title: Discovery of synergistic permeation enhancers for oral drug delivery.
abstract: Oral drug delivery offers an attractive method of needle-free drug administration. Unfortunately, oral delivery is often hampered by the poor permeability of drugs across the intestinal epithelium. Although several single chemical permeation enhancers have been shown to alleviate permeability difficulties, this often occurs at the expense of safety. This in vitro study demonstrates the use of binary and ternary combinations of permeation enhancers to create synergistic enhancer formulations (SEFs) that offer a high level of potency while inducing very little toxicity in Caco-2 cells. Although relatively rare in the explored formulation space, SEFs were abundant enough to significantly increase the repertoire of permeation enhancers that are safe and effective in vitro. The most promising enhancers from the binary study led to easily identifiable ternary SEFs, thus increasing the efficiency of the discovery process. Some of the best performers of the study included binary combinations of hexylamine and chembetaine and ternary combinations of sodium laureth sulfate, decyltrimethyl ammonium bromide, and chembetaine, all at a total concentration of 0.1% (w/v). Furthermore, several SEFs were shown to be capable of increasing mannitol and 70 kDa dextran permeability across Caco-2 monolayers 15- and 8-fold, respectively. These results encourage further exploration of several leading formulations for in vivo applications in oral drug delivery.
authors.affiliation: Department of Chemical Engineering, University of California, Santa Barbara, CA 93106-5080, United States.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Whitehead
authors.forename: Natalie
authors.initials: N
authors.lastname: Karr
authors.forename: Samir
authors.initials: S
authors.lastname: Mitragotri
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000008:administration & dosage / Q000494:pharmacology*; D000284:Administration, Oral; D000588:Amines / Q000008:administration & dosage / Q000494:pharmacology; D000081008:Bicyclic Monoterpenes; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002793:Cholic Acids / Q000008:administration & dosage / Q000494:pharmacology; D003652:Decanoic Acids / Q000008:administration & dosage / Q000494:pharmacology; D003911:Dextrans / Q000378:metabolism; D004338:Drug Combinations; D004357:Drug Synergism; D017097:Electric Impedance; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008353:Mannitol / Q000378:metabolism; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage / Q000494:pharmacology; D012521:Sarcosine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D012967:Sodium Dodecyl Sulfate / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D013501:Surface-Active Agents / Q000008:administration & dosage / Q000494:pharmacology; D013729:Terpenes / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: C521343:1-octyl-2-pyrrolidone; D000277:Adjuvants, Pharmaceutic; D000588:Amines; D000081008:Bicyclic Monoterpenes; D002793:Cholic Acids; D003652:Decanoic Acids; D003911:Dextrans; D004338:Drug Combinations; D011760:Pyrrolidinones; D000644:Quaternary Ammonium Compounds; D013501:Surface-Active Agents; D013729:Terpenes; C013912:decyltrimethylammonium; C053997:2-pinene oxide; D012967:Sodium Dodecyl Sulfate; D008353:Mannitol; C025231:sarkosyl; C408148:sodium laureth sulfate; C007940:hexylamine; C029410:ethyl sebacate; D012521:Sarcosine