Effect of Common Excipients on the Oral Drug Absorption of Biopharmaceutics Classification System Class 3 Drugs Cimetidine and Acyclovir

Abstract

The objective was to assess the impact of larger than conventional amounts of 14 commonly used excipients on Biopharmaceutics Classification System (BCS) class 3 drug absorption in humans. Cimetidine and acyclovir were used as model class 3 drugs across three separate four-way crossover bioequivalence (BE) studies (n = 24 each) in healthy human volunteers, denoted as study 1A, 1B, and 2. In study 1A and 1B, three capsule formulations of each drug were manufactured, collectively involving 14 common excipients. Capsule formulations that incorporated hydroxypropyl methylcellulose (HPMC) or magnesium stearate exhibited lower absorption. The cimetidine commercial solution contained sorbitol and also resulted in lower absorption. Hence, in study 2, two capsule formulations with lower amounts of HPMC and magnesium stearate, the sorbitol-containing commercial solution, and a sorbitol-free solution were assessed for BE. Overall, 12 common excipients were found in large amounts to not impact BCS class 3 drug absorption in humans, such that these excipients need not be qualitatively the same nor quantitatively very similar to reference, but rather simply be not more than the quantities studied here. Meanwhile, for each HPMC and microcrystalline cellulose, BCS class 3 biowaivers require these two excipients to be qualitatively the same and quantitatively very similar to the reference.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Amoxicillin Trihydrate

“…By contrast, in a human pharmacokinetic study by Vaithianathan et al, 50 mg of SLS did not increase permeability of either cimetidine or acyclovir. 85 According to the excipient details given in Table 4, the typical amount of SLS present in amoxicillin products are in the range of 0.65-96 mg, giving a concentration range of 0.0026-0.384 mg/mL of SLS when dissolved in 250 mL water. This upper concentration in this range could potentially affect permeability.…”

“…From stability data generated by Tsuji et al, 30 the authors concluded that after a 30-min dissolution test, the pH of the sample would have to be adjusted immediately to avoid excessive degradation. 85 The study by Reddy et al was conducted on 14 different 500 mg amoxicillin capsule products available in South Africa and India. 97 Two different reference products were used because the innovator product was not available in either market.…”

Biopharmaceutical Understanding of Excipient Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties. Case Study: Superdisintegrants

“…Introduction of the Quality by Design (QbD) initiative in pharmaceutical development requires the scientific understanding of the components and processes affecting final product qualities (1). The critical role of excipients in product performance and oral bioavailability is highlighted as presence of excipients in oral formulations may affect the biopharmaceutical profile of drugs with potential implications on drug absorption (2,3). Excipient variability or variation and the use of different excipients with the same intended functionality may further complicate the impact of excipients on oral drug bioavailability (4).…”

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Ondansetron

“…105 Sodium lauryl sulfate (at an amount of 25 mg per dosage unit) has been shown not to impact the absorption of the BCS class 3 drug cimetidine. 106 From the composition listings, it is likely that these surfactants are included as composition of the film coat in ondansetron tablets. As the film coat usually constitutes~3%-5% of total tablet weight, it can be reasonably assumed that the small quantities involved would not alter the intestinal absorption characteristics of ondansetron.…”