Long-acting injectable (LAI) parenteral formulations are complex dosage forms designed for controlled drug release over weeks to months, administered intramuscularly (i.m.) or subcutaneously (s.c.). After injection, a nanosuspension forms an active pharmaceutical ingredient (API) depot in muscle tissue, enabling gradual release. Long-acting injections reduce dosing frequency, improve patient adherence and offer a solution for continuous treatment of chronic diseases.
The main aim of this master’s thesis is to develop a selective in vitro dissolution method that can distinguish between API particles of different sizes in an extended-release nanosuspension, while also ensuring robustness. To this end, we evaluated samples of the suspension prepared using a wet bead milling method with glass beads. The samples had the same composition as the innovator product – API, polysorbate 20, mannitol, macrogol, and water for injection. The individual samples differed in the manufacturing process – variations mixing speeds and durations, the sequence of component addition, the use of milling beads of different sizes. As a result, API particle size in the nanosuspension varied.
We developed the method using a USP 4 apparatus with a flow-through cell, operating in a closed-loop configuration. Initially, we evaluated parameters such as flow rate, sampling method, media volume, API dose, and the impact of the medium's composition and ionic strength. To simulate drug release in muscle tissue, we used a medium that mimics the composition of interstitial fluid so called the simulated muscle fluid. In parallel, we attempted to simulate release under physiological muscle tissue conditions using a dialysis device called »Slide-A-Lyzer.« In both methods, significant precipitation of the API was observed, which we attributed to the high ionic strength of the medium, therefore we proceeded with further testing in water. We also employed a method using cell culture plates to evaluate the initial drug release, known as the »burst effect.«
In conclusion, the choice of apparatus and parameters influences the release rate of the API from the intramuscular nanosuspension. The method using the USP 4 apparatus provides reproducible results (RSD of time points from the 60th minute onward < 20%), but it cannot be considered robust (f2 ≤ 50). In contrast, the method using cell culture plates offers added value, as it allows for evaluation of the »burst effect« and is selective, as it differentiates between nanosuspensions obtained through different manufacturing processes and varying particle sizes.
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