Kinetic release, zero-order

The investigators studied various blends of the three polymers in order to control the rate of chain scission and thus influence the induction period and onset of drug release. None of the blends provided the desired 1-week zero-order kinetics. However, blends of different microsphere types did show promise in vitro (88). 

Recently, Tsakala et al. (90) formulated pyrimethamine systems based on several lactide/glycolide polymers. These studies were conducted with both microspheres (solvent evaporation process) and implants (melt extrusion process). In vitro studies indicated that pyrimethamine-loaded implants exhibited apparent zero-order release kinetics in aqueous buffer whereas the microspheres showed an initial high burst and considerably more rapid drug release. In vivo studies in berghi infected mice confirmed that the microspheres did not have adequate duration of release for practical application. However, the implants offer promise for future clinical work as more than 3 months protection was observed in animals. 

Apatite is used to remediate Pb contaminated soils because apatite dissolution releases phosphate, which combines with Pb to form highly insoluble Pb-phosphate minerals. Apatites follow linear (zero-order) dissolution kinetics (Manecki et al., 2000) with rates of Pb uptake by the apatites decreasing in the same order as the apparent dissolution rate... 

Silverman has pointed out that several criteria must be met to demonstrate that a compound is a true suicide substrate 1101 (1) Loss of enzyme activity must be time-dependent, and it must be first-order in [inactivator] at low concentrations and zero-order at higher concentrations (saturation kinetics), (2) substrate must protect the enzyme from inactivation (by blocking the active site), (3) the enzyme must be irreversibly inactivated and be shown to have a 11 stoichiometry of suicide substrate active site (dialysis of enzyme previously treated with radiolabeled suicide substrate must not release radiolabel into the buffer), (4) the enzyme must unmask the suicide substrate s potent electrophile via a catalytic step,1121 and (5) the enzyme must not be covalently labeled with the activated form of the suicide substrate following its escape from the active site (the presence of bulky scavenging thiol nucleophiles in the buffer must not decrease the observed rate of inactivation). 

Another example of zero-order kinetics is the rate of dissolution of encapsulated solutes restricted in the egress by passage through a small orifice in the capsule. If a soluble salt is added in addition to the encapsulated solute, one obtains an osmotically driven solute release system. See also Order of Reaction Molecularity Michaelis-Menten Equation Eirst-Order Reaction... 

Liu G, Zhou J. First- and zero-order kinetics of porogen release from the cross-linked cores of diblock nanospheres. Macromolecules 2003 36 5279-5284. 

A further development of this system has been the preparation of drug delivery systems whereby the releasing area exposed has been reduced by an impermeable partial coating. As a result, the kinetics of release was zero order [9,10]. 

Release rates (%/min) were calculated from the best fits of released drug vs. time plots. The slopes ( ) of the log(released drug) vs. log(time) plots were calculated from the linear least-squares regression lines. A slope of 0.5 in the log-log plot indicates diffusional, square root of time, dependence and a slope of 1.0 indicates zero-order release kinetics [6]. Times of 50% drug release (t50%) were calculated from the best fits of drug released vs. time plots. 

In other indications such as hypertension, the OROS technology (oral osmotic system developed by ALZA) has already proven its value, and therefore it seemed appropriate to use this technology with its typical, virtually constant, release rate (zero-order kinetics) for once-daily opioid tablets. Such a morphine tablet is already available, but is not yet on the market, and a hydromorphone OROS is currently being clinically developed by Knoll. 

Chen, G L. and W. FI. Plao. 1998. Factors affecting zero-order release kinetics of porous gelatin capsulesDrug Dev Ind Pharrr24 557-562. 

In the case of controlled drug-delivery systems, the goal is to have the drug released at a relatively constant rate (zero-order kinetics) at a concentration within the therapeutic range. It is obviously important to minimize the amount of time the concentration is in... 

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