Intravitreal poly(L-lactide) microparticles sustain retinal and choroidal delivery of TG-0054, a hydrophilic drug intended for neovascular diseases

While poorly soluble drugs such as corticosteroids sustain drug delivery in the vitreous humor by virtue of slow dissolution, macromolecules such as antibodies and their fragments sustain their levels due to their slow clearance. However, currently there are no approaches to sustain the delivery of well water-soluble small molecule drugs in the vitreous. In this study, we optimized a poly(L-lactide) (PLA) microparticle formulation for sustained intravitreal delivery of TG-0054, a well water-soluble anti-angiogenic drug that is of potential value in treating choroid neovascularization. After determining the influence of process parameters on particle size and drug loading, spherical microparticles syringeable through a 27-G needle, with a mean diameter of 7.6 mu m, 10% (w/w) TG-0054 loading, sustained in vitro drug release for at least 6 months, and low residual organic solvent content (similar to 1 ppb/mg) were prepared. Microparticles as well as drug solution were assessed for their in vivo drug delivery over 3 months following intravitreal injection in New Zealand white rabbits. Drug levels in the microparticle dosed eyes at 3 months were 43.7 +/- 16.2, 243 +/- 42.6, and 62.8 +/- 22.6 mu g/g vitreous, retina, and choroid-retinal pigment epithelium (RPE), respectively, and similar to levels at 1 month. Intravitreal injection of plain drug solution resulted in significantly lower amounts of drug in the dosed eye, with the levels being 0.8 +/- 0.5, 2.7 +/- 2.8, and 4.9 +/- 4.2 mu g/g in vitreous, retina, and choroid-RPE, respectively, at 1 month, with no detectable drug at 3 months. Although surface degradation was evident, microparticles maintained their spherical structure during the 6-month in vitro study and the 3-month in vivo study, with the vitreal particle retention at 1 and 3 months being 60% and 27%, respectively. Thus, PLA microparticles capable of sustaining retinal and choroidal delivery of TG-0054 for 3 to 6 months were developed.