Possible reduction of effective thickness of intestinal unstirred water layer by particle drifting effect.
According to the present theory of oral absorption, in the case of solubility limited absorption, the absorbed amount would not increase despite an increase in dose or a decrease in particle size. However, many experimental observations suggested that the absorbed amount was often increased (though sub-proportionally) as the dose strength increased. In addition, the particle size reduction was often effective to increase the absorbed amount even in the case of solubility limited absorption. Since an increase of the dose strength and a decrease of the particle size cause no or little change in solubility and the mean intestinal transit time, effective intestinal membrane permeability (P(eff)) should have changed. The previous theory postulated that drug particles do not exist in the unstirred water layer (UWL) which is adjacent to the intestinal membrane. However, many reports suggested that nano- to micro-scale drug particles existed in the UWL. In this case, the effective thickness of the UWL (h(eff)) could be smaller than the nominal thickness, resulting in an increase of P(eff). In the present study, h(eff) was simply calculated assuming that the reduction of h(eff) is in proportion to the surface area of drug particles in the UWL. When the particle drifting effect was taken into account, the discrepancy between the theoretical calculation and experimental observations was reduced. It was suggested that when the dose (mg)/particle diameter (microm) ratio exceeds 20, the particle drifting effect would become significant.
Sugano
Kiyohiko
K
Global Research & Development, Sandwich Laboratories, Research Formulation, Pfizer Inc., CT13 9NJ, Sandwich, Kent, UK. Kiyohiko.Sugano@pfizer.com
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004285:Dogs; D005772:Gastrointestinal Transit; D006801:Humans; D007408:Intestinal Absorption; D008962:Models, Theoretical; D010316:Particle Size; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility; D014867:Water / Q000378:metabolism*
D004364:Pharmaceutical Preparations; D014867:Water