Zero-order release kinetics

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. 

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. 

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

Kim, C. Compressed donut-shaped tablets with zero-order release kinetics. Pharm. Res. 12 1045-1048, 1995. 

Aliquots were removed from the flask periodically and were assayed for the released 5-FU at 265 nm using a Beckman DU-7 spectrophotometer. These hydrolysis studies were run for several weeks. The reproducibility of each technique was determined by rerunning the same sample at a different time. Host of these reproducibility studies were run using EHCF monomer because the release rates were faster than with the copolymers and because this EHCF monomer did not show zero-order release kinetics. The copolymer hydrolysis rates were determined at least two times and these results showed excellent agreement with each other. No detailed studies were made on any effect the stirring speed might have on the observed release rates, but the results obtained at either 300 or 600 RPH appeared to be the... 

The EHCF copolymers studied showed zero-order release kinetics in this simplified procedure and showed identical release profiles as in our earlier study (1 ) using the more complex dialysis membrane/ stainless steel mesh basket technique. The actual 5-FU release rates increased in the co-monomer order HHA>HA>BA. Within a given set of copolymers, the release rate for 5-FU increased as the EHCF content increased. 

A device consisting of an array of frustum-shaped cells that contain a drug dispersed in a permeable matrix is shown to obey zero-order release kinetics following an initial burst phase. Geometric shapes of dissolving solids or diffusion systems and the constraints of impermeable barriers influence mass transport and can be exploited as in the constant release wedge- or hemispheric-shaped devices. 

A sustained drug release is favourable for drugs with short elimination half-life. It can be controlled by hydration and diffusion mechanisms or ionic interactions between the drug and the polymeric carrier. In the case of diffusion control the stability of the carrier system is essential, as its disintegration leads to a burst release. Therefore, the cohesiveness of the polymer network plays a crucial role in order to control the release over several hours. Due to the formation of disulphide bonds within the network thiomers offer adequate cohesive stability. Almost zero-order release kinetics could be shown for insulin embedded in thiolated polycarbophil matrices (Clausen and Bernkop-Schnurch 2001). In the case of peptide and protein drugs release can be controlled via ionic interactions. An anionic or cationic polymer has to be chosen depending... 

Equation (6.94) illustrates that zero-order release kinetics are obtained if drug dissolution controls the release kinetics. However, as soon as the last particle in the matrix dissolves, the controlling mechanism of drug release shifts to Fickian diffusion. Figure 6.19 shows the dissolution-controlled release of KC1 at the early stage of release and the diffusion-controlled release at the later stage of release from an ethyl cellulose tablet. 

Zero-order release kinetics expressed by Equation (6.139) agree with Equation (6.126) for heterogeneous erosion-controlled systems. However, when the rate of polymer erosion is very slow, the rate of drug diffusion through the swollen gel layer controls drug release kinetics (i.e., B2 A), and Equation (6.134) becomes ... 

Among various initial concentration distributions in a matrix, the sigmoidal drug distribution or a staircase distribution resembling a sigmoidal pattern furnishes zero-order release kinetics for the planar geometry. There are various methods to build concentration gradient matrix systems. The most convenient way to achieve the... 

Thus a reservoir system can provide constant release with time (zero-order release kinetics) whereas a matrix system provides decreasing release with time (square root of time-release kinetics). A summary of the drag release properties of reservoir and matrix nondegradable devices in given in Table 4.3. 

In non-porous polymeric systems the rate of drug release is dictated by the device surface area which is linked directly to its shape. Drug release from polymeric systems with a variety of geometries has been described. " Zero-order release kinetics may be more easily achieved with slab or rod geometries than spheres. The rate of release from spheres may result from polymer diffusion or erosion. " " " Diffusion-mediated release has been studied extensively and described mathematically. " ... 

One complication which arises when we are carrying out stability testing of suspensions is the changes in the solubility of the suspended drug with increase in temperature. With suspensions, the concentration of the drug in solution usually remains constant because, as the decomposition reaction proceeds, more of the dmg dissolves to keep the solution saturated. As we have seen, this situation usually leads to zero-order release kinetics. If the acmal decomposition of dissolved dmg is first-order, then we can express the decrease of concentration, c, with time, t, as... 

APPROACHES TO ACHIEVING ZERO-ORDER RELEASE KINETICS... 

Although the hemisphere design resulted In zero-order release kinetics for macromolecules such as BSA, the release mechanism for these systems has not yet been fully established. However,... 

Rhine, W., et ai, A new approach to achieve zero-order release kinetics from diffusion-controlled polymer matrix systems, in R.W. Baker, Controlled Release of Bioactive Materials. New York Academic Press, 1980, pp. 177-187. 

The practically zero-order release kinetics for the release of the radiolabeled by-products ii i ... 

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