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Myocardial infarction is a leading cause for morbidity and mortality worldwide. The only
viable treatment for the ischemic insult is timely reperfusion, which further exacerbates myocardial
injury. Maintaining mitochondrial function is crucial in preserving cardiomyocyte function in
ischemia reperfusion (IR) injury. Poloxamer (P) 188 has been shown to improve cardiac IR injury
by improving cellular and mitochondrial function. The aim of this study was to show if P188
postconditioning has direct protective effects on mitochondrial function in the heart. Langendorff
prepared rat hearts were subjected to IR injury ex-vivo and reperfused for 10 min with 1 mM P188
vs. vehicle. Cardiac mitochondria were isolated with 1 mM P188 vs. 1 mM polyethylene glycol
(PEG) vs. vehicle by differential centrifugation. Mitochondrial function was assessed by adenosine
triphosphate synthesis, oxygen consumption, and calcium retention capacity. Mitochondrial function
decreased significantly after ischemia and showed mild improvement with reperfusion. P188 did
not improve mitochondrial function in the ex-vivo heart, and neither further P188 nor PEG induced
direct mitochondrial protection after IR injury in this model.
The present study focused on a new formulation approach to improving the solubility of drugs with poor aqueous solubility. A hot melt extrusion (HME) process was applied to prepare drug-loaded solid self-nanoemulsifying drug delivery systems (S-SNEDDS) by co-extrusion of liquid SNEDDS (L-SNEDDS) and different polymeric carriers. Experiments were performed with L-SNEDDS formulations containing celecoxib, efavirenz or fenofibrate as model drugs. A major objective was to identify a polymeric carrier and process parameters that would enable the preparation of stable S-SNEDDS without impairing the release behavior and storage stability of the L-SNEDDS used and, if possible, even improving them further. In addition to commercially available (co)polymers already used in the field of HME, a particular focus was on the evaluation of different variants of a recently developed aminomethacrylate-based copolymer (ModE) that differed in Mw. Immediately after preparation, the L-SNEDDS and S-SNEDDS formulations were tested for amorphicity by differential scanning calorimetry. Furthermore, solubility and dissolution tests were performed. In addition, the storage stability was investigated at 30 °C/65% RH over a period of three and six months, respectively. In all cases, amorphous formulations were obtained and, especially for the model drug celecoxib, S-SNEDDS were developed that maintained the rapid and complete drug release of the underlying L-SNEDDS even over an extended storage period. Overall, the data obtained in this study suggest that the presented S-SNEDDS approach is very promising, provided that drug-loaded L-SNEDDS are co-processed with a suitable polymeric carrier. In the case of celecoxib, the E-173 variant of the novel ModE copolymer proved to be a novel polymeric carrier with great potential for application in S-SNEDDS. The presented approach will, therefore, be pursued in future studies to establish S-SNEDDS as an alternative formulation to other amorphous systems.