Dose Escalation Study to Assess the Pharmacokinetic Parameters of a Nano-amorphous Oral Sirolimus Formulation in Healthy Volunteers.

Background And Objectives: Sirolimus (Rapamune) exhibits low bioavailability, high variability and moderate food effect following oral administration. This makes therapeutic blood monitoring of sirolimus concentrations necessary for kidney transplant patients. Furthermore, reaching therapeutic blood sirolimus concentrations in renal cancer patients was found to be challenging when the marketed drug was administered alone.

Investigations of the mechanism behind the rapid absorption of nano-amorphous abiraterone acetate.

Abiraterone acetate is indicated for patients with metastatic castration resistant prostate cancer. The marketed drug product (Zytiga®) exhibits very low bioavailability in the fasted state and a substantial positive food effect. We recently developed a nano-amorphous formulation of this drug which exhibited higher apparent solubility and dissolution rate, and significantly improved absorption and bioavailability in the fasted state in beagle dogs and in a phase I clinical study.

Development of an abiraterone acetate formulation with improved oral bioavailability guided by absorption modeling based on in vitro dissolution and permeability measurements.

Particle size reduction of drug crystals in the presence of surfactants (often called "top-down" production methods) is a standard approach used in the pharmaceutical industry to improve bioavailability of poorly soluble drugs. Based on the mathematical model used to predict the fraction dose absorbed this formulation approach is successful when dissolution rate is the main rate limiting factor of oral absorption. In case compound solubility is also a major factor this approach might not result in an adequate improvement in bioavailability.

Novel formulation of abiraterone acetate might allow significant dose reduction and eliminates substantial positive food effect.

Purpose: Zytiga (abiraterone acetate, AA) is known to exhibit very low bioavailability and a significant positive food effect in men. The unfavorable pharmacokinetic properties are attributed to the inadequate and variable dissolution of the compound. Using a continuous flow precipitation technology, a novel AA formulation has been developed with improved solubility and dissolution characteristics.

Sirolimus formulation with improved pharmacokinetic properties produced by a continuous flow method.

The oral bioavailability of Sirolimus is limited by poor dissolution of the compound in the gastrointestinal tract resulting in a low bioavailability and large inter-individual differences in blood levels. Several different formulation approaches were applied to overcome these disadvantageous pharmacokinetic properties including the marketed oral solution and a tablet form containing wet milled nanocrystals. These approaches deliver improved pharmacokinetics, yet, they share the characteristics of complex production method and composition.

Novel continuous flow technology for the development of a nanostructured aprepitant formulation with improved pharmacokinetic properties.

The oral bioavailability of Aprepitant is limited by poor dissolution of the compound in the gastrointestinal tract which is more prominent in the fasted state resulting in significant positive food effect. Due to the low aqueous solubility of the active substance the product development has been focused on decreasing the particle size of the active compound down to the submicron range in order to overcome this disadvantageous pharmacokinetic property. The marketed drug consisting of wet-milled nanocrystals exhibits significantly higher oral bioavailability in the fasted state and reduced food effect when compared to the unformulated compound.