Nicardipine Loaded Solid Phospholipid Extrudates for the Prevention of Cerebral Vasospasms: In Vitro Characterization.

The aim of the study was to develop nicardipine loaded phospholipid extrudates as an alternative for PLA/PLGA-based implants for the prevention of cerebral vasospasms. Extrudates of different mixtures of saturated and unsaturated phosphatidylcholine (PC) were produced and characterized by DSC, microscopy and texture analysis. Single phospholipid components were identified by ELSD-HPLC. Extrudates of 2 mm diameter were obtained by twin screw extrusion temperatures below 50 °C. The ratio of unsaturated and saturated phosphatidylcholine components determines the physicochemical properties of the extrudates as well as the rate of erosion. Nicardipine loaded phospholipids extrudates released the drug over several weeks in vitro. The phospholipid composition of the remaining extrudate changed during the release, the content of unsaturated phospholipids decreased faster compared to the saturated ones. In conclusion, solid phospholipid extrudates are promising materials for the development of new parenteral controlled release systems.

Polymer degradation induced drug precipitation in PLGA implants - Why less is sometimes more.

Nifedipine and nicardipine loaded PLGA extrudates have a great potential to prevent cerebral vasospasms after subarachnoid hemorrhage or surgical clipping of aneurysm. A constant release over approx. two weeks is desired. Although in vivo studies on humans have been reported, there is limited knowledge about the release kinetics and the underlying mechanisms. Therefore, nifedipine and nicardipine loaded PLGA implants with different drug loads were manufactured by extrusion and investigated. In addition to the measurements of the release kinetics, GPC, DSC, X-ray diffraction and light microscopic investigations were performed for a detailed characterization. The water uptake and polymer erosion studies showed an initial lag phase of 5-7 days and an acceleration of both processes thereafter. With 5% loaded implants a higher drug release compared to 10% drug loaded polymers could be achieved and not only the relative amount of drug release (% of loaded drug), but surprisingly also the absolute amount of the released drug increased. The drugs were initially in an amorphous state. For nifedipine, formation of drug crystals with time has been observed by light microscopy and X-ray diffraction. The analysis of the drug content in the degrading polymer showed a very large increase from 10% to about 20% (nifedipine) and over 50% (nicardipine). In contrast, no or only a moderate increase of the drug content occurred for initially 5% loaded polymer implants. We postulate that water penetration and polymer degradation induced changes of the microenvironment lead to supersaturated systems. A supersaturated state is faster reached for polymers with higher drug load and therefore, drug precipitation takes place at earlier time points. As a result, drug release might be incomplete for poorly soluble drugs and paradoxically, the total amount of drug release might be higher for systems with a lower drug load. Drug release is initially controlled by the PLGA matrix, but later by the dissolution kinetics of the precipitated drug which are very slow for poorly soluble drugs according to the Noyes-Whitney equation.

PLGA nanoparticles for peroral delivery: How important is pancreatic digestion and can we control it?

Biodegradable nanoparticles made of Poly(lactide-co-glycolide) are increasingly proposed for the improvement of oral drug absorption, but also as carriers for the treatment of colonic diseases. Unfortunately, our knowledge of the digestibility of PLGA-NPs is rather limited. Therefore, we investigated the impact of pancreatin on the digestibility of PLGA-NPs stabilized with different emulsifiers. The pancreatin induced degradation was monitored by the pH-stat method and an enzymatic l-lactic acid assay. A high digestibility was found for poloxamer 188 and polysorbate 80 stabilized PLGA-NPs. The digestion could be blocked by Orlistat, indicating a major role of pancreatic lipase. PLGA-NPs stabilized with Poly(vinyl alcohol) (=PVA) were not digested at comparable surfactant concentrations (0.6%). However, PLGA-NPs stabilized with very low amounts of PVA (0.1%) were digestible. In conclusion, PLGA-NPs are substrates for the pancreatic lipase. The digestibility can be enhanced or blocked by the proper selection of the surfactant composition and concentration.