Biopharmaceutic Profiling of Salts to Improve Absorption of Poorly Soluble Basic Drugs.

AZD1175 and AZD2207 are 2 highly lipophilic compounds with a significant risk of not achieving therapeutic plasma concentrations due to solubility-limited absorption. The compounds have the same molecular weight and minimal structural differences. The aim of the present work was to investigate whether salts could be applied to improve the intestinal absorption, and the subsequent in vivo exposure.

Oral bioavailability of cinnarizine in dogs: relation to SNEDDS droplet size, drug solubility and in vitro precipitation.

The in vivo performance of self-nanoemulsifying drug delivery systems (SNEDDSs) with different in vitro physicochemical properties were determined with the purpose of elucidating the parameters determining the in vivo performance of SNEDDSs. The in vitro characterisation included the use of pulsed field gradient NMR and the dynamic lipolysis model. In vivo characterisation was carried out in dogs with elevated gastric pH.

Modification of gastric pH in the fasted dog.

Objectives: The aim was to compare the ability of pretreatments to consistently adjust gastric conditions to low or high pH in the fasted state in dogs.

Methods: Four male Labrador/Labrador-cross dogs weighing 25-35 kg were surgically equipped with a ventricle fistula cannula in the stomach and a jejunal nipple valve stoma. Dogs were fasted overnight before the experiments, with free access to water.

Canine intestinal contents vs. simulated media for the assessment of solubility of two weak bases in the human small intestinal contents.

Purpose: This study was conducted to assess the relative usefulness of canine intestinal contents and simulated media in the prediction of solubility of two weak bases (dipyridamole and ketoconazole) in fasted and fed human intestinal aspirates that were collected under conditions simulating those in bioavailability/bioequivalence studies.

Methods: After administration of 250 mL of water or 500 mL of Ensure plus [both containing 10 mg/mL polyethylene glycol (PEG) 4000 as nonabsorbable marker], intestinal aspirates were collected from the fourth part of the duodenum of 12 healthy adults and from the mid-jejunum of four Labradors. Pooled samples were analyzed for PEG, pH, buffer capacity, osmolality, surface tension, pepsin, total carbohydrates, total protein content, bile salts, phospholipids, and neutral lipids.

The delayed dissolution of paracetamol products in the canine fed stomach can be predicted in vitro but it does not affect the onset of plasma levels.

Although it is generally believed that paracetamol can be used as a marker of gastric emptying, there have been reports in the literature that show delayed dissolution of immediate release paracetamol tablets using standard in vitro setups and food-simulating media, delayed disintegration of paracetamol products in the fed stomach, and no correlation of paracetamol absorption with gastric emptying in the fed state. In this study, we confirmed that dissolution of Panodil and Apotel tablets is delayed in food-simulating media regardless of the in vitro hydrodynamics and on a formulation dependent manner. Further, we assessed the usefulness of in vitro dissolution data in the prediction of delayed disintegration time in the fed stomach and we examined the importance of delayed gastric disintegration on the onset of plasma levels using the canine model.

Influence of hydrodynamics and particle size on the absorption of felodipine in labradors.

Purpose: To study the influence of GI hydrodynamics and drug particle size on felodipine absorption in the dog.

Methods: Labradors fistulated at midjejunum were used to selectively study the influence of hydrodynamics and particle size on the in vivo dissolution and absorption of the poorly soluble, lipophilic drug felodipine. A combination of infusion and oral administration of either normal saline or a 5% glucose solution was used to maintain "fasted" and establish "fed" state motility patterns, respectively.