Development of new Amide Based Surfactants to improve Drug Solubility and Permeability

The oral bioavailability of a drug is mainly limited by two factors: 1) the water-solubility of the drug, which determines the extent to which the drug dissolves and how fast the drug dissolves in gastrointestinal (GI) medium; 2) the intestinal permeability of the drug, which determines rate and extent to which the drug crosses the epithelial cells to reach the systemic circulation.

One of our research areas is to develop new amide-base amphiphiles to act as a drug solubilizer and oral absorption enhancer to improve oral bioavailability of some drugs.  A group of linear tri-amide surfactant (one of the surfactants, peptoad G, shown below) were synthesized and evaluated.         

peptoadG

Peptoad G can solubilize poorly water-soluble drugs very efficiently, by enhancing the water solubility ranging from about 20 to 1100-fold for eleven drugs tested.  Molecular dynamic simulations on solubilizing paclitaxel by peptoad G showed that peptoad molecules, hydrogen-bonded to the drug, surround the drug with hydrocarbon chains that embed themselves into the interior of peptoad “clumps”. (As shown in the figure below)

peptoadclump

Currently, investigation on epithelial permeation enhancement by peptoad G is underway.  Both in-vitro and in-vivo studies will be carried out to characterize the permeability enhancing effect of this new non-ionic surfactant.

Our studies showed peptoad G is comparable to Cremophor EL regarding in-vitro toxicity.  We are expecting that peptoad G may be less toxic if given orally compared to most existing solubilizers on the market, since it is a small molecule and possesses a biodegradable amide functional group.

Publications in this area

  • Maroju R.K.; Turner D.C.; Zhang, H.“Solubilizing Effeciency and in vitro cytotoxicity of Peptoad G” J. Pharm. Sci., 2010.  99(4):2196-8
  • Stjerndahl, M.; Lundberg, D.; Zhang, H.; Menger, F. M. “NMR Studies of Aggregation and Hydration of Surfactants Containing Amide Bonds”
    J. Phys. Chem. B.; 2007; 111, 2008-2014.
  • Menger, F.M.; Zhang, H.; de Joannis, J.; Kindt, J. K.  “Solubilization of Paclitaxel (Taxol) by Peptoad Self-Assemblies” Langmuir  2007, 23, 2308 – 2310. 
  • Zhang, H.; Menger, F. M.  “Peptoads, A Group of Amphiphilic Long-Chain Triamides.”  Abstracts of Papers, 230st ACS National Meeting, Washington D.C.USA, Aug. 28-sept.1, 2006.  
  • Menger, F. M.; Zhang, H.  “Peptoads, A Group of Amphiphilic Long-Chain Triamides.”  Langmuir  2005, 21, 10428-10432.