Potential Excipient Effect on Bioavailability

The Biopharmaceutics Classification System (BCS) (Amidon et al., 1995) allows waivers of in vivo bioequivalence for rapidly dissolving immediate-release (IR) formulations of drugs with high solubility and high permeability. One potential issue in possibly extending BCS biowaivers to low-permeability drugs is the potential for excipients to modulate the intestinal permeability of the drug. Rege et al. (2001) investigated the effects of common excipients on Caco-2 transport of such low-permeability drugs. The effects of nine individual excipients (lactose monohydrate, hydroxypropyl methyl cellulose (HPMC), sodium lauryl sulfate (SLS), EDTA, Tween 80, docusate sodium (dioctyl sodium sulfosuccinate), propylene glycol, poly(ethylene glycol 400), and anhydrous cherry flavor) on the Caco-2 permeability were investigated using seven low-permeability compounds that differ in their physical properties. With the exception of SLS no excipients affected Caco-2 cell monolayer integrity. SLS moderately increased the permeability of almost all the drugs. Tween 80 significantly increased the apical-to-basolateral directed permeability of furosemide, cimetidine, and hydrochloroth-iazide, presumably by inhibiting their active efflux, without affecting mannitol permeability. Additionally, docusate sodium moderately increased cimetidine permeability. Other excipients did not have a significant effect on the permeability of these drugs.

In another study, Rege et al. (2002) investigated the transporter inhibition activity of three nonionic surfactant (Tween 80, Chromophor EL, and vitamin E

TPGS) on P-glycoprotein, the human intestinal peptide transporter, and the mono-carboxylic acid transporter in Caco-2 monolayers. Additionally they evaluated the role of membrane fluidity of protein kinase C in surfactant-induced transporter inhibition. All three surfactants inhibited P-glycoprotein (P-gp). Tween 80 and Cremophor EL increased apical-to-basolateral permeability and decreased basolateral-to-apical permeability of the P-gp substrate rhodamine 123. The effect of vitamin E TPGS was equally large, but essentially only reduced the basolateral-to-apical permeability on rhodamine 123. These P-gp inhibition effects would appear to be related to these excipients' modulation of membrane fluidity, where Tween 80 and Cremophor EL fluidized cell lipid bilayers, while vitamin E TPGS rigidized the bilayers. However, among the three surfactants, only Tween 80 inhibited the peptide transporter, as measured by glycyl sarcosine permeability. A common functional feature of these three surfactants was their ability to modulate fluidity, although the results indicated that even strong membrane fluidity modulation alone was not sufficient to reduce transporter activity. Protein kinase C inhibitor failed to affect rhodamine 123 and glycyl sarcosine permeability, suggesting that protein kinase C inhibition was not the mechanism of transporter inhibition. These results suggest that surfactants, which are absorption enhancers, can inhibit multiple transporters, but that changes in membrane fluidity may not be the generalized mechanism to reduce transporter activity.

In a summary of a workshop report on BCS - Implementation Challenges and Extension Opportunities (Polli et al., 2004) it is stated:

The BCS guidance indicates that excipients that are currently in US FDA-approved IR solid oral dosage forms will generally not affect the rate and extent of absorption of a highly soluble and highly permeable drug substance that is formulated in a rapidly dissolving IR product. Quantities of excipients should be consistent with intended function. The guidance further indicates that when new excipients or atypically large amounts of common excipients are used, there needs to be a documentation of the absence of an excipient effect. The FDA has recently made available to the public the Inactive Ingredients Database, which lists inactive ingredients in FDA-approved drug products. The Inactive Ingredients Database can be accessed at http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm. This list is searchable by ingredient name. Each database cites for each route/dosage form containing the inactive ingredient.

Given the consensus to extend potential biowaivers to include drugs whose fraction dose absorbed is less than 85%, with perhaps some lower limit (e.g., 40%), excipient effects were discussed as a potential concern. There was no consensus on this potential concern. There was general acknowledgement that most products only employ common excipients in typical quantities. There was some level of support for the expectation that common excipients in typical quantities do not modulate permeability or gastrointestinal transit of low permeability drugs. This viewpoint was countered by the growing understanding of the role of transporters in drug permeation and disposition, including transporter-mediated drug interactions. There was consensus that dose linearity extending sufficiently above the highest dose strength is a basis to conclude that excipients in such studies do not represent a significant risk for the drug.

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  • Sophia Scholz
    What is the impact of different excipient on drug absorption?
    5 months ago

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