Gastrointestinal absorption of drugs

In this paper, those subjects that are important to drug absorption in the gastrointestinal tract are reviewed. First the anatomy of the gastrointestinal system is discussed in some detail. This is followed by a general review of the some of the animal models that are used to study drug absorption. In later sections, the physiological factors that affect drug absorption (pH and bile fluid), different mechanisms of drug absorption (passive, facilitated, and active transport, peptide and macromolecule absorption, and lymphatic uptake), and adjuvants (promoters of drug absorption) are discussed.     

Rate-limiting steps in oral absorption of a leucotriene D4 antagonist in the beagle dog.

Oral administration of a leucotriene D4 antagonist drug (1) in the Beagle dog at doses of 2, 20, 100, 300, and 800 mg/kg resulted in dose-dependent bioavailability values (4-50%). To understand the dose dependence of the absorption of 1 in the dog, initial rates of absorption of 1, which were estimated from Loo-Riegelman analysis of the concentration in blood data, were analyzed in terms of dissolution and absorption rates. From the Loo-Riegelman plots, the initial rates of absorption of 1 were estimated as 8.2, 41.9, 41.1, 76.1, and 72.8 micrograms.mL-1.h-1, respectively, for the doses given earlier. These data, which indicate leveling of the initial absorption rates at high doses, were consistent with an absorption model in which the dissolution rate is the rate-controlling step in the intestinal absorption of 1 at doses less than 100 mg/kg. The powder dissolution rate of 1 in 17 mM bile salt solution was estimated as 14 and 700 micrograms.mL-1.h-1 for amounts of 1 equivalent to the amounts given to dogs at 2- and 100-mg/kg doses, respectively. After consideration of the volume of distribution and the volume of intestinal fluid in the dog, the value of the initial dissolution rate was much lower than the initial absorption rates at the 2-mg/kg dose. Oral administration of 1 at 2 mg/kg in a 3% polysorbate 80 solution enhanced both the rate and the extent of absorption of the compound. These results confirm the validity of the conclusion that the intestinal absorption of 1 is limited by dissolution rate at low doses.     

Enhancement of Nasal Delivery of a Renin Inhibitor in the Rat Using Emulsion Formulations

Nasal absorption of O-(N-morpholino-carbonyl-3-L-phenylaspartyl-L-leucinamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (I), a renin inhibitor, was evaluated in two rat nasal models, one involving surgery and the other requiring no surgical intervention. Oleic acid/monoolein emulsion formulations were tested along with a control PEG 400 solution. The percent absolute bioavailability of the compound was enhanced from 3–6% (PEG 400 solution) to 15–27% when the emulsion formulations were used. The different nasal model techniques (with and without surgery) did not produce any statistical difference in the absolute bioavailability values for I. Emulsion formulations did not produce appreciable damage as assessed morphologically. It is suggested that emulsion formulations containing membrane adjuvants such as oleic acid and monoolein can be used to enhance the nasal delivery of low-bioavailable, lipid-soluble drugs.____________________     

Stabilization of Misoprostol with Hydroxypropyl Methylcellulose (HPMC) Against Degradation by Water

The stability of misoprostol oil is significantly improved in a hydroxypropyl methylcellulose (HPMC) dispersion (1:100). In order to assess the effect of water on misoprostol stability, the rate of misoprostol degradation was investigated in the misoprostol/HPMC dispersion at 55°C, along with the water sorption isotherm, under seven different relative humidity (RH) conditions ranging from 0 to 81%. The results indicated that the first-order rate constants of misoprostol degradation increased in a concave-up fashion as the water content of the dispersion increased. Below 30% relative humidity (2% water), the first-order rate constants of misoprostol degradation were found to be minimum. The results of the stability study were interpreted in terms of the changing structure of HPMC as it related to the mobility of water and misoprostol within the HPMC dispersion.     

Examination of Arrhenius Kinetics for an Antiarrhythmic Compound

Pharmaceutical Research -     

Solid-State Interaction of Magnesium Oxide and Ibuprofen to Form a Salt

During formulation development work involving ibuprofen, a solid-state interaction between MgO and ibuprofen was observed. In this study the interaction of MgO and ibuprofen was investigated for 1:1 and 2:1 M mixtures of ibuprofen and MgO, which had been stored at 55°C, using the differential scanning calorimetric (DSC), thermogravic analysis (TGA), and multiple internal reflectance infrared (MIR) techniques. Evidence for the reaction was the disappearance of the melting endotherm at 79°C and appearance of a new endotherm at 161°C after less than 1 day of storage at 55°C and, also, the change in the physical appearance of the mixtures. Comparison of the DSC, TGA, and MIR data for the reacted ibuprofen and MgO mixtures and synthetic Mg(ibuprofen)₂ indicated that MgO and ibuprofen react to form the Mg salt of ibuprofen. The interaction of ibuprofen and MgO was also studied at 30 and 40°C, using 1:1 M mixtures. At 30°C no significant interaction was observed for up to 80 days; however, at 40°C a reaction was evident on day 1. NaHCO₃, K₂CO₃ 1.5H₂O, CaO, and Mg(OH)₂ also showed solid-state reactions with ibuprofen. MgCl₂ and Al(OH)₃ did not show this reaction.     

