A formulation strategy for gamma secretase inhibitor ELND006, a BCS class II compound: development of a nanosuspension formulation with improved oral bioavailability and reduced food effects in dogs.

ELND006 is a novel gamma secretase inhibitor previously under investigation for the oral treatment of Alzheimer's disease. ELND006 shows poor solubility and has moderate to high permeability, suggesting it is a Biopharmaceutics Classification System Class II compound. The poor absolute oral bioavailability of the compound in fasted dogs (F ∼11%) is attributed to poor aqueous solubility.

Nanosizing for oral and parenteral drug delivery: a perspective on formulating poorly-water soluble compounds using wet media milling technology.

A significant percentage of active pharmaceutical ingredients identified through discovery screening programs is poorly soluble in water. These molecules are often difficult to formulate using conventional approaches and are associated with innumerable formulation-related performance issues, e.g.

In vitro-in vivo correlation for wet-milled tablet of poorly water-soluble cilostazol.

The purpose of the present study was to investigate oral bioavailability of an immediate release tablet containing wet-milled crystals of a poorly water-soluble drug, cilostazol, and to establish in vitro-in vivo correlation. Sub-micron sized cilostazol (median diameter: 0.26 microm) was successfully prepared using a beads-mill in water in the presence of a hydrophilic polymer and an anionic surfactant.

Drug nanoparticles: formulating poorly water-soluble compounds.

More than 40% of compounds identified through combinatorial screening programs are poorly soluble in water. These molecules are difficult to formulate using conventional approaches and are associated with innumerable formulation-related performance issues. Formulating these compounds as pure drug nanoparticles is one of the newer drug-delivery strategies applied to this class of molecules.

Effect of particle size reduction on dissolution and oral absorption of a poorly water-soluble drug, cilostazol, in beagle dogs.

The purpose of the present study was to investigate the effects of particle size on the dissolution and oral absorption of cilostazol. Three types of suspensions having different particle size distributions were prepared of the hammer-milled, the jet-milled cilostazol crystals and the NanoCrystal spray-dried powder of cilostazol. In vitro dissolution rate of cilostazol was significantly increased by reducing the particle size.

Insulin nanoparticles: a novel formulation approach for poorly water soluble Zn-insulin.

Purpose: To determine the feasibility of using wet milling technology to formulate poorly water soluble zinc-insulin as a stable, biologically active, nanoparticulate dispersion.

Methods: The feasibility of formulating zinc-insulin as a nanoparticulate dispersion using wet milling technology was studied. An insulin nanoparticulate formulation was reproducibly obtained after milling zinc-insulin in the presence of F68, sodium deoxycholate and water at neutral pH.

Nanosizing: a formulation approach for poorly-water-soluble compounds.

Poorly-water-soluble compounds are difficult to develop as drug products using conventional formulation techniques and are frequently abandoned early in discovery. The use of media milling technology to formulate poorly-water-soluble drugs as nanocrystalline particles offers the opportunity to address many of the deficiencies associated with this class of molecules. NanoCrystal Technology is an attrition process wherein large micron size drug crystals are media milled in a water-based stabilizer solution.

Formulation and antitumor activity evaluation of nanocrystalline suspensions of poorly soluble anticancer drugs.

Purpose: Determine if wet milling technology could be used to formulate water insoluble antitumor agents as stabilized nanocrystalline drug suspensions that retain biological effectiveness following intravenous injection.

Methods: The versatility of the approach is demonstrated by evaluation of four poorly water soluble chemotherapeutic agents that exhibit diverse chemistries and mechanisms of action. The compounds selected were: piposulfan (alkylating agent), etoposide (topoisomerase II inhibitor), camptothecin (topoisomerase I inhibitor) and paclitaxel (antimitotic agent).

The electrophoretic mobility of tripeptides as a function of pH and ionic strength: comparison with iontophoretic flux data.

Capillary electrophoresis (CE) is an extremely efficient separations tool which can also be used to determine fundamental molecular parameters, e.g., the electrophoretic mobility of a molecule.

Liquid chromatographic analysis of a potential polymeric-pendant drug delivery system for peptides. Application of high-performance size-exclusion chromatography, reversed-phase high-performance liquid chromatography and ion chromatography to the evaluation of biodegradable poly[(chloromethoxytrialanine methyl ester)phosphazenes].

A novel water-soluble polymer, poly[(chloromethoxytrialanine methyl ester)phosphazene] (poly-Tame), was characterized and evaluated using high-performance size-exclusion chromatography, gradient reversed-phase high-performance liquid chromatography and ion chromatography. These novel liquid chromatographic methods were validated for application to in vitro biodegradation experiments of poly-Tame in aqueous solutions. Results from method validation experiments are presented.

Simultaneous determination of allopurinol and oxypurinol by liquid chromatography using immobilized xanthine oxidase with electrochemical detection.

A novel liquid chromatographic method using an immobilized xanthine oxidase reactor and an electrochemical detector was developed for the simultaneous determination of allopurinol and oxypurinol in rat plasma, intestinal wash and bile. Xanthine oxidase was immobilized on 5-microns aldehyde silica (prepacked into a 2 mm x 10 mm cartridge) in a simple procedure. Allopurinol eluted from an analytical column was converted to oxypurinol in the enzyme reactor with the eluent as the reaction medium and detected with high selectivity using an amperometric detector with a glassy carbon electrode at the applied potential of +0.

Influence of indomethacin amphoteric gel on gastric ulcerogenicity and absorption of indomethacin in rats.

Indomethacin is a potent and efficacious antiinflammatory agent. However, a limiting side effect is its ability to cause gastric ulceration. This study was designed to investigate the effects of an amphoteric gel on the gastric ulcerogenicity and pharmacokinetics of indomethacin.

Nasal delivery of a vasopressin antagonist in dogs.

The dosage form (drop or spray) and site of administration (dorsal or ventral surface of the nostril) profoundly affect the distribution and clearance of a gamma-emitting 99mTc-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA) solution in dogs. The slowest nasal clearance was observed for dorsally administered drops. Administration of drops to the ventral surface or sprays to either dorsal or ventral surface results in rapid clearance and little deposition in the turbinates.

Enhanced serum concentrations of Ara-C using suppositories containing tetrahydrouridine as a deamination inhibitor of Ara-C.

Rectal bioavailability of Ara-C (serum AUC 4 h: 65 micrograms h-1 ml-1) administered in a suppository formulation containing tetrahydrouridine (a deamination inhibitor) and sodium salicylate (an adjuvant) to dogs was better than that from a suppository formulation without tetrahydrouridine (serum AUC 4 h: 18 micrograms h-1 ml-1).

Simultaneous analysis of 1-beta-D-arabinofuranosylcytosine, 1-beta-D-arabinofuranosyluracil and sodium salicylate in biological samples by high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatographic column switching system is described for the rapid and complete separation of 1-beta-D-arabinofuranosylcytosine (Ara-C), 1-beta-D-arabinofuranosyluracil (Ara-U) and sodium salicylate using an internal standard of sodium cefmetazole. The system is highly selective and separates these compounds from interfering compounds commonly in biological matrices. The system was tested by following the pharmacokinetics of Ara-C after rectal administration in the presence of sodium salicylate which is an aid to drug absorption.