A Bioequivalence Study of Empagliflozin/Metformin Fixed-Dose Combination in Healthy Subjects under Fasting Conditions

Background: This study evaluated the bioequivalence of empagliflozin 12.5 mg/metformin 1000 mg tablets compared to Synjardy® (Empagliflozin 12.5 mg/metformin 1000 mg) tablets in healthy male subjects under fasting conditions. Methods: This was a phase I, randomized, single-dose, two-period, two-sequence, crossover study to evaluate the bioequivalence (BE) profiles of two fixed-dose combinations (FDCs) of empagliflozin/metformin. Cmax, AUC0-t and AUC0-∞ from test and reference formulations were evaluated to access BE. The plasma concentrations were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) method. Of the 24 subjects enrolled, 23 completed both periods of the study. The two formulations test and reference were considered bioequivalent if 90% confidence interval (CI) fell within 80.00% - 125.00% for Cmax, AUC0-t and AUC0-∞. Tolerability and safety were assessed throughout the study. Results: The pharmacokinetic (PK) parameters were similar between the test product (T) and reference product (R) Synjardy®. The 90% CI of the test/reference ratios of log-transformed PK parameters point estimates was Cmax: 89.87% (85.68% - 94.27%), AUC0-t: 87.91% (83.65% - 92.39%) and AUC0-∞: 87.16% (82.80% - 91.75%) to empagliflozin and Cmax: 92.19% (87.95% - 96.65%), AUC0-t: 91.38% (84.42% - 98.91%) and AUC0-∞: 93.78% (83.82% - 104.93%) to metformin respectively (90% CI for all PK parameters fell within 80.00% - 125.00%). Conclusion: Our results demonstrated BE between the test and reference formulations of oral tablets of empagliflozin 12.5 mg/metformin 1000 mg (FDC) in healthy male subjects under fasting conditions.

Benefits of Fixed Dose Combination of Ramipril/Amlodipine in Hypertensive Diabetic Patients： A Subgroup Analysis of RAMONA Trial

Background： Combination of angiotensin-converting enzyme inhibitors and calcium channel blockers has been successfully used in the ant±hypertensive therapy for many years. Fixed dose combinations of ramipril/amlodipine have a benefit effect for patients to achieve target blood pressure （BP）. This study aimed to assess the efficacy and safety of fixed dose combinations oframipril and amlodipine （Egiramlon） in hypertensive diabetic patients. Methods： Hypertensive diabetic patients who were enrolled into the RAMONA trial were included in this open, prospective, Phase Ⅳ observational clinical study. Patients had mild-to-moderate hypertension and failed to reach target BP levels through their previous therapy. During the four months of observation, patients took part in three visits （1 st day - visit 1, 1 st month = visit 2, and 4th month = visit 3） where they received a fixed dose combination of 5/5, 5/10, 10/5, or 10/10 nag ramipril/amlodipine, respectively, with the possibly required dose titrations, based on the decision of their attending physician. Target BP for diabetic patients was 〈 140/85 mmHg. BP levels were measured in all visits, by taking two readings at 2-min interval. Laboratory tests including full blood count, renal function test, electrolytes, blood glucose, serum cholesterol, uric acid, triglycerides, liver function test, creatinine kinase, and midstream urinalysis were performed at visit 1 and visit 3. Results： The 6423 patients completed the study. Among these patients, 1276 （19.9%） patients suffered from type 2 diabetes mellitus. The mean age of these diabetic patients was 64.2 ±10.0 years; 707 （55.4%） patients were males. Target BP was achieved by 891 （69.8%） of diabetic patients at visit 3 （primary endpoint）. BP decreased from 157.5/91.3 ±9.6/7.6 mmHg （visit 1） to 130.9/79.6 ± 7.4/5.8 mmHg （visit 3）. As for the secondary endpoint of the study, total cholesterol decreased from 5.50 ±1.13 mmol/L （visit 1 ） to 5.20 ±0.95 mmol/L （P = 0.000）, low-density lipoprotein cholesterol decreased from 3.20 ±0.93 mmol/L to 3.00 ±0.77 mmol/L （P = 0.000）, triglyceride decreased from 2.20 ±1.14 mmol/L to 2.00 ±1.97 mmol/L （P = 0.000）, while high-density lipoprotein cholesterol increased from 1.30 ±0.42 to 1.35 ±0.30 mmol/L （P = 0.001） until the end of the 4th month （visit 3）. Fasting blood glucose of the hypertensive diabetic patients decreased from 7.20 ± 1,88 mmol/L to 6.70 ± 1.38 mmol/L （P = 0.000）, while HbAlc decreased from 7.90 ± 1.78% to 7.60 ± 1.83% （P = 0.000）. Various fixed dose combinations of ramipril/amlodipine were well tolerated and no adverse event related to the use of the medicine has appeared. Conclusions： The fixed dose combination of ramipril/amlodipine was effective in hypertensive diabetic patients who failed to reach target BP previously.

Portable and automated analyzer for rapid and high precision in vitro dissolution of drugs

We developed a novel portable and automated dissolution test analyzer for rapid and high precision in vitro dissolution testing of drugs.The analyzer consists of a flow-through-cell drug dissolution system,an automated sequential sampling system,a high-speed capillary electrophoresis(HSCE)system,and a data acquisition system.Combining the high-temporal resolution flow-gating sampling approach with HSCE,which has outstanding advantages of efficient separation and resolution,the analyzer can achieve rapid analysis and exhibits the ability in miniaturization for on-site assessment of different active pharmaceutical ingredients.To integrate the flow-through-cell dissolution system with HSCE,a specially designed flow-gating-injection(FGI)interface was employed.The performance of the analyzer was investigated by analyzing the dissolution of immediate-release drugs including single dose(amoxicillin dispersible tablets)and fixed dose combination(amoxicillin and clavulanate potassium)drug tablets with the high-temporal resolutions of 12 s and 20 s,respectively.The dissolution profiles of different active pharmaceutical ingredients could be simultaneously and automatically monitored with high repeatability and accuracy.The analyzer was successfully utilized for the pharmaceutical quality control and bio-relevant dissolution testing,as well as in vivo-in vitro correlation analysis.Our portable analyzer is miniaturized,convenient and of low-cost,and will provide a valuable tool for dissolution testing in pharmaceutical research and development.