Development and Validation of a Stability-Indicating Method for Perillyl Alcohol Incorporated in Poly(lactide-co-glycolide) Nanoparticles and Stress Degradation Studies

<div><p>Perillyl alcohol has been studied in the treatment of cancer disease. However, its high toxicity is a drawback, which can be overcome by its incorporation in nanostructured systems. The aim of this work was to develop and validate a chromatographic method for determination of perillyl alcohol encapsulation efficiency in a polymeric nanoparticles formulation and evaluation of the presence of related degradation products. Perillyl alcohol was subjected to forced conditions of hydrolysis (acidic, alkaline and neutral), oxidation, photolysis and thermal stress, as suggested in the International Conference of Harmonization (ICH) guidelines. The drug showed significant degradation under acidic conditions. The degradation products could be adequately separated on an XBridge C18 column (100 × 2.1 mm, 3.5 µm) using isocratic elution (350 µL min−1) of water/acetonitrile (65 : 35, v/v) at 210 nm. Data from validation studies demonstrated that the method is selective, linear (coefficient of determination (R2) > 0.999) over the range of 20.0-80.0 µg mL−1, precise (relative standard deviation (RSD) < 2.0%), accurate (98.07 to 101.99%) and robust for minor changes. The method was successfully applied to determine the encapsulation efficiency of perillyl alcohol in polymeric nanoparticles, both for product development and for quality control purposes. After nanoparticles production, the presence of degradation products was not observed indicating that the single-emulsion solvent-evaporation technique used does not favor chemical degradation of the drug.</p></div

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P &lt; 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)