Development of a furosemide-containing expandable system for gastric retention.

More than 50 years ago, the first gastroretentive dosage forms came up. Since then, no practical and at the same time reliable gastroretentive system is available on market. A major obstacle in the development of novel gastroretentive systems is the lack of proper predictive test methods. In the present work, we aimed at developing and fully characterizing an expandable gastroretentive system containing furosemide as model drug. On the one hand, we used well-established in vitro tests for drug dissolution and gastroretentive properties (paddle apparatus, swelling characteristics). On the other hand, we used two novel models (dissolution stress test device, mechanical antrum model) to assess these properties under biorelevant conditions. Moreover, we performed an in vivo study under fed and fasted conditions that combined blood sampling and a high-resolution imaging technique (magnetic marker monitoring) to determine gastrointestinal location with the assessment of a pharmacodynamic endpoint (urinary sodium excretion). In vitro dissolution tests confirmed prolonged drug release over more than 8 h independent from pH and with slight pressure sensitivity. Swelling studies indicated good swelling behavior within 4 h along with medium gastroretentive properties as determined with the mechanical antrum model. In vivo imaging showed prolonged gastric residence time after fed compared to fasted administration (481 min vs 38 min). Comparison of geometric means of AUCo-tlast of the model drug confirmed this observation with 10 times higher value after fed administration. Urinary excretion of sodium well reflected the increased sodium-reuptake inhibition due to higher furosemide exposure under fed conditions. However, the poor performance after fasted intake of the system is in line with data from several other gastroretentive formulations. The present study highlighted the value of novel test methods during the development of gastroretentive formulations. Yet, a system with reproducible gastroretentive properties especially under fasted conditions has to be designed.

Pharmacokinetic evaluation of a transdermal anastrozole-in-adhesive formulation.

BACKGROUND AND OBJECTIVE: Anastrozole is a well-established active pharmaceutical ingredient (API) used for the treatment of hormone-sensitive breast cancer (BC) in postmenopausal women. However, treatment with the only available oral formulation is often associated with concentration-dependent serious side effects such as hot flashes, fatigue, muscle and joint pain, nausea, diarrhea, headache, and others. In contrast, a sustained-release system for the local application of anastrozole should minimize these serious adverse drug reactions. METHODS: Anastrozole-in-adhesive transdermal drug delivery systems (TDDS) were developed offering efficient loading, avoidance of inhomogeneity or crystallization of the drug, the desired controlled release kinetics, storage stability, easy handling, mechanical stability, and sufficient stickiness on the skin. In vitro continuous anastrozole release profiles were studied in Franz diffusion cells. In vivo, consecutive drug plasma kinetics from the final anastrozole transdermal system was tested in beagle dogs. For drug analysis, a specific validated liquid chromatography- mass spectrometry method using fragment ion detection was developed and validated. RESULTS: After efficient drug loading, a linear and sustained 65% drug release from the TDDS over 48 h was obtained. In vivo data showed a favorable anastrozole plasma concentration-time course, avoiding side effect-associated peak concentrations as obtained after oral administration but matching therapeutic plasma levels up to 72 h. CONCLUSION: These results provide the basis for establishing the transdermal application of anastrozole with improved pharmacokinetics and drug safety as novel therapeutic approach and promising option to treat human BC by decreasing the high burden of unwanted side effects.