Dr. Vanessa Zann contributes to Drug Development & Delivery special feature on bioavailability & solubility

Dr. Vanessa Zann, Vice President of Scientific Consulting, Translational Pharmaceutics^® and Clinical Pharmacology USA, contributes to Drug Development & Delivery's special feature on bioavailability & solubility. 

Dr. Zann says she has seen positive results with spray dried dispersion (SDD) formulations to help enhance fraction absorbed, which in turn increases exposure. Quotient Sciences uses biorelevant dissolution to rank solu­bility-enhanced technology platforms and then selects the most promising for clinical assessment.

“Note there is often a disconnect be­tween preclinical in vivo data and clinical outcomes,” she says. “We recommend as­sessing the SDD platform initially as a sus­pension formulation, which provides gold standard data for what is likely to be achieved with a good performing SDD tablet.”

For example, Tranquis approached Quotient Sciences in the preclinical stage to help develop clinical formulations for first in human (FIH). The compound in question was a BCS II compound (poor solubility and high solubility) and had shown solubility limited exposure preclini­cally, hence an enhanced formulation was anticipated to be required to achieve effi­cacious clinical exposures, explains Dr. Zann. Quotient Sciences used an inte­grated approach for drug product devel­opment, manufacturing, and clinical testing (this is the Translational Pharma­ceutics^® platform) to rapidly identify and overcome solubility and bioavailability challenges for this compound.

Three suspension formulations were developed for assessment in the FIH: a methylcellulose crystalline (MC) suspen­sion; a spray-dried dispersion (SDD) sus­pension; and a hot melt extrusion (HME) suspension. The regulatory package was filed with 90 days stability for the SDD and HME GMP intermediates and seven days for the powder in bottle (PiB). The suspen­sion had four hours in use stability and a rinsing trial performed on each to allow total dosing volume to be 240mL. She ex­plains that the SDD and HME both showed superior dissolution to the crystalline API in a biorelevant dissolution assessment, demonstrating a spring and parachute ef­fect with reduced precipitation in the intes­tinal phase. A number of SDD suspensions were also assessed in the rat prior to the FIH but didn’t show any improvement over the MC suspension.

The FIH study started dosing SAD co­hort 1 (60mg) and 2 (180mg) with a methylcellulose crystalline suspension, which gave three-fold higher exposure than anticipated from the preclinical species. At SAD cohort 3 (540mg), the subjects were initially dosed with the MC suspension, but then returned to the clinic for dosing with the SDD and HME suspen­sions. The dose of the SDD and HME sus­pension was reduced to 180mg to ensure that the exposure caps were not exceeded due to the already higher exposure in the clinic than originally predicted. The SDD had the highest exposure showing a four-fold increase compared to the MC suspen­sion. This formulation was selected for dosing the remainder SAD and MAD co­horts.

“The Translational Pharmaceutics^® platform allowed the study not only to de­liver safety, tolerability, and pharmacoki­netic data, but also formulation selection assessment ahead of Phase II patient tri­als,” says Dr. Zann.

Read the full article on Drug Development & Delivery's website here.