Implantable polymeric drug-delivery devices have been constructed to deliver drugs at welldefined rates. Typically, these devices have been designed to deliver drugs at a constant rate, or in response to the concentration of a certain body metabolite. For some drugs, pulsatile delivery is sought. For example, under normal conditions, human growth hormone is released in the body in periodic bursts. Current treatments for HGH deficiency often fail because HGH is not administered following the endogenous pattern. Thus, pulsatile hormone-replacement therapy should be considered. Also, it may be useful to deliver in a periodic, pulsatile manner drugs that exhibit significant acute tolerance.
Currently, an oscillator is under development that is fueled by endogenous compounds and contains a variable-permeability membrane. The membrane's permeability to the substrate of an enzymatic reaction is assumed to be dependent on the concentration of the product of the reaction in a manner that displays product inhibition. Under certain conditions, this negative-feedback control can lead to oscillations in the membrane's permeability to substrate. If the membrane's permeability to a drug is simultaneously affected, then this will lead to oscillatory drug release.
We report encouraging initial studies. A simple theoretical model has been developed for the membrane oscillator, and results of simulations based on the model are discussed.
Diffusion-cell studies have been performed with a variable-permeability poly(N-isopropylacrylamide- co-methacrylic acid) hydrogel membrane. Using glucose as a probe solute, the results show that lowering the pH induces hydrogel volume collapse and cessation of glucose permeation across the membrane.