Harma Ellens

Formulation and Intestinal Absorption Enhancement Evaluation of Water-in-Oil Microemulsions Incorporating Medium-Chain Glycerides

We developed self-emulsifying water-in-oil (w/o) microemulsions incorporating medium-chain glycerides and measured their conductance, viscosity, refractive index and particle size. Formulation of Calcein (a water-soluble marker molecule, MW = 623), or SK&F 106760 (a water-soluble RGD peptide, MW = 634) in a w/o microemulsion having a composition of Captex 355/Capmul MCM/Tween 80/Aqueous (65/22/10/3, % w/w), resulted in significant bioavailabil-ity enhancement in rats relative to their aqueous formulations. Upon intraduodenal administration the bioavailability was enhanced from 2% for Calcein in isotonic Tris, pH 7.4 to 45% in the microemulsion and from 0.5% for SK&F 106760 in physiological saline to 27% in the microemulsion formulation. The microemulsion did not induce gross changes in GI mucosa at a dosing volume of 3.3 ml/kg. These results suggest that water-in-oil microemulsion systems may be utilized for enhancement of intestinal drug absorption.

Water-in-Oil Microemulsions Containing Medium-chain Fatty Acids/Salts: Formulation and Intestinal Absorption Enhancement Evaluation

AbstractPurpose. Water-in-oil (w/o) microemulsions have been developed which, in addition to non-ionic medium-chain glycerides, incorporate ionic lipids, primarily medium-chain fatty acids, such as caprylic (C8) capric (C10) and lauric (C12) acids and their corresponding sodium salts. The absorption enhancing activity of w/o microemulsions incorporating these lipids was evaluated in the rat using Calcein (MW = 623) a water-soluble and poorly absorbed marker molecule. Methods. Phase diagrams were constructed where C8/C10 or C12 fatty acids were treated as lipophilic surfactants and their sodium salts as hydrophilic ones. The anesthetised rat model was employed to evaluate Calcein absorption upon a single intraduodenal administration from a solution and the various w/o microemulsions. Results. A wide range of clear and transparent w/o microemulsions were obtained at ambient temperature either in liquid or solid form when a fixed blend of medium chain fatty acid/salt was titrated by a fixed ratio of the oil containing the oil-soluble mono- and diglycerides and deionized water or physiological saline. Upon intraduodenal administration in the anesthetised rat, the absorption of Calcein was improved from about 2% in aqueous solution up to about 37% in w/o microemulsions. Solid and liquid formulations were equally effective in improving bioavailability. The absorption enhancement activity of the fatty acids/salts followed the order C8 ≈ C10 > C12. Absorption enhancement of Calcein was significantly reduced in the absence or presence of low levels of C8/C10 mono-/diglycerides. Conclusions. These results further support the use of medium-chain glycerides and fatty acids/salts in microemulsion formulations to improve intestinal absorption of water-soluble compounds.

Effect of Medium-Chain Glycerides on Physiological Properties of Rabbit Intestinal Epithelium in Vitro

Medium chain glycerides (MCGs) have been reported to enhance intestinal absorption of hydrophilic drugs. However, the mechanisms involved in absorption enhancement are not well understood. The effects of MCGs (CapMul MCM) on physiological properties of rabbit ileum and distal colon, including active ion transport, transepithelial resistance (Rt) and passive permeability, have been investigated in vitro. CapMul MCM inhibited active ion transport (measured as a decrease in short-circuit current, Isc) in both intestinal segments in a concentration-dependent manner. The inhibition of Isc was rapidly reversible (within 100 min) upon removal of CapMul MCM. The data indicate that CapMul MCM preferentially affected ion transport by villus cells in the ileum and surface cells in the distal colon. Ion transport in crypt cells in both segments was not significantly altered. Rt of the ileum was not significantly affected by 5% CapMul MCM, while mannitol transport was 6 fold enhanced. Treatment of distal colon with 1% CapMul MCM reduced Rt by 95%, while mannitol transport was 100 fold enhanced. In a parallel experiment, mucosal(m)-to-serosal(s) transport of cephalexin, a β-lactam antibiotic, in the ileum was about 40% reduced in the presence of 5% CapMul MCM, whereas transport in the s-to-m direction was 2.5 fold enhanced. Treatment of the distal colon with 1% CapMul MCM resulted in 25 fold enhancement of cephalexin transport in either direction. These results suggest that absorption enhancement by MCGs results from an increased permeability of the intestine confined to the villus or surface epithelium.

