The intestinal uptake of "enzymatically-stable" peptide drugs in rats as influenced by D-glucose in situ.

In previous in situ and in vivo rat perfusion studies, the intestinal absorption of several low molecular weight drugs was increased by the presence of luminal D-glucose. The intent of this study was to determine the potential of this fed-state effect to improve the intestinal uptake of poorly permeable, small peptide and peptide-like drugs. Jejunal wall permeabilities (Pw*) of di-(D-kyotorphin), tri-(cephradine), hexa-(growth hormone releasing peptide, GHRP-6) and octa-(octreotide, a somatostatin analogue) peptides and corresponding net water fluxes were determined in rats using an in situ single-pass perfusion technique. Glucose was shown to enhance the uptake of the smaller (di- and tri-) peptides but not the larger peptides despite the fact that glucose elicited a significant net water absorption with each of the four peptide drugs. It is concluded that glucose enhances jejunal permeabilities of smaller peptides by solvent drag and the enhancement is limited in situ by peptide molecular size. The studies with nonmetabolizable 3-O-methylglucose suggest that the augmentation of the proton gradient across the transmucosal membrane by glucose contributes to the carrier-mediated transport observed with the smaller peptides.

Biopharmaceutical characterisation of a low-dose (75 mg) controlled-release aspirin formulation.

The release of aspirin from a 75 mg controlled-release formulation, designed to inhibit maximally thromboxane A2 production while sparing stimulated prostacyclin biosynthesis, was characterised in healthy subjects. The calculated in vivo release rate of aspirin matched the design goal of approximately 10 mg h(-1). The C(max) of aspirin associated with the controlled-release formulation was lowered 15-fold relative to a solution formulation of the same dose. The bioavailability of aspirin (based on salicylate concentrations) from the controlled-release formulation was approximately 90% relative to the solution, and drug release was not affected by co-administration of a standard breakfast.

Solution stability of cephradine neutralized with arginine or sodium bicarbonate.

The solution stability of two formulations of cephradine--one using L-arginine and the other sodium carbonate as the neutralizer--was studied. Solutions of each formulation of 1% cephradine were prepared in the following diluents: 0.9% sodium chloride injection, lactated Ringer's injection, Ringer's injection, Normosol-R injection, 5% dextrose injection, and sterile water for injection; 5 and 25% solutions were made with sterile water for injection. All solutions were maintained at 25 degrees C, and at least five samples of each were assayed at various time intervals. Assay methods were HPLC, hydroxylamine colorimetric assay, microbiological agar diffusion, and iodometric analysis. By all assay methods, degradation rates of 1% solutions were lower for the arginine-neutralized product than for the one neutralized with sodium carbonate. This may be attributable to the lower pH values of solutions of the formulation with arginine, because one mechanism of degradation is pH-dependent. At concentrations of 5%, the difference in cephradine stability between the two formulations was minimal. At the 25% concentration, the formulations containing sodium carbonate were more stable. At these higher concentrations, the effect of pH is less important because degradation occurs by a combination of mechanisms. The 1% cephradine-arginine formulation was more stable than the same strength cephradine-sodium carbonate formulation in all the i.v. diluents studied. At 5 and 25% cephradine concentrations, the differences in stability between the two formulations were not substantial.

Stability of aqueous solutions of pirbuterol.

The hydrolytic degradation of pirbuterol was investigated under saturated oxygen conditions over a wide range of pH values and at different temperatures. Two of the five observed breakdown products were positively identified. The first-order decomposition rate appeared to depend on the rate constants of the four dissociated ionic species. The most stable region for the drug was pH 1-2, where the diprotonated molecule predominated; appropriate thermodynamic parameters were calculated.