betadex and decanoic-acid

According to Biopharmaceutics Classification System (BCS), acyclovir is a class III (high solubility, low permeability) compound, and it is transported through paracellular route by passive diffusion. The aim of this study was to investigate the effect of various pharmaceutical excipients on the intestinal permeability of acyclovir.. The single-pass in-situ intestinal perfusion (SPIP) method was used to estimate the permeability values of acyclovir and metoprolol across different intestinal segments (jejunum, ileum and colon). Permeability coefficient (Peff ) of acyclovir was determined in the absence and presence of a permeation enhancer such as dimethyl β-cyclodextrin (DM-β-CD), sodium lauryl sulfate (SLS), sodium caprate (Cap-Na) and chitosan chloride.. All enhancers increased the permeability of paracellularly transported acyclovir. Although Cap-Na has the highest permeability-enhancing effect in all segments, permeation-enhancing effect of chitosan and SLS was only significant in ileum. On the other hand, DM-β-CD slightly decreased the permeability in all intestinal segments.. These findings have potential implication concerning the enhancement of absorption of paracellularly transported compounds with limited oral bioavailability. In the case of acyclovir, Cap-Na either alone or in combination with SLS or chitosan has the potential to improve its absorption and bioavailability and has yet to be explored.

Topics: Acyclovir; Administration, Oral; Animals; beta-Cyclodextrins; Biological Availability; Chitosan; Colon; Decanoic Acids; Drug Compounding; Excipients; Female; Ileum; Intestinal Absorption; Jejunum; Perfusion; Permeability; Rats, Sprague-Dawley; Sodium Dodecyl Sulfate

The purpose of the present study was to gain quantitative mechanistic insight into the role cyclodextrin carriers may play in the intestinal absorption of highly lipophilic molecules. The physical model approach was employed to investigate capric acid absorption in the rat ileum using the in situ single-pass method with 2-hydroxypropyl-β-cyclodextrin (HPB) present in the perfusate. Two physical models were examined: the flat surface model in which the intestinal wall was treated as a hollow, smooth, circular cylinder, and the villus model in which the intestinal surface allowed for the presence of villi. Capric acid absorption was found to be essentially 100% aqueous boundary layer controlled at low HPB concentrations and increasingly membrane controlled at the higher HPB concentrations. Theoretical calculations based on the experimental data and model parameters were found to be consistent with: at low HPB concentrations, capric acid was mainly absorbed at the villus tips and there was very little capric acid penetration into the intervillus space; in contrast, at 50 mM HPB, there was considerable capric acid penetration into the intervillus space, this corresponding to around a 4.5-fold increase in the accessible area for absorption when compared with 0 mM HPB.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins; Biological Availability; Computer Simulation; Decanoic Acids; Diffusion; Drug Delivery Systems; Finite Element Analysis; Ileum; In Vitro Techniques; Intestinal Absorption; Male; Models, Biological; Perfusion; Rats; Rats, Sprague-Dawley

The present study describes a physical model approach applicable to understanding the transport of highly lipophilic, ionizable drugs across a lipophilic membrane between two aqueous compartments in the presence of a cyclodextrin in the aqueous phase. Model predictions were compared with experimental results of capric acid (HA) transport across a silicone polymer membrane in the presence and in the absence of 2-hydroxypropyl-β-cyclodextrin (HPB) in the aqueous phase over wide ranges of conditions. Key parameters entering into the physical model calculations were the HA-HPB and the A(-)-HPB binding constants, the unionized and ionized free and the complexed HA species diffusion coefficients, the HA pKa, the HA intrinsic silicone polymer membrane permeability coefficient, and the aqueous boundary layer thickness. All of these key parameters were determined from independent or essentially independent experiments. The agreement between the model predictions and the experiments were generally quite good over the entire ranges of the studied independent variables. The results of this study provide an approach that is useful in the mechanistic understanding of how cyclodextrins may enhance the passive absorption of highly lipophilic, low solubility drug molecules in the intestinal tract.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Antifungal Agents; beta-Cyclodextrins; Decanoic Acids; Diffusion; Membranes, Artificial; Models, Chemical; Permeability; Pharmaceutical Vehicles; Silicones

We have investigated the effect of sodium salt of capric acid (C10) on major tight junction proteins such as claudin and occludin, and also examined the involvement of lipid rafts with C10-induced alterations on these proteins. We firstly examined the C10 effect on the barrier function of tight junctions by measuring transepithelial electrical resistance (TER) and the flux of FITC dextran 4400 (FD-4). As a result, the increase in the FD-4 flux and decrease in the TER value were observed by incubation with C10 (10 mM) for 30 min, suggesting loss of the barrier function. In addition, C10 incubation produced an increase in solubility to Triton X-100 for claudin 4, 5 and occludin but not for claudin 1, 2, 3. Since it has been reported lipid raft disruption causes an increase in Triton X-100 solubility, it is suggested that effect of C10 on these proteins are involved with lipid rafts. From the lipid raft isolation study, we clarified the distribution of these proteins in lipid rafts. These results strongly indicate the displacement of specific tight junction proteins, claudin 4, 5 and occludin, from lipid raft by the treatment with C10 and involvement of this displacement with the absorption enhancing mechanism of C10.

Topics: Animals; beta-Cyclodextrins; Cell Line; Cell Membrane; Claudin-1; Claudin-3; Claudin-4; Decanoic Acids; Dextrans; Dogs; Electric Impedance; Epithelial Cells; Fluorescein-5-isothiocyanate; Membrane Microdomains; Membrane Proteins; Occludin; Octoxynol; Permeability; Tight Junctions