A general scheme for achieving periodic pulsatile drug release through a membrane is described, with application to the delivery of hormonal agents and drugs that exhibit tolerance. The permeability of the membrane to a substrate of an enzymatic reaction is assumed to be dependent on the concentration of the product of that reaction in a manner that displays product inhibition. Under certain conditions this negative feedback control can lead to oscillations in membrane permeability to the substrate. If the membrane permeability to a drug is simultaneously affected, then this will lead to oscillatory drug release. The scheme is analogous to certain biochemical oscillators whose mechanisms are based on product inhibition. A simple model is introduced for illustration, and results of simulations based on the model are displayed. Sustained oscillations are achieved with certain conditions on the model parameters, while other sets of parameters lead to decaying oscillations. Parameter requirements for sustained oscillations are discussed qualitatively, with detailed theoretical analysis to appear in a subsequent publication.
Bibliographical noteFunding Information:
This work was funded in part by Amgen, Inc. The authors are grateful to Professor John Ross and Dr. Milos Dolnik for helpful discussions, as well as Drs. John Baker and Lennart Lindfors for critical reading of the manuscript.
- Feedback inhibition
- Hormone delivery
- Mathematical modelling
- Periodic release
- Pulsatile release