In vitro permeability screening for identification of orally bioavailable endothelin receptor antagonists

Abstract In vitro intestinal permeability screening identified a compound, SB 217242, in the indane carboxylic acid series of endothelin receptor antagonists, with greatly improved permeability over the initial lead compound in this series. Based on mucosal-to-serosal and serosal-to-mucosal permeability studies, and on the fact that SB 217242 transport does not correlate with changes in mannitol permeability, it was concluded that SB 217242 follows a passive transcellular pathway. Permeability studies at different pH values demonstrate that the permeating species is the unionized form of SB 217242. This compound is well absorbed upon intraduodenal dosing in the rat (Ohlstein et al. (1996) J. Pharm. Exp. Ther. 276, 609–615).

Transdermal iontophoretic delivery of [3H]GHRP in rats

Abstract In this study, we demonstrate transdermal iontophoretic delivery of radiolabeled growth hormone-releasing peptide ([ 3 H]GHRP, [ 3 H]SK&F 110 679) from an iontophoretic patch delivery device in rats. [ 3 H]SK&F 110 679 was adsorbed on a hydrophilic microporous membrane, which was positioned on a support in the device and sealed in place. A silver/silver chloride electrode system was used for iontophoresis and a potential of 4.5 V (rectangular pulse, 40 kHz, 30% duty cycle) was applied using an Advance depolarizing pulse iontophoresis system (ADIS-4030). Current-dependent appearance of [ 3 H]SK&F 110 679 equivalents in blood, bile and urine did not depend on membrane loading between 1.8 and 8 mg adsorbed on the membrane. Blood levels of [ 3 H]SK&F 110 679 equivalents persisted for at least 2 h after the current was turned off, indicative of depot formation in the skin. Fractions of bile and urine were analyzed by reversed-phase high-performance liquid chromatography (HPLC). The radiochemical profiles were dominated by a single species, coeluting with intact [ 3 H]SK&F 110 679. A flux of at least 0.8–1.2 ug/h per cm 2 was achieved, indicating that, with appropriate optimization of the patch device, therapeutic levels of SK&F 110 679 in man may be attainable by transdermal iontophoresis.

Hepatobiliary Disposition of Atovaquone: A Case of Mechanistically Unusual Biliary Clearance

Atovaquone, an antiprotozoal and antipneumocystic agent, is predominantly cleared by biliary excretion of unchanged parent drug. Atovaquone is ≥10,000-fold concentrated in human bile relative to unbound plasma. Even after correcting for apparent nonspecific binding and incomplete solubility in bile, atovaquone is still concentrated ≥100-fold in bile, consistent with active biliary excretion. Mechanisms of atovaquone hepatobiliary disposition were studied using a multiexperimental in vitro and in vivo approach. Atovaquone uptake was not elevated in HEK293 cells singly overexpressing OATP1B1, OATP1B3, OATP2B1, OCT1, NTCP, or OAT2. Hepatocyte uptake of atovaquone was not impaired by OATP and OCT inhibitor cocktail (rifamycin and imipramine). Atovaquone liver-to-blood ratio at distributional equilibrium was not reduced in Oatp1a/1b and Oct1/2 knockout mice. Atovaquone exhibited efflux ratios of approximately unity in P-gp and BCRP overexpressing MDCK cell monolayers and did not display enhanced uptake in MRP2 vesicles. Biliary and canalicular clearance were not decreased in P-gp, Bcrp, Mrp2, and Bsep knockout rats. In the present study, we rule out the involvement of major known basolateral uptake and bile canalicular efflux transporters in the hepatic uptake and biliary excretion of atovaquone. This is the first known example of a drug cleared by biliary excretion in humans, with extensive biliary concentration, which is not transported by the mechanisms investigated herein.