Polymeric Precipitation Inhibitors Promote Fenofibrate Supersaturation and Enhance Drug Absorption from a Type IV Lipid-Based Formulation

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Abstract

The ability of lipid based formulations (LBFs) to increase the solubilization, and prolong the supersaturation, of poorly water-soluble drugs (PWSDs) in the gastro-intestinal (GI) fluids has generated significant interest in the last decade. One mechanism to enhance the utility of LBFs is to prolong supersaturation via the addition of polymers to the formulation that inhibit drug precipitation (polymeric precipitation inhibitors or PPIs). In this work, we have evaluated the performance of a range of PPIs and have identified PPIs that are sufficiently soluble in LBF to allow the construction of single phase formulations. An in vitro model was first employed to assess drug (fenofibrate) solubilization and supersaturation on LBF dispersion and digestion. An in vitro-in situ model was subsequently employed to simultaneously evaluate the impact of PPI enhanced drug supersaturation on drug absorption in rats. The stabilizing effect of the polymers was polymer specific, and most pronounced at higher drug loads. Polymers that were soluble in LBF allowed simple processing as single phase formulations, while formulations containing more hydrophilic polymers required polymer suspension in the formulation. The lipid soluble polymers Eudragit (EU) RL100 and poly-(propylene glycol) bis(2-aminopropyl ether) (PPGAE) and the water soluble polymer hydroxypropylmethyl cellulose (HPMC) E4M were identified as the most effective PPIs in delaying fenofibrate precipitation in vitro. An in vitro model of lipid digestion was subsequently coupled directly to an in situ single pass intestinal perfusion assay to evaluate the influence of PPIs on fenofibrate absorption from LBFs in vivo. This coupled model allowed for real-time evaluation of the impact of supersaturation stabilization on absorptive drug flux, and provided better discrimination between the different PPIs and formulations. In the presence of the in situ absorption sink, increased fenofibrate supersaturation resulted in increased drug exposure and a good correlation was found between the degree of in vitro supersaturation, and in vivo drug exposure. Improved in vitro-in vivo correlation was apparent when comparing the same formulation under different supersaturation conditions. These observations directly exemplify the potential utility of PPIs in promoting drug absorption from LBF, via stabilization of supersaturation, and further confirm that relatively brief periods of supersaturation may be sufficient to promote drug absorption, at least for highly permeable drugs such as fenofibrate.

Original languageEnglish
Pages (from-to)2355-2371
Number of pages17
JournalMolecular Pharmaceutics
Volume15
Issue number6
DOIs
Publication statusPublished - 2018

Keywords

  • fenofibrate
  • lipid-based formulation
  • drug flux
  • in vivo absorption
  • in vitro digestion
  • in situ perfusion
  • polymer precipitation inhibitors
  • supersaturation

Cite this

@article{bdaca79304934811855197a4e08a3a47,
title = "Polymeric Precipitation Inhibitors Promote Fenofibrate Supersaturation and Enhance Drug Absorption from a Type IV Lipid-Based Formulation",
abstract = "The ability of lipid based formulations (LBFs) to increase the solubilization, and prolong the supersaturation, of poorly water-soluble drugs (PWSDs) in the gastro-intestinal (GI) fluids has generated significant interest in the last decade. One mechanism to enhance the utility of LBFs is to prolong supersaturation via the addition of polymers to the formulation that inhibit drug precipitation (polymeric precipitation inhibitors or PPIs). In this work, we have evaluated the performance of a range of PPIs and have identified PPIs that are sufficiently soluble in LBF to allow the construction of single phase formulations. An in vitro model was first employed to assess drug (fenofibrate) solubilization and supersaturation on LBF dispersion and digestion. An in vitro-in situ model was subsequently employed to simultaneously evaluate the impact of PPI enhanced drug supersaturation on drug absorption in rats. The stabilizing effect of the polymers was polymer specific, and most pronounced at higher drug loads. Polymers that were soluble in LBF allowed simple processing as single phase formulations, while formulations containing more hydrophilic polymers required polymer suspension in the formulation. The lipid soluble polymers Eudragit (EU) RL100 and poly-(propylene glycol) bis(2-aminopropyl ether) (PPGAE) and the water soluble polymer hydroxypropylmethyl cellulose (HPMC) E4M were identified as the most effective PPIs in delaying fenofibrate precipitation in vitro. An in vitro model of lipid digestion was subsequently coupled directly to an in situ single pass intestinal perfusion assay to evaluate the influence of PPIs on fenofibrate absorption from LBFs in vivo. This coupled model allowed for real-time evaluation of the impact of supersaturation stabilization on absorptive drug flux, and provided better discrimination between the different PPIs and formulations. In the presence of the in situ absorption sink, increased fenofibrate supersaturation resulted in increased drug exposure and a good correlation was found between the degree of in vitro supersaturation, and in vivo drug exposure. Improved in vitro-in vivo correlation was apparent when comparing the same formulation under different supersaturation conditions. These observations directly exemplify the potential utility of PPIs in promoting drug absorption from LBF, via stabilization of supersaturation, and further confirm that relatively brief periods of supersaturation may be sufficient to promote drug absorption, at least for highly permeable drugs such as fenofibrate.",
keywords = "fenofibrate, lipid-based formulation, drug flux, in vivo absorption, in vitro digestion, in situ perfusion, polymer precipitation inhibitors, supersaturation",
author = "Suys, {Estelle J.A.} and Chalmers, {David K.} and Pouton, {Colin W.} and Porter, {Christopher J.H.}",
year = "2018",
doi = "10.1021/acs.molpharmaceut.8b00206",
language = "English",
volume = "15",
pages = "2355--2371",
journal = "Molecular Pharmaceutics",
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TY - JOUR

T1 - Polymeric Precipitation Inhibitors Promote Fenofibrate Supersaturation and Enhance Drug Absorption from a Type IV Lipid-Based Formulation

AU - Suys, Estelle J.A.