Physical State of Misoprostol in Hydroxypropyl Methylcellulose Films

Scanning electron (SEM) and light microscopy (LM), differential scanning calorimetry (DSC), and dynamic mechanical analysis (DMA) techniques were utilized to determine the miscibility of misoprostol and HPMC in the films with a misoprostol content from 0 to 29%, prepared using ethanol and methylene chloride/methanol (MeCl₂/methanol, 50:50). Transmission infrared (TIR) analysis was used to look for evidence of any interaction between misoprostol and HPMC. The LM and SEM analysis of the ethanol cast films indicated no oil droplets. The DSC thermograms of the films showed no evidence of a –33°C transition, which is characteristic of pure misoprostol. The DMA showed that the glass–rubber transition temperature (T _g) of the pure HPMC was lowered from 163 to 125–130 and 85–87°C in the presence of 10 and 27–28% misoprostol. Based on these results it is suggested that misoprostol is solubilized in HPMC at concentrations up to 29%. The TIR analysis of the films showed no evidence of interaction between misoprostol and HPMC.     

Glass-rubber transitions of cellulosic polymers by dynamic mechanical analysis

The glass-rubber transition temperatures (Tg) of several cellulosic polymers [hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC)] have been examined using dynamic mechanical analysis (DMA). The melting temperatures of the above polymers were examined using a hot stage melting point apparatus. The primary Tg of three different grades of HPMC (3, 6, and 15 cps) were determined to be 160, 170, and 175 degrees C, respectively. The primary Tg of the HEC film was determined as 120 degrees C. The HPC film did not indicate a primary Tg. These cellulosic polymers also displayed secondary transitions. Hot stage melting of HPMC and HPC was observed at 225 to 254 degrees C and 190 to 195 degrees C, respectively. The HEC powder did not exhibit a melting temperature, but became darker at temperatures greater than 150 degrees C.     

Reduced Systemic Availability of an Antiarrhythmic Drug,Bidisomide, with Meal Co-administration: Relationship with Region-Dependent Intestinal Absorption

Purpose. The aim of this research was to determine the mechanism by which a co-administered meal decreases the oral absorption of bidisomide and does not influence the oral absorption of the chemically-related antiarrhythmic agent, disopyramide. Methods. Bidisomide plasma levels, following oral administration and intravenous infusion in the fasted state and with various meal treatments, were determined in human subjects. A dialysis technique was employed to examine the potential for drug binding to meal homogenates. Plasma levels, following drug administration through duodenal and jejunal intestinal access ports and following various meal treatments with oral drug co-administration, were compared for bidisomide and disopyramide in a canine model. Results. Bidisomide plasma AUC was significantly reduced following oral drug co-administration with breakfast compared to fasted-state controls in human subjects and in dogs independent of the composition of the solid cooked breakfast. While intravenous bidisomide infusion in human subjects showed a statistically significant reduction in AUC 15 minutes after oral administration of a high fat breakfast as compared to drug infusion in the fasted state, the reduction (–13%) was substantially smaller than the reduction (from –43% to –63%) observed with oral bidisomide meal co-administration. The percentages of bidisomide and disopyramide lost by binding to homogenates of cooked breakfast were 25.0 ± 5.7% and 23.7 ± 7.7%, respectively, as determined by dialysis at 4 hours. In dogs, the extent of absorption of disopyramide was comparable from oral, duodenal and mid-jejunal administration while the extent of bidisomide absorption from mid-jejunal administration was significantly lower than for oral or duodenal administration. Non-viscous liquid meals decreased C_max but not AUC, while viscous homogenized solid meals decreased both C_max and AUC for bidisomide with oral drug-meal co-administration. Oral non-caloric hydroxypropyl methylcellulose meals decreased bidisomide to the same extent as homogenized solid meals but did not lower disopyramide AUC. Conclusions. The significant reduction in bidisomide plasma levels observed with meal co-administration in human subjects was predominantly mediated through a reduction in drug absorption and was independent of solid meal composition. The difference in meal effect on the absorption of the two drugs in humans did not appear to be a function of drug binding to cooked meal components over typical human upper gastrointestinal residence times. In dogs, the high-viscosity medium generated by oral co-administration of a solid meal reduced the upper intestinal absorption of bidisomide and disopyramide. Bidisomide AUC was decreased since it was well absorbed in the upper but not lower small intestine. Disopyramide AUC was not significantly affected since it was well absorbed from both regions. A similar mechanism may play a role in drug plasma level reductions following oral co-administration with solid meals for drugs showing similar regionally-dependent absorption profiles.     

Oral Delivery of a Renin Inhibitor Compound Using Emulsion Formulations

The oral delivery of O-(N-morpholino-carbonyl-3-L-phenylaspartyl-L-leucinamide of (2S,3R,4S)-2-amino-l-cyclohexyl-3,4-dihydroxy-6-methylheptane (I), a new renin inhibitor, was studied in the in vivo rat model using emulsion formulations. The components of the emulsion formulations were chosen based on their proposed effects on membrane structure, membrane fluidity, and solute transport. The percent absolute bioavailability (%AB) of I was increased from 0.3% (water suspension) to 5.1% when long-chain unsaturated fatty acid (oleic acid, linoleic acid, etc.)- and mono- and diglyceride (monolein, dilaurin, etc.)-containing emulsion formulations were used. Considering very high first-pass liver extraction of the compound (80%), it is suggested that emulsion formulations increased the intestinal transport of the compound significantly. The solubility of I in aqueous media with and without bile salt (20 mM) was found to be low (~1 µg/ml). Incubation in 0.01 N HC1 did not affect the particle size of the emulsion. The titration of oleic acid/monoolein emulsion in a pH 6.5 medium with a mixed bile salt system indicated reduction in the particle size of the emulsion. Drug precipitation was observed above 30 mM bile salt concentrations. No drug crystals could be detected in the intestinal contents of the rats when emulsion formulations were ingested. These results suggest that in the intestine of the animals, the particle size of the emulsions is reduced in the presence of bile fluid while the drug resides primarily in the oil phase. The mechanism of enhanced transport of I from the emulsion formulations is discussed along with the possibility of cotransport for the drug and oil. Emulsion formulations can be a potential delivery form for low-bioavailable lipid-soluble drugs.