• Effects of Formulation Factors and Pharmaceutical Quality on Oral Drug Absorption

      Vaithianathan, Soundarya; Polli, James E. (2016)
      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.
    • Understanding Curing of Ethylcellulose Film Coating and In Vitro In Vivo Performance of Oral Dosage Forms with Scientific Regulatory Implications on Biowaiver

      Lin, Zhongqiang; Hoag, Stephen W. (2015)
      The aim of this study focus on the extended release formulation on two aspects: the quantification and mechanistic research on pharmaceutical coating curing with a specific focus on how the moisture affect the curing; and in vivo and in vitro release of matrix ER tablets with implications on regulatory biowaiver using marketed products as practical examples. In all cases, it was found that the relative humidity of the environments were more important to reach higher extent of coalescence for EC pseudolatex films and temperature along cannot achieve sufficient polymer coalescence. A quantitative relationship was established that could be used to quantify the extent of coalescence in EC curing to a reasonable accuracy. The NIR spectral data with the tool of chemometrics can enable accurate prediction of physicomechanical properties accurately. Dissolution models demonstrated the release mechanism of EC coated ER multiparticulate was predominately determined by the breaking down of the coating rather than diffusion of drugs through the EC coating layer. Fluoresence anisotropy was found to be useful in the solid system for the first time. By measuring fluorescence anisotropy in the fluorescence labeled EC films can allow real time monitoring of the curing process. To justify biowaiver, it is essential to understand effects of API properties, formulation design, product characteristics, test method and its in vivo relevance. It is therefore concluded that the biowaiver criteria specified in the regulatory guidance should apply only to multiparticulate beaded dosage forms where strengths only differ in the number of beads containing the active moiety.