Because a significant proportion of microparticles suspended in phosphate-buffered saline tended to adhere to the syringe wall, some researchers have employed viscous solutions of hydroxypropylmethyl­ cellulose (HPMC) and hyaluronic acid (HA). These vehicles are commonly employed as surgical aids in ophthalmology.

Several reactions have been described after administration of PLGA microspheres. Some authors have pointed out the presence of white material that disappeared 20–25 days after injection.32 However, retinal and choroidal damage were not reported after 35 days of administration. Signs of inflammation have been described associated with intravitreal injection of microparticles. These signs were similar to the ones reported for sutures and disappeared 2–4 weeks after administration.

A secondary concern is regarding the behavior of the spheres and the possibility of causing a visual-impairing vitreous haze following a single intravitreous injection. However, preliminary investigation using triamcinolone microspheres for the treatment of diabetic macular edema in human eyes has showed the opposite. In fact, in contrast to initial fears, the tendency of the microspheres to aggregate and condensate at the site of the injection and leave a free visual axis was clinically observed in all 25 patients.31 Furthermore, aggregation of microparticles yields in a lower surface area. Then the drug is being released slower from the particles.

Sterility is a critical factor for the intraocular systems. A final sterilization is preferred over aseptic conditions. Nevertheless, devices derived for PLGA are sensitive to most sterilization methods usually employed (heat and ethylene chloride). A few years ago several authors reported the employment of ionizing sterilization methods for PLGA microparticles destined for parenteral and intravitreal injection. Gamma irradiation has a high capacity for penetration and the required dose to achieve sterilization is 25–49 kGy. The dose required to assure sterilization of a pharmaceutical product is 25 kGy. This dose produces a significant reduction of the molecular weight of the polymer affecting the properties of the final product. This problem seems to be solved by using low temperatures during the exposure time of the microparticles to gammaradiation. This method has presented optimal results with formulations including ganciclovir.33 Cellular uptake of PLGA microand nanoparticles by RPE has been observed.34 PLA and PLGA microparticles up to 1–2 m can be phagocytosed by RPE cells.

Nanoparticles have the advantage of cellular entry, which can be used in the delivery of DNA and proteins inside the cells.35 While particles in the range 200–2000 nm were almost completely retained at the site of administration (subconjunctivally) for at least 2 months, smaller nanoparticles (20 nm) were rapidly cleared from the site of administration.36 Nanoparticles were retained within RPE cells up to 4 months after intravitreal injection.37 Albumin has been employed for the elaboration of ganciclovir nanoparticles for intravitreal administration. These particles did not show inflammatory reactions and retinal alterations. The particles were observed in the vitreous cavity and ciliary body for at least 2 weeks after injection. Polymeric nanoparticles are useful for DNA delivery to the eye. Although viral vectors resulted more efficient in gene transfection, nonviral vectors have fewer side-effects.

Other nano systems such as liposomes, self-assembled micelles, dendrimers, and carbon nanostructure nanotubes have been proposed for intraocular drug delivery.38

ACKNOWLEDGMENTS

The authors thank Vanessa Andres-Guerrero for technical assistance 920415 and Spanish Ministry of Education (MAT2007-65288) and UCM Research Group 920415 (GR58/08) grants for financial support.

REFERENCES

1.Maurice DM, Mishima S. Ocular pharmacokinetics. In: Sears ML, editor. Handbook of Experimental Pharmacology. Berlin: Springer-Verlag; 1984. p. 19–116.

2.Urtti A. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv Drug Deliv Rev 2006;58:1131–1135.

3.Montero JA, Ruiz-Moreno JM, Fernandez-Muñoz M, et al. Effect of topical anesthesics on intraocular pressure and pachymetry. Eur J Ophthalmol 2008;18:748–750.

4.Shirasaki Y. Molecular design for enhancement of ocular penetration. J Pharm Sci 2008;7:2462–2496.

5.Hosoya K, Lee VHL, Kim K. Roles of conjunctiva in ocular drug delivery: a review of conjunctival transport mechanism and their regulation. Eur J Pharm Biopharm 2005;60:227–240.

6.Ranta VP, Urtti A. Transscleral drug delivery to the posterior eye. Prospects of pharmacokinetic modeling. Adv Drug Deliv Rev 2006;58:1164–1118.

7.Robinson MR, Lee SS, Kim H, et al. A rabbit model for assessing the ocular barriers to the transscleral delivery of triamcinolone acetonide. Exp Eye Res 2006:82:479–487.

8.Dib E, Maia M, Longo-Maugeri IM, et al. Subretinal bevacizumab detection after intraviteous injection in rabbits. Invest Ophthalmol Vis Sci 2008;49: 1097–1100.

9.Herrero-Vanrell R, Fernández-Carballido A, Frutos G, et al. Enhancement of the mydriatic response to tropicamide by bioadhesive polymers. J Ocular Pharmacol Ther 2000;16:419–428.

10.Nelson MD, Barlett JD, Karkkainen T, et al. Ocular tolerability of timolol in Gelrite in young glaucoma patients. J Am Optom Assoc 1996;67: 659–663.

11.Chetoni P, Burgalassi S, Monti D, et al. Ocular toxicity of some corneal penetration enhancers evaluated by electrophysiology measurements on isolated rabbit corneas. Toxicol In Vitro 2003;17:497–504.

12.Vandervoort J, Ludwig A. Ocular drug delivery: nanomedicine applications. Nanomed 2007;2:11–21.

