The Use of Modeling Tