Single-dose and steady-state bioequivalence of fexofenadine and pseudoephedrine combination tablets compared with individual formulations in healthy adults.

OBJECTIVE: A 24-h extended-release formulation of fexofenadine HCl 180 mg/pseudoephedrine HCl 240 mg (FEX 180 mg/PSE 240 mg) has recently been approved by the US Food and Drug Administration for symptom relief of seasonal allergic rhinitis, including nasal congestion. When considering a combination formulation, it is important to confirm that the metabolism and pharmacokinetics of the drugs remain unchanged when combined. Thus, the aim of this study was to evaluate single-dose and steady-state bioequivalence of FEX 180 mg/PSE 240 mg 24-h compared with the individual formulations taken concurrently. RESEARCH DESIGN AND METHODS: This was an open-label, randomized, two-treatment, two-period, 10-day, crossover study. In Treatment A, healthy subjects received a single, oral dose of FEX 180 mg/PSE 240 mg combination tablet on Day 1 followed by 6 days of once-daily dosing beginning on Day 4. Participants in Treatment B were concurrently administered a single oral dose of FEX 180 mg immediate-release tablet and a PSE 240 mg extended-release tablet with a similar dosing schedule. After an 8-day washout period, subjects crossed over to the alternate treatment. Plasma concentrations of FEX and PSE were determined using high-performance liquid chromatography/mass spectrometry. RESULTS: Pharmacokinetic parameters AUC0-infinity1 and Cmax1 following a single-dose (Day 1, dose 1), Cmax7, AUC0-24(7) at steady-state and Cmin7 measured at the end of the dosing interval (Day 9, dose 7) revealed bioequivalence between FEX 180 mg/PSE 240 mg combination tablet and the individual components taken concurrently. The 90% confidence intervals for the treatment ratios fell entirely within the bioequivalence range (80% to 125%). The combination tablet was well tolerated by all subjects, with a safety profile comparable to the individual components. CONCLUSIONS: These findings demonstrate that the pharmacokinetics of the new 24-h FEX 180 mg/PSE 240 mg combination formulation are bioequivalent to the concurrent administration of the individual drug components. Furthermore, both treatments were well tolerated in this population.

Investigation of various factors affecting encapsulation on the in-cap automatic capsule-filling machine.

The purpose of this study was to determine the factors that influence fill weight and weight variability of capsules produced on the In-Cap and to assess any differences in terms of capsule defects between gelatin and HPMC (Quali-V) shells. The In-Cap is an automatic tamping type capsule-filling machine and the low output of approximately 3000 capsules/hour makes it ideal for early formulation development and phase I/IIa clinical supplies manufacture. Four commonly used excipients (Avicel PH101, Avicel PH302, A-Tab, and Prosolv HD90) and a poorly flowing drug blend were encapsulated at various pin settings and powder bed heights. The average fill weight and coefficient of weight variation were determined. The percentage of defective capsules formed during encapsulation was calculated. Results of the study showed that pin setting was critical for controlling the fill weight and the weight variation. The order of pin setting with pin 1 (closer to the powder chute) set to a relatively higher position and pin 4 (before ejection) set to a lower position was found to give higher fill weights with relatively lower weight variability. The powder bed height influenced the fill weight for poorly flowing powders. The capsule machine speed did not appear to significantly influence the fill weight. The fill weight and weight variation were found to depend on the flow property of the material. A large percentage of defective capsules was obtained using HPMC shell size #00. Some of the commonly observed defects included split caps and improperly closed filled capsules. In general, appropriate selection of pin settings and bed height can reduce the weight variability seen, especially with poorly flowing high-dose formulations.