13.Yasukawa T, Ogura Y, Tabata Y, et al. Drug delivery systems for vitreoretinal diseases. Prog Retin Eye Res 2004;23:253–281.

14.Callanan DG, Jaffe GJ, Martin DF, et al. Treatment of posterior uveitis with a fluocinolone acetonide implant: three-year clinical trial results. Arch Ophthalmol 2008;126:1191–1201.

15.Okabe K, Kimura H, Okabe J, et al. Intraocular tissue distribution of betamethasone after intrascleral administration using a non-biodegradable sustained drug delivery device. Invest Ophthalmol Vis Sci 2003;44: 2702–2707.

16.http://www.alimerasciences.com/medidur_overview.asp.

17.Sieving PA, Caruso RC, Tao W, et al. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc Natl Acad Sci USA 2006;103:3896–3901.

18.Cheng L, Hostetler KY, Lee J, et al. Characterization of a novel intraocular drug-delivery system using crystalline lipid antiviral prodrugs of ganciclovir and cyclic cidofovir. Invest Ophthalmol Vis Sci 2004;45:4138–4144.

19.Bochot A, Corvreur P, Fattal E. Intravitreal administration of antisense oligonucleotides: potential of liposomal delivery. Prog Retin Eye Res 2000;19:131–147.

20.Fattal E, De Rosa G, Bochot A. Gel and solid matrix systems for the controlled delivery of drug carrier-associated nucleic acids. Int J Pharm 2004;277(11):25–30.

21.Odergren A, Algvere PV, Seregard S, et al. A prospective randomised study on low-dose transpupillary thermotherapy versus photodynamic therapy for neovascular age-related macular degeneration. Br J Ophthalmol 2008;92: 757–761.

22.Antoszyk AN, Tuomi L, Chung CY, et al. Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration (FOCUS): year 2 results. Am J Ophthalmol 2008;145: 862–874.

23.Chakravarthy U, Soubrane G, Bandello F, et al. Evolving European guidance on the medical management of neovascular age related macular degeneration. Br J Ophthalmol 2006;90:1188–1196.

24.Yasukawa T, Kimura H, Tabata Y, Ogura Y. Biodegradable scleral plugs for vitroretinal drug delivery. Adv Drug Deliv Rev 2001;52:25–36.

25.Gould L, Trope G, Cheng YL, et al. Fifty : fifty poly (dl glycolic acid-lactic acid) copolymer as a drug delivery system for 5-fluorouracilo: a histopathological evaluation. Can J Ophthalmol 1994;29:168–171.

26.Gould L, Trope G, Cheng YL, et al. Fifty : fifty poly (dl glycolic acid-lactic acid) copolymer as a drug delivery system for 5-fluorouracilo: a histopathological evaluation. Can J Ophthalmol 1994;29:168–171.

27.Herrero R, y Refojo M. Biodegradable microspheres for vitreoretinal drug delivery. Adv Drug Deliv Rev 2001;52:5–16.

28.Kompella UB, Bandi N, Ayalasomayajula SP. Subconjunctival nanoand microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression. Invest Ophthalmol Vis Sci 2003;44:3562–3569.

29.Jiang C, Moore MJ, Zhang X, et al. Intravitreal injection of GDNF-loaded microspheres are neuroprotective in a rat model of glaucoma. Mol Vis 2007;13:1783–1792.

30.Saishin Y, Silva RL, Saishin Y, et al. Periocular injection of microspheres containing PKC412 inhibits thyroidal neovascularization in a porcine model. Invest Ophthalmol Vis Sci 2003;44:4989–4993.

31.Cardillo JA, Souza-Filho AA, Oliveira AG. Intravitreal bioerudivel sustained-release triamcinolone microspheres system (retaac). Preliminary report of its potential usefulnes for the treatment of diabetic macular edema. Arch Soc Esp Oftalmol 2006;81:675–682.

Delivery Drug Retinal for Routes and Models Animal • 2 section

Systems Delivery Drug Intraocular and Bioavailability, Drug Pharmacokinetic,•chapteOcular9

32.Veloso AAA, Zhu Q, Herrero-Vanrell R, et al. Ganciclovir-loaded polymer microspheres in rabbit eyes inoculated with human cytomegalovirus. Invest Ophthalmol Vis Sci 1997;38:665–675.

33.Herrero-Vanrell R, Ramírez L, Fernández-Carballido A y Refojo MF. Biodegradable PLGA microspheres loaded with ganciclovir for intraocular administration. Encapsulation technique, in vitro release profiles and sterilization process. Pharm Res 2000;17:1323–1328.

34.Moritera T, Ogura Y, Yoshimura N, et al. Feasability of drug targeting to the retinal pigment epithelium with biodegradable microspheres. Curr Eye Res 1994;13:171–176.

35.Bejjani RA, BenEzra D, Cohen H, et al. Nanoparticles for gene delivery to retinal pigment epithelial cells. Mol Vis 2005;11:124–132.

36.Amrite AC, Kompella UB. Size-dependent disposition of nanoparticles and microparticles following subconjunctival administration. J Pharm Pharmacol 2005;57:1555–1563.

37.Merodio M, Irache HM, Valamenesh F, et al. Ocular disposition and toleranci of ganciclovir/loaded albumin nanoparticles after intravitreal injection in rats. Biomaterials 2002;23:1587–1594.

38.Edelhauser H, Boatright JH, Nickerson JM, et al. Drug delivery to posterior intraocular tissues: third annual ARVO/Pfizer Ophthalmics Research Institute conference. Invest Ophthalmol Vis Sci 2008;49:4712–4720.