Retina Today - Overview of Sustained-Release Drug-Delivery Systems (March 2015)

摘要

The number of intravitreal injections performed for the treatment of posterior segment diseases has dramatically escalated as new therapies have become available. Intravitreal injections, however, have limited efficacy. Monthly dosing of a drug would seem to deliver a consistent effect of that drug; however, very high local concentrations immediately after injection are typically followed by rapid clearance of the drug, thus necessitating frequent treatment. Several approaches described in this article have been approved or are being explored for extended release of drugs for the treatment of retinal diseases. In general, the rationale for these innovative delivery systems is to deliver sustained drug concentrations to the target site so as to decrease the treatment burden associated with repeated injections (Table).1-5 Such systems may be combinations of drug and biomaterial and can be classified according to size as implants (> 1 mm), microparticles (1??to??1000 ??m), or nanoparticles (1??to??1000 nm). The biomaterial may be biodegradable or nonbiodegradable. Depending on their size, implants and microparticles may release drug for longer durations compared with nanoparticles. However, drug-releasing implants may require a surgical procedure or special injection devices. It is our belief that a microparticle-based approach administered in the doctora??s office can be formulated into an ideal therapy that would reach therapeutic doses in the target tissue with infrequent administration and a positive safety profile. IMPLANT PREPARATION Implants act as reservoirs for a drug or drugs so that the therapy can be delivered over a long interval. Commonly used techniques for implant preparation include solvent casting and extrusion.6,7 Solvent Casting and Compression Molding In this method, polymer and drug are dissolved in a common solvent and cast at a temperature to completely evaporate the solvent. The resultant structure is a composite material of drug together with polymer; the material is then compression-molded into the desired implant geometry. Solvent casting methods are not ideal for industrial scale-up because the process requires large quantities of organic solvent. In addition, solvent casting is not a continuous process and may result in batch-to-batch variability. Extrusion The extrusion process mitigates the disadvantages associated with solvent casting. It is a continuous process of drawing a polymer mixture through a die (mold cavity) to manufacture implants of a fixed cross-sectional profile. In this process, the polymer-drug mixture is heated to a semiliquid state by a heating element and by the stress from the extrusion screw. The screw pushes the mixture through a die, and the resulting extrudate is cooled and solidified before being cut into the desired implant lengths. The disadvantage of this technique is that the drug is exposed to high temperatures, and denaturation may occur. MICROPARTICLE PREPARATION The commonly used techniques for the manufacture of drug-incorporated microparticles are emulsion methods, phase separation, and spray drying.8-11 Emulsion Methods Single emulsion methods have been used to encapsulate hydrophobic drugs through an oil-in-water (o/w) process. In this process, the polymer is dissolved in a water-immiscible volatile organic solvent (eg, dichloromethane), and the drug is dissolved or suspended into the polymer solution. The resulting mixture is emulsified in a large volume of water in the presence of an emulsifier (eg, polyvinyl alcohol). The solvent in the emulsion is removed either by evaporation at elevated temperatures or extraction in large quantities of water. To encapsulate hydrophilic drugs (eg, peptides or proteins), double emulsion methods like water-in-oil-in-water (w/o/w) have been used. The aqueous solution of the water-soluble drug is emulsified with polymer-dissolved organic solvent to form a water-in-oil (w/o) emulsion. The em