(97b) Long-Term Dissolution Method for Intramuscular Suspension

Sustained release (SR) injectable suspensions – also called “nanoparticle depot systems” – are already used in clinical practice because they have a number of advantages: lower frequency of administration, blood levels remain within therapeutic range, greater effectiveness and reduced side effects, as well as improved patient compliance. Such suspensions may be administered in the form of a low soluble drug, but the release time of such medication is dependent on the particle size and the specific surface area. In drug development, it is very important to have reliable method how to evaluate drug dissolution profile in in vitro conditions before clinical trials on animals and humans. In the case of low soluble drug, common dissolution tests are not applicable because of drug insolubility. Therefore, we have developed a new in vitro dissolution method to evaluate the dissolution profile of such nanoparticle medication. Moreover, this method is also useful for the development of generic drugs, in order to compare their dissolution profile to those of the reference. Enzymatic dissolution tests of our drug suspensions were conducted with various PSD by the enzyme serine esterase in a physiological solution at 37 C. We prepared those suspensions of various PSD by wet nano milling in a ball mill containing ZrO₂ beads, based on previous parametric study where we investigated the impact of variable process parameters such as time, ball diameter, fill level and agitation rate. For each sample taken at various time intervals, the increase of API concentration and reduction of PSD of the suspension were evaluated using HPLC and laser diffraction, respectively. Based on the results of this work, the rate of kinetic release was found to correlate directly with an increase in the specific surface area of the particles in the suspensions. The proposed in vitro method is used to predict the pharmacokinetics of the medication under in vivo conditions. Thus, it can serve as a cheaper and faster alternative for bioequivalence studies (BES) on animals used in generic drug development. However, further validation studies will be required to relate our method quantitatively to real in vivo conditions.