The impact of food components on the intrinsic dissolution rate of ketoconazole

To accurately predict the in vivo performance of drugs from an in vitro dissolution test, the dissolution conditions used are supposed to be similar to those present in the gastrointestinal milieu. Post-prandial gastric fluid contains partially digested food mixtures consisting of fat, protein and carbohydrate. Despite this, the compendia dissolution medium recommended to simulate the gastric fluid is still composed of a simple solution of hydrochloric acid and sodium chloride with or without the addition of pepsin. Therefore, in this investigation, biorelevant dissolution media were developed to evaluate the impact of food constituents; milk with different fat contents, egg albumin, gelatin, casein, gluten, carbohydrates and amino acids on the intrinsic dissolution behavior of ketoconazole. Most of the food additives that were evaluated enhanced the apparent solubility of the drug but to different extents. The greatest enhancement in dissolution was observed in media containing either neutral amino acids or media based on milk mixtures. The formation of complexes between the drug and the additives most likely accounted for the solubilizing effect and in milk-containing media, the effect was attributed to the whole complex structure of milk rather than simply its fat content. These results highlight the potential effect of the type of ingested meal on drug dissolution and subsequent bioavailability

Pancreatic surgery outcomes: multicentre prospective snapshot study in 67 countries

Background: Pancreatic surgery remains associated with high morbidity rates. Although postoperative mortality appears to have improved with specialization, the outcomes reported in the literature reflect the activity of highly specialized centres. The aim of this study was to evaluate the outcomes following pancreatic surgery worldwide.Methods: This was an international, prospective, multicentre, cross-sectional snapshot study of consecutive patients undergoing pancreatic operations worldwide in a 3-month interval in 2021. The primary outcome was postoperative mortality within 90 days of surgery. Multivariable logistic regression was used to explore relationships with Human Development Index (HDI) and other parameters.Results: A total of 4223 patients from 67 countries were analysed. A complication of any severity was detected in 68.7 percent of patients (2901 of 4223). Major complication rates (Clavien-Dindo grade at least IIIa) were 24, 18, and 27 percent, and mortality rates were 10, 5, and 5 per cent in low-to-middle-, high-, and very high-HDI countries respectively. The 90-day postoperative mortality rate was 5.4 per cent (229 of 4223) overall, but was significantly higher in the low-to-middle-HDI group (adjusted OR 2.88, 95 per cent c.i. 1.80 to 4.48). The overall failure-to-rescue rate was 21 percent; however, it was 41 per cent in low-to-middle-compared with 19 per cent in very high-HDI countries.Conclusion: Excess mortality in low-to-middle-HDI countries could be attributable to failure to rescue of patients from severe complications. The authors call for a collaborative response from international and regional associations of pancreatic surgeons to address management related to death from postoperative complications to tackle the global disparities in the outcomes of pancreatic surgery (NCT04652271; ISRCTN95140761)