 mg of adriamycine in comparison with the administration of 10 mg of PLA microspheres containing 10 mg of the drug with neither histological abnormalities nor electrophysiologic changes in the eye. Regarding to antiproliferative properties, the RD was decreased from 50 to 10% after 4 weeks of the administration. On the contrary, a dose of 3 mg of PLA microspheres containing 3 mg of adriamycine did not decrease the rate of RD.

Moritera et al. (1991) demonstrated the influence of the polymer composition and the molecular weight of the polymer on the release in vitro and in vivo of 5-fluorouracil (5-FU) from microspheres 50 mm size. The polymers employed were two low molecular weight PLAs (3,400 and 4,700 Da) and PLGA (70:30, 3,300 Da). PLGA microspheres showed an in vitro release of almost the whole 5FU (98%) in only 2 days while the PLA took 7 days to release 85% of the encapsulated drug. Microspheres prepared from PLGA 4,700 daltons released 70% of 5FU over 7 days.

In the in vivo studies, the authors reported a faster clearance of the drug and the microspheres in vitrectomized and pathologic eyes compared with healthy animals. Authors observed that microspheres disappear from the vitreous cavity in 48 ± 5.2 days for normal eyes and 14 ± 2.4 days in animals that underwent vitrectomy before the injection of the microspheres.

Peyman et al. (1992) evaluated the release kinetic of radiolabeled 5-FU and cytosine arabinoside in primates. Both drugs exhibited similar release kinetics with detectable drug levels in the vitreous up to 11 days after the administration of the formulation.

Giordano et al. (1993) studied the intravitreous release of RA in a rabbit model of PVR caused by lipopolysaccharide (LPS) injection. The incidence of tractional retinal detachment (TRD) resulted effectively reduced when compared to blank microspheres 2 months after a single injection of 5 mg of RA-loaded microspheres (110 mg RA). In the same study, 82% of the encapsulated RA was released in vitro for 40 days at room temperature.

In all reported studies, the rate or incidence of retinal traction detachment decreased after injection of PLGA microspheres.

10.9.2  Uveitis

The term “uveitis” is used to denote any intraocular inflammatory condition without reference to the underlying cause (Rodríguez et al. 1996). In fact, uveitis is considered to be an intraocular autoimmune or inflammatory disease involving the ciliary body, choroids, and/or adjacent tissues. The disease has both acute and chronic manifestations.

Corticosteroids have demonstrated to be the most efficient anti-inflammatory drugs for the treatment of acute ocular inflammations, including uveitis. Current treatment for chronic features usually includes topical, periocular, or systemic corticosteroids (Smith 2004). In fact, transitory therapeutic drug levels can be attained through the administration of steroids by intravitreal injections (Gaudio 2004). Nevertheless, therapeutic drug concentrations are difficult to attain in the vitreous for a prolonged period of time due to the short, intravitreal half-life of corticosteroids (Kwak and D¢Amico 1992).

Barcia et al. (2009) developed PLGA microspheres for the sustained delivery of dexamethasone destined to prevent intraocular inflammation. Ten milligrams of the PLGA 50:50 (0.2 dl/g) microspheres containing 1,410 mg of dexamethasone were injected in 0.1 ml of PBS in an animal model of inflammation. The active substance was released in vitro for at least 45 days. In this study, a LPS injection was carried out 7 days after the injection of the microspheres (53–106 mm). Intraocular inflammation, caused by LPS injection was significantly lower in animals receiving the dexamethasone loaded microspheres than blank microspheres. In order to simulate secondary uveitis, a second injection of LPS was performed 30 days after microparticles injection. No inflammation was observed in the animals treated with dexamethasone loaded PLGA microspheres after second LPS injection (Fig. 10.12).