Effect of oseltamivir phosphate versus placebo on platelet recovery and plasma leakage in adults with dengue and thrombocytopenia; a phase 2, multicenter, double-blind, randomized trial

Background Thrombocytopenia, bleeding and plasma leakage are major complications of dengue. Activation of endogenous sialidases with desialylation of platelets and endothelial cells may underlie these complications. We aimed to assess the effects of the neuraminidase inhibitor oseltamivir on platelet recovery and plasma leakage in dengue. Methods We performed a phase 2, double-blind, multicenter, randomized trial in adult dengue patients with thrombocytopenia (<70,000/μl) and a duration of illness ≤ 6 days. Oseltamivir phosphate 75mg BID or placebo were given for a maximum of five days. Primary outcomes were the time to platelet recovery (≥ 100,000/μl) or discharge from hospital and the course of measures of plasma leakage. Results A total of 70 patients were enrolled; the primary outcome could be assessed in 64 patients (31 oseltamivir; 33 placebo). Time to platelet count ≥100,000/μl (n = 55) or discharge (n = 9) were similar in the oseltamivir and placebo group (3.0 days [95% confidence interval, 2.7 to 3.3] vs. 2.9 days [2.5 to 3.3], P = 0.055). The kinetics of platelet count and parameters of plasma leakage (gall bladder thickness, hematocrit, plasma albumin, syndecan-1) were also similar between the groups. Discussion In this trial, adjunctive therapy with oseltamivir phosphate had no effect on platelet recovery or plasma leakage parameters. Trial registration ISRCTN35227717.

OPTIMIZED FAST DISINTEGRATING TABLETS, BOOSTED OSELTAMIVIR PHOSPHATE ORALLY FAST DISINTEGRATING TABLETS

Background Around 33% of the populace (fundamentally pediatric and geriatric) has gulping hardships, bringing about helpless consistence with oral tablet drug treatment which prompts decreased in general treatment viability. For this explanation, tablets that can quickly break down or deteriorate in the oral cavity have drawn in a lot of consideration. Objective research was designed to develop and evaluate boosted orally fast disintegrating tablets (OFDT) for oro-buccal drug delivery of oseltamivir phosphate. Methods In the present study six formulations of mouth dissolving tablet of oseltamivir were prepared by direct compression method using SSG as a super disintegrating agent with lactose, talcum, mannitol, SLS and starch. The prepared tablets were then subjected to various evaluation parameters. Results every one of the outcomes was observed to be inside satisfactory reaches. The formulation F6 manufacturing utilizing SSG 50mg and SLS 10mg showed the higher medication content (98%), while the formulation F2 showed the least medication content (92%). It was seen that with the increment in SSG concentration, the medication content was additionally increased. SEM concentrate on showed request of expanding unpleasantness of tablet surface is F1<F2<F3<F4<F5<F6. The expanding unpleasantness may be answerable for higher % of medication release. Formulation F1 showed the most elevated medication discharge (97.735%), while the formulation F5 showed the least medication discharge (56.24%). Finally, it was inferred that SSG, SLS, D-mannitol, starch, lactose, and talcum powder can be effectively utilized in the formulation of Oseltamivir phosphate mouth dissolving tablets. Conclusion: From the above work it was presumed that the formulation of the Oseltamivir Phosphate was observed to be more achievable than the regular one.

Method Development and Validation for the Trace Level Quantification of Genotoxic Impurity Oseltamivir Phosphate Related Compound-a in Oseltamivir Phosphate Using LC-MS

A selective and sensitive method has been developed for the determination of ethyl-(3S,4R,5S)-4-acetamido-5-amino-2-azido-3-(pentan-3-yloxy)cyclohexanecarboxylate (OSPRC-A) by using liquid chromatography coupled with mass spectrometer with single mass analyzer (LC-MS).The method was developed by using column DEVELOSIL ODS-UG-5, (50×3.0 mm, 5.0 µm) with linearity range of 0.005% to 0.0151% which meets to quantification level of 150% range. The column oven temperature was maintained at 40ºC. The flow rate was set as 1.5 mL/min. Injection volume was 10 µL and the detection wavelength was 215 nm. The signal to noise ratio values obtained were found to be 4.79 at concentration level of 0.00015% for the limit of detection (LOD) and 13.46 at concentration level of 0.0005% for the limit of quantification (LOQ). The % recovery was found to be in between the range 80.0% to 101.32% at LOQ to 150% level. The result obtained in method precision and intermediate precision are found to be within the specification limit. The percentage RSD for the content of OSPRC-A of method precision was 4.26. The percentage RSD for the content of OSPRC-A for intermediate precision was 4.00. The sample prepared in analytical solution was found to be stable for 24 h. This method can be used for the identification of impurity, OSPRC-A in Oseltamivir phosphate drug substances in its manufacturing.

CHARACTERIZATION OF OSELTAMIVIR PHOSPHATE API AND SIMULTANEOUS QUANTIFICATION AND VALIDATION OF ITS IMPURITIES BY UPLC

Objective: The purpose of the study is to develop a high sensitive and short runtime method to quantify oseltamivir phosphate impurities (C and D) and characterization of oseltamivir phosphate API. Methods: The active pharmaceutical ingredient (API) characterization was done using spectroscopic techniques such as mass, infrared spectroscopy (IR), differential scanning calorimetry (DSC), proton nuclear magnetic resonance (H-NMR), phosphorus nuclear magnetic resonance (P-NMR), carbon-13 nuclear magnetic resonance (C13-NMR), and two-dimensional nuclear magnetic resonance (2D-NMR). The impurities (C and D) quantification was done using ACQUITY UPLC BEH C18- 100 mm × 2.1 mm, 1.7 μm column connected to ACQUITY UPLC with PDA detector. The optimized chromatographic conditions were achieved at 0.3 mL/min flow rate using gradient system with 0.1% orthophosphoric acid in water and acetonitrile as mobile phase. Both impurities are measured at λmax 210 nm at 30°C column temperature. Results: The finalized method has given good peak shape and resolution for impurity-C and impurity-D at Rt = 3.39 and 4.33 min, respectively, and the quantification method is linear and its r2 > 0.999 as a correlation coefficient. The recoveries of impurity-C and impurity-D were found in the range of 100±15% at 0.05, 0.1, and 0.15 and limit of quantitation (LOQ) % concentration levels. The other validation parameters such as specificity, system precision, sensitivity, method precision, ruggedness, robustness, and solution stability were established for this method, and the results are satisfactory as per International Council for Harmonization (ICHQ2). Conclusion: The characterization data confirm the structure of oseltamivir phosphate active pharmaceutical ingredient (API). The validated method shall be used for regular analysis as well as release analysis in quality control (QC).