AU - Chalmers, David K.

AU - Pouton, Colin W.

AU - Porter, Christopher J.H.

PY - 2018

Y1 - 2018

N2 - The ability of lipid based formulations (LBFs) to increase the solubilization, and prolong the supersaturation, of poorly water-soluble drugs (PWSDs) in the gastro-intestinal (GI) fluids has generated significant interest in the last decade. One mechanism to enhance the utility of LBFs is to prolong supersaturation via the addition of polymers to the formulation that inhibit drug precipitation (polymeric precipitation inhibitors or PPIs). In this work, we have evaluated the performance of a range of PPIs and have identified PPIs that are sufficiently soluble in LBF to allow the construction of single phase formulations. An in vitro model was first employed to assess drug (fenofibrate) solubilization and supersaturation on LBF dispersion and digestion. An in vitro-in situ model was subsequently employed to simultaneously evaluate the impact of PPI enhanced drug supersaturation on drug absorption in rats. The stabilizing effect of the polymers was polymer specific, and most pronounced at higher drug loads. Polymers that were soluble in LBF allowed simple processing as single phase formulations, while formulations containing more hydrophilic polymers required polymer suspension in the formulation. The lipid soluble polymers Eudragit (EU) RL100 and poly-(propylene glycol) bis(2-aminopropyl ether) (PPGAE) and the water soluble polymer hydroxypropylmethyl cellulose (HPMC) E4M were identified as the most effective PPIs in delaying fenofibrate precipitation in vitro. An in vitro model of lipid digestion was subsequently coupled directly to an in situ single pass intestinal perfusion assay to evaluate the influence of PPIs on fenofibrate absorption from LBFs in vivo. This coupled model allowed for real-time evaluation of the impact of supersaturation stabilization on absorptive drug flux, and provided better discrimination between the different PPIs and formulations. In the presence of the in situ absorption sink, increased fenofibrate supersaturation resulted in increased drug exposure and a good correlation was found between the degree of in vitro supersaturation, and in vivo drug exposure. Improved in vitro-in vivo correlation was apparent when comparing the same formulation under different supersaturation conditions. These observations directly exemplify the potential utility of PPIs in promoting drug absorption from LBF, via stabilization of supersaturation, and further confirm that relatively brief periods of supersaturation may be sufficient to promote drug absorption, at least for highly permeable drugs such as fenofibrate.

AB - The ability of lipid based formulations (LBFs) to increase the solubilization, and prolong the supersaturation, of poorly water-soluble drugs (PWSDs) in the gastro-intestinal (GI) fluids has generated significant interest in the last decade. One mechanism to enhance the utility of LBFs is to prolong supersaturation via the addition of polymers to the formulation that inhibit drug precipitation (polymeric precipitation inhibitors or PPIs). In this work, we have evaluated the performance of a range of PPIs and have identified PPIs that are sufficiently soluble in LBF to allow the construction of single phase formulations. An in vitro model was first employed to assess drug (fenofibrate) solubilization and supersaturation on LBF dispersion and digestion. An in vitro-in situ model was subsequently employed to simultaneously evaluate the impact of PPI enhanced drug supersaturation on drug absorption in rats. The stabilizing effect of the polymers was polymer specific, and most pronounced at higher drug loads. Polymers that were soluble in LBF allowed simple processing as single phase formulations, while formulations containing more hydrophilic polymers required polymer suspension in the formulation. The lipid soluble polymers Eudragit (EU) RL100 and poly-(propylene glycol) bis(2-aminopropyl ether) (PPGAE) and the water soluble polymer hydroxypropylmethyl cellulose (HPMC) E4M were identified as the most effective PPIs in delaying fenofibrate precipitation in vitro. An in vitro model of lipid digestion was subsequently coupled directly to an in situ single pass intestinal perfusion assay to evaluate the influence of PPIs on fenofibrate absorption from LBFs in vivo. This coupled model allowed for real-time evaluation of the impact of supersaturation stabilization on absorptive drug flux, and provided better discrimination between the different PPIs and formulations. In the presence of the in situ absorption sink, increased fenofibrate supersaturation resulted in increased drug exposure and a good correlation was found between the degree of in vitro supersaturation, and in vivo drug exposure. Improved in vitro-in vivo correlation was apparent when comparing the same formulation under different supersaturation conditions. These observations directly exemplify the potential utility of PPIs in promoting drug absorption from LBF, via stabilization of supersaturation, and further confirm that relatively brief periods of supersaturation may be sufficient to promote drug absorption, at least for highly permeable drugs such as fenofibrate.

KW - fenofibrate

KW - lipid-based formulation

KW - drug flux

KW - in vivo absorption

KW - in vitro digestion

KW - in situ perfusion

KW - polymer precipitation inhibitors

KW - supersaturation

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U2 - 10.1021/acs.molpharmaceut.8b00206

DO - 10.1021/acs.molpharmaceut.8b00206

M3 - Article

VL - 15

SP - 2355

EP - 2371

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 6

ER -