Effects of Formulation Factors and Pharmaceutical Quality on Oral Drug Absorption

Abstract

The overall objective of this dissertation was to study the effects of formulation factors and pharmaceutical quality on oral drug absorption. Aim 1 investigated the impact of large amounts of 14 commonly used excipients on oral absorption of Biopharmaceutics Classification System (BCS) class 3 drugs. FDA and EMA allow biowaivers for BCS class 3 drugs but indicate that test product should be qualitatively the same and quantitatively very similar in composition to the reference product. Capsules containing combination of three excipients in quantities larger than those present in immediate-release (IR) solid oral dosage forms were investigated. Results indicated that 12 out of 14 common excipients were found 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. Aim 2 addressed the question concerning therapeutic equivalence of brand and generic lamotrigine tablets. A potential contributor to such concerns is pharmaceutical quality. Biopharmaceutics risk of brand and generic lamotrigine 100 mg tablets from several manufacturers was assessed. Results indicated that lamotrigine's favorable biopharmaceutics from a drug substance perspective and favorable quality characteristics from a tablet formulation perspective suggest multisource lamotrigine tablets to exhibit a low biopharmaceutic risk. Aim 3 investigated impact of in vitro dissolution volume on dissolution of IR tablets of three anti-epileptic drugs (AEDs), levetiracetam, lamotrigine, and oxcarbazepine. FDA recently issued two draft guidances that recommend 500 mL dissolution media for BCS class 1 and 3 drugs. Results indicate that reducing dissolution volume from 900 mL to 500 mL was of no apparent significance when at least 3-fold sink conditions prevailed at 500 mL. However, reducing dissolution volume from 900 mL to 500 mL slowed dissolution in the absence of 3-fold sink conditions, per f2. Aim 4 describes the case report of an epileptic patient who observed levetiracetam extended-release (ER) tablet remnants in stool from one generic source but not others. Analysis of tablet remnant indicates that no drug remained in the tablet, even though tablets are mostly composed of drug.