Development and Validation of a Discriminatory Dissolution Model for an Immediately Release Dosage Form by DOE and Statistical Approaches.

A discriminatory dissolution model was built through DOE with multivariate analysis of variance (MANOVA) and multiple linear regression (MLR) modeling to assess dissolution operational space for a highly water soluble immediate-release solid dosage drug product. The dissolution was utilized in the following five aspects: (1) understand the impact of individual variables and their interactions on dissolution performance through effect analysis; (2) explain the lack of discriminatory power of the initial dissolution condition used in early phase development by prediction profiler; (3) predict discriminatory dissolution operational space to differentiate photo degraded drug products from control with contour profiler analysis; (4) validate by the external experimental data acquired with the initial nondiscriminatory dissolution condition and the predicted discriminatory dissolution condition, followed by model independent statistical analysis (e.g., f2); and (5) establish correlation of the discriminatory dissolution with disintegration. The selected discriminatory dissolution method was validated by demonstrating accuracy, precision and linearity, specificity, repeatability, intermediate precision, stability, filter verification, and robustness.

Buccal mucosal irritation studies of sublingual apomorphine film (APL-130277) in Syrian golden hamsters.

AIM: Determine the potential for cheek pouch buccal mucosa irritation in hamsters following administration of apomorphine hydrochloride film (APL-130277). METHODS: Three studies were conducted with Syrian golden hamsters. (First study, four hamsters received APL-130277 three times a day [TID] for 7 days. Second study, four hamsters received APL-130277 once a day [QD] for days 1-3, twice a day [BID] for days 4-7 and TID for days 8-21. Third study, 32 hamsters received either a placebo strip or APL-130277-dosed TID for 28 days). For all the studies, the macroscopic appearance of the buccal cavities was evaluated throughout the study. In the third study, all animals were necropsied on day 29, and macroscopic and histopathological examinations were performed. RESULTS: In the first and second studies, the buccal mucosa of the cheek pouch did not show any signs of irritation. In the third study, administration of APL-130277-dosed TID for 28 consecutive days did not result in observable local irritation of the buccal mucosa. CONCLUSION: In all the studies, APL-130277 produced no irritation of the cheek pouch buccal mucosa.

Sublingual apomorphine (APL-130277) for the acute conversion of OFF to ON in Parkinson's disease.

INTRODUCTION: OFF episodes negatively impact quality of life in patients with Parkinson's disease (PD). There remains a need for an acute, effective, noninvasive treatment. BACKGROUND: APL-130277 is a sublingually administered apomorphine oral strip. METHODS: The authors conducted a phase 2, open-label, proof-of-concept study. Patients presented to clinic in the morning in the practically defined OFF state and were dosed with APL-130277 10 mg. Assessments of OFF or ON state and MDS-UPDRS part III were conducted predose and at 15, 30, 45, 60, and 90 minutes. If a full ON was not achieved within 3 hours, the dose was increased in 5 mg increments until a full ON was achieved or to a maximum dose of 30 mg. Patients could be dosed up to two times a day over 3 days. Patients were pretreated with trimethobenzamide for 3 days, which was continued during the study. RESULTS: Of 19 patients, 15 (78.9%) achieved a full ON response. All 15 achieved a full ON response within 30 minutes and 6 of the 15 patients (40.0%) achieved a full ON response within 15 minutes. The mean (SD) duration of ON was 50 (19.4) minutes. Of the 15 patients, 9 (60.0%) remained fully ON for ≥90 minutes. There were no discontinuations as a result of an adverse event. The most common adverse events were dizziness (36.8%), somnolence (31.6%), and nausea (21.1%). CONCLUSION: This was the first study of a new sublingual apomorphine formulation in PD patients. In this open-label study, APL-130277 appeared to provide a convenient, rapid, and reliable method for treating OFF episodes. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Effect of fluoride/essential oils-containing mouthrinse on the microhardness of demineralized bovine enamel.

PURPOSE: To assess the ability of a fluoride mouthrinse containing a fixed combination of essential oils (thymol, menthol, eucalyptol, and methyl salicylate) to inhibit demineralization as compared with that of a clinically established NaF rinse. METHODS: Inhibition in sound bovine enamel to demineralization was assessed utilizing a cyclic T/R/D (treatment/remineralization/demineralization) in vitro model where Knoop microhardness was monitored over 6, 12, and 18 T/R/D cycles. RESULTS: Both fluoride-containing mouthrinses resulted in statistically significant increase in microhardness when compared to the non-fluoride control mouthrinse, possibly demonstrating and validating the in vitro model's ability to parallel the clinically established benefit of a 0.022% NaF rinse to inhibit demineralization. In addition, the test formulation was shown to be "at least as good as" the NaF positive control in increasing enamel microhardness following each of the 6, 12, and 18 T/R/D cycles.