Effect of excipients on the stability and transport of recombinant human epidermal growth factor (rhEGF) across Caco-2 cell monolayers.
The effect of sixteen excipients on the transport of recombinant human epidermal growth factor (rhEGF) across Caco-2 cell monolayers was examined at 37 degrees C. The apparent apical to basolateral (A-B) permeability (Papp) of 30 microM rhEGF was 8.15 x 10(-7) cm/sec, indicative of a poor level of absorption in the GI tract. The Papp was 1.7- and 6.3-fold greater than the Papp in the basolateral to apical (B-A) direction and the A-B permeability of mannitol, respectively, and decreased dramatically to a negligible level at 4 degrees C, consistent with a receptor mediated transcytosis of rhEGF. The stability of rhEGF was very poor, undergoing more than 85% degradation in 2 h in the transport medium at 37 degrees C. A significant increase in the Papp could be achieved by the addition of certain excipients, as exemplified by 23, 21, 20 and 16-fold increases, in the presence of sodium taurochenodeoxycholate (NaTCDC), sodium taurodeoxycholate (NaTDC), sodium glycodeoxycholate (NaGDC) and sodium laurylsulfate (SLS) (all at a concentration of 1% w/v), respectively. A significant increase in stability could also be achieved by the addition of some of the excipients, as represented by 1% SLS, which nearly completely stabilized the rhEGF. Unfortunately, however, an increase in the Papp of rhEGF could not be achieved without a simultaneous and extensive decrease in the integrity of the cell membranes. Thus, more efficient excipients, that specifically enhance the permeation of rhEGF and do not alter the membrane integrity, should be pursued in order to safely enhance the permeation of rhEGF.
Research Institute Development of Pharmaceutical Resources, Chungbuk National University, San 48, Gaeshin-dong, Hungduk-gu, Cheongju, Chungbuk 361-763, Korea.
In-Wha
IW
Kim
Ho-Jung
HJ
Yoo
Im-Sook
IS
Song
Youn-Bok
YB
Chung
Dong-Cheul
DC
Moon
Suk-Jae
SJ
Chung
Chang-Koo
CK
Shim
D000042:Absorption / Q000187:drug effects / Q000502:physiology*; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology*; D018938:Caco-2 Cells / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D004355:Drug Stability; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005079:Excipients / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D026901:Membrane Transport Proteins / Q000493:pharmacokinetics*; D010592:Pharmaceutic Aids / Q000493:pharmacokinetics*; D011310:Preservatives, Pharmaceutical / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000378:metabolism*
D005079:Excipients; D026901:Membrane Transport Proteins; D010592:Pharmaceutic Aids; D011310:Preservatives, Pharmaceutical; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor