title: Theory of effective drug release from medical implants based on the Higuchi model and physico-chemical hydrodynamics.
abstract: Combining the approach of colloid transport with the generalized Higuchi theory of drug release and with the concept of minimum inhibitory concentration (MIC) known in microbiology, the theory of effective drug release from implants has been developed. Effective release of an antibiotic at a concentration above MIC is a necessary condition to achieve protection against infection from implants such as central catheters. The Higuchi theory in its present form is not predictive of the therapeutic effect from medical implants. The theory of effective release presented in this paper specifies two release modes, namely: one with therapeutic usefulness (effective release) and another without therapeutic effect. Therapeutic usefulness may be achieved when the antibiotic concentration,Cti, on the implant surface kills the organisms of interest and prevents the formation and propagation of biofilm whenCtiexceeds the corresponding MIC of the released antibiotic compound. Currently, neither the Higuchi theory nor any other theory can provide such prediction. The present approach requires quantification of the antibiotic transport from the drug-polymer blend implant surface into the tissue and accounts for its coupling with drug diffusion inside the blend, a task that has not been developed in existing theories. Our solution to this task resulted in the derivation of an equation for the time of duration of effective release,Te, which depends on MIC, the Higuchi invariant and the characteristics of convective diffusion within the tissue. The latter characteristics include: diffusivityDtiand diffusion layer thickness δ which is controlled by the velocity of the interstitial fluid in tissue. A smallerDtiis favorable because transport from the catheter surface is weaker, while a thinner diffusion layer is harmful because this transport is stronger. The influence of the tangential component of interstitial velocity in the tissue is especially harmful because the diffusion within the incision exit site (IES) will be extremely enhanced such that it may decreaseCtito zero. The incorporation of convective diffusion into the theory of antibacterial protection by means of antibiotic release has revealed that physicochemical mechanisms predict the effectiveness of antibiotic-loaded catheters and defines the conditions necessary to achieve better protection by means of combining the level of catheter loading with antibiotics and the use of wound (IES) dressing.
authors.affiliation: NovaFlux Technologies, 1 Wall Street, Princeton, NJ 08540, USA.
authors.forename: Stanislav S
authors.initials: SS
authors.lastname: Dukhin
authors.forename: Mohamed E
authors.initials: ME
authors.lastname: Labib
keywords: Antibiotic-loaded catheter; Catheter; Controlled drug release; Convective diffusion; Diffusion layer thickness; Diffusivity within tissue; Effective drug release; IES; Incision exit site; MIC; Minimum inhibitory concentration; Monolithic nonporous polymer implant; Physicochemical hydrodynamics