On-demand release by ultrasound from osmotically swollen hydrophobic matrices

Ethylene-vinyl acetate copolymer (EVAc) based controlled release systems are composed of a continuous hydrophobic polymer phase and of dispersed solid drug particles. In matrices with high drug loadings (≥ 50%) most drug particles are interconnected. Thus, when these matrices are immersed in water, release rates are relatively high. In matrices with low drug loadings (< 40%) most drug particles are isolated within the continuous hydrophobic polymer matrix. Thus, release rates are very low. Matrices containing water soluble particles at a low loading swell intensely after immersion in water; this is caused by the osmotic force of the isolated particles which causes the water to permeate into the hydrophobic polymer. The enclosed drug particles absorb water, and at the end of the swelling process the matrices consist of an immense number of fluid pockets containing dissolved drugs. In attempt to develop on-demand release systems, we studied the effect of ultrasound (US) on the release rates of these swollen matrices. We found that low-frequency ultrasound (20 kHz) reversibly increased the release rates from these swollen matrices by a factor of 30-500, in contrast to the unswollen matrices, where the release rates increased only by a factor of 2-3. Unswollen and swollen matrices react differently to US, as unswollen matrices contain drug particles which absorb ultrasound on the surface of the matrices, causing ultrasound attenuation. On the other hand, swollen matrices contain a compact arrangement of fluid pockets separated from each other by thin membranes containing a solution of the dissolved drug, therefore ultrasound penetrates through the matrix volume. Ultrasound penetration causes tearing of these membranes within the matrices. As a result, the fluid pockets interconnect, and drug molecules diffuse out through these interconnected pockets.