Abstract
Despite the importance of drug release testing of parenteral depot formulations, the current in vitro methods still require ameliorations in biorelevance. We have investigated here the use of muscle tissue components to better mimic the intramuscular administration. For convenient handling, muscle tissue was used in form of a freeze-dried powder, and a reproducible process of incorporation of tested microspheres to an assembly of muscle tissue of standardized dimensions was successfully developed. Microspheres were prepared from various grades of poly(lactic-co-glycolic acid) (PLGA) or ethyl cellulose, entrapping flurbiprofen, lidocaine, or risperidone. The deposition of microspheres in the muscle tissue or addition of only isolated lipids into the medium accelerated the release rate of all model drugs from microspheres prepared from ester-terminated PLGA grades and ethyl cellulose, however, not from the acid-terminated PLGA grades. The addition of lipids into the release medium increased the solubility of all model drugs; nonetheless, also interactions of the lipids with the polymer matrix (ad- and absorption) might be responsible for the faster drug release. As the in vivo drug release from implants is also often faster than in simple buffers in vitro, these findings suggest that interactions with the tissue lipids may play an important role in these still unexplained observations.
Highlights
The drug release rate from implantable formulations is a critical parameter of their therapeutic effectiveness
When the stock solution of flurbiprofen was added to the release medium with 20 mg/ml suspended muscle tissue powder, only 79.2 ± 0.9% recovery was determined in relation to the simultaneously performed blank
Muscle tissue in its freeze-dried pulverized form offered a worthwhile approach in the development of a first model simulation of intramuscular environment for drug release testing
Summary
The drug release rate from implantable formulations is a critical parameter of their therapeutic effectiveness. An ideal “biorelevant” in vitro method would consider all factors affecting drug release in vivo. Enhancing simple buffers used as dissolution media by additional physiological parameters (e.g., surfactants, enzymes, concomitant food intake, biphasic dissolution, etc.) has been in many cases shown to provide better in vitro-in vivo correlations [5,6,7]. Few studies have described attempts on application of biorelevant media, either with respect to the ionic composition [8] or with additional specific components of extracellular matrix (ECM)—such as hyaluronic acid either in a dialysis model mimicking the subcutaneous tissue [9] or as a component of a simulated synovial fluid [10,11,12]. An alternative approach is the release testing in hydrogels which are supposed to simulate the gellike physical nature of the ECM [13,14,15,16,17,18,19]; the
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