10.1  Introduction

Successful ophthalmic therapy requires effective concentrations of the drug in the target site. Therapeutic concentrations of the active substance in cornea and conjunctiva are mandatory for the treatment of ocular surface diseases such as dry eye syndrome, surface inflammation, or infection. However, if the drug has to reach the

Fig. 10.2  Administration routes of microparticles: Intravitreal, subretinal, and periocular

Microparticles are adequate for the intraocular route, bypassing the blood–­ocular barrier. One of their advantages is that microparticles can release the drug over the time with one single administration, having the same effect than multiple injections (Fig. 10.2). Furthermore, injection of microparticles is carried out as a conventional suspension.

Microparticles are usually prepared with a polymer or mixture of polymers and one or several active substances. Depending on the nature of the polymer (erodible or biodegradable and nonerodible or nonbiodegradable) microparticles remain or disappear from the site of injection after delivering the drug. In the case of posterior segment diseases, biodegradable microparticles are preferred.

Microparticles are capable to provide sustained and controlled release of the bioactive agent, while the remaining drug still present inside the particle is protected from degradation and physiological clearance.

By physical structure, microparticles are classified in microcapsules and microspheres. Microcapsules are constituted by a drug core, which is surrounded by a polymer layer (reservoir structure). Conversely, in the microspheres the drug is dispersed through the polymeric network (matrix structure) (Fig. 10.3).

Among the biodegradable polymers employed to prepare microparticles are gelatin, albumin, polyorthoesters, polyanhydrides, and polyesters (Colthrust et al. 2000; Herrero-Vanrell and Refojo 2001). Since several years ago, the most employed polymers to prepare biodegradable microspheres are the poly(lactic) acid (PLA), poly(glycolic) acid (PGA), and their copolymers poly(lactic-co-glycolic) acid (PLGA). PLA and PGA have crystalline structure whereas PLGA is amorphous. Experience has shown that the PLGA 50:50 (50% lactide and 50% glycolide) degrades relatively fast to metabolic lactic and glycolic acid that are readily eliminated from the body after suffering metabolism to carbon dioxide and water mediated by Krebs cycle (Zimmer and Kreuter 1995). Regarding to molecular weight, polymers with small chains degrade faster than high molecular weight polymers. For the back of the eye, PLA and PLGA polymers have been employed to prepare different devices: implants, scleral plugs, pellets, discs, films, and rods (Yasukawa et al. 2004; Mansoor et al. 2009).

Fig. 10.3  Structure of microparticles. Microcapsules (reservoir system) and microspheres (matrix structure)

10.2  Manufacturing of Microparticles

Manufacturing of microparticles are mainly based on four basic techniques: aggregation by pH adjustment or heat, coacervation (phase separation), spray drying, and solvent extraction/evaporation (Freitas et al. 2005). Coacervation required the use of solvents and coacervating agents that can remain in the microparticles once prepared and low micrometer size is difficult to obtain. The use of supercritical gases as phase separating agents has been introduced to avoid potentially harmful residues in the microspheres. Spray drying is relatively simple but not useful for highly tem- perature-sensitive drugs. Microspheres prepared according to this technique are highly porous. Microspheres loaded with triamcinolone acetonide (TA) and ciprofloxacin have been prepared by the spray drying technique for intraocular injection (Paganelli et al. 2009).

The most commonly reported technique for microspheres formation is the solvent extraction/evaporation method (evaporation of a solvent from an emulsion) (Herrero-Vanrell et al. 2000; Amrite et al. 2006) (Fig. 10.4). It requires a dissolution or dispersion of the active substance in a first solvent containing the matrix forming polymer (inner phase). After that, an emulsification of the polymer organic solution in a second continuous phase immiscible with the inner phase is carried out. Then, an extraction of the organic solvent from the formed emulsion by evaporation is