Cumulative drug release rate

The cumulative drug release and the drug release rate for constant activity and nonconstant activity reservoirs of other geometrical barriers are shown in Table 6.3. 

The Cumulative Drug Release and Release Rate for Constant Activity and Nonconstant Activity Reservoirs... 

Methotrexate Microsphere The drug release in PBS (pH 7.4) and simulated gastric fluids followed similar release rate, while there was a significant increase in percent cumulative drug release (91.0%) in the medium containing rat cecal content. [143]... 

The performance of this system is shown in Figure 17 for the release of nifedipine from the GITS system [47], The reproducibility of the release rates is remarkable. Also note that the fractions released over time from three separate doses are basically superimposable. It should also be noted that these systems have an inherent delay in the onset of drug delivery which arises from the time required to build up a sufficient hydrostatic pressure to permit release of the gel that is formed within the tablet during delivery. Figure 18 shows the comparison of the in vitro and in vivo cumulative fraction released for the 30 mg system. Clearly, the in vitro performance is mirrored in the in vivo data. 

Time profiles in vitro and in vivo represent distribution functions in a mathematical and statistical sense. For example, a release profile Fj)(t) in vitro expresses the distribution of drug released at time t the corresponding probability distribution function (PDF) profile fo(t) characterizes the rate of release. Similarly, a plasma concentration profile fp(t) represents the distribution of drug in the plasma at any time t, i.e., absorbed but not yet eliminated its cumulative distribution function (CDF) equivalent FP(t) represents the drug absorbed and already eliminated. 

If tlie release characteristics of the formulation can be described by a zero-order process for some period of time (e.g., 5%/hr from 4 to 12 hours), and the dissolution profile appears to fit a linear function for that period of time, a release rate specification may be established to describe the dissolution characteristics of that formulation. A release rate specification may be an addition to the specifications established on the cumulative amount dissolved at the selected time points. Alternatively, a release the rate specification may be the only specification except for the specification for time when at least 80% of drug has dissolved. 

PG release curves into buffer from formulations (a) and (b) are in Figures 1 and 2, respectively. The Figures show mean ( S.D.) release rate of drug as a function of time and a representative plot of the cumulative PG liberated from the delivery system during the experiment. The free PG system [(a)] released 90.4% ( 5.5%) of the dose in 24 hours compared to the EPC device [(b)] from which 24.8% ( 3.8%) was liberated during the same period. The values are significantly different at p < 0.01. 

The rate of release decreases with time since drug molecules near the surface are released first (they have the shortest distance to travel by diffusion). The common matrix form of a slab has a cumulative release proportional to the square root of time therefore, the release rate decreases with the square root of time (this fact can be demonstrated by taking the first derivative of Equation 9-19). However, if the matrix is formed as a hemisphere with an... 

Figure 9.7 Drug release from a planar matrix drug delivery system. The cumulative mass of drug released from a planar drug delivery system as predicted by Equation 9-18 is shown as a function of the rate of diffusion of the dissolved drug in the matrix, Dj.p. The left panel shows release as a function of time and the right panel shows release as a function of the square root of time (with the expected linear dependence). The thickness of the matrix is 1 mm.

Fig. 9 Drug release from oLG tetrole derived SMP in phosphate buffer pH 7 at 37°C. (a) Cumulative release of well soluble ethacridme lactate (EL) tmd less soluble enoxadne (EN) and nitioluiantom (NF). (b) Release rates of EL from the permement shape = 0%) and the slowly recovering program mcd shape = 130%). Reprinted from [30]. Copyright 2009, with peimission from Elsevier...

Figure 4.52. Coefficients of variation that reflect both tablet to tablet and analytical variability. For formulation B, particularly strengths 2 and 3, the drop in CV with higher cumulative release (a - b) is marked, cf. Fig, 4.50. When the dissolution rate is high, individual differences dominate, while towards the end analytical uncertainty is all that remains. The very low CVs obtained with strength 3 of formulation A ( 0.7-0.8%, data offset by +10% for clarity) are indicative of the analytical uncertainty. Because content uniformity is harder to achieve the lower the drug-to-excipient ratio, this pattern is not unexpected.

Fig. 11. Cumulative mean diuresis versus cumulative mean furosemide excretion following 60 mg doses given as two controlled release tablets (boxes), as plain tablets (closed triangles) and following an intravenous dosage of 0.5 mg/kg (open triangles). (From Paintaud G. Kinetics of drug absorption and infiuence of absorption rate on pharmacological effect. Diss. Karolinska Institutet, Stockholm 1993, reproduced by permission.)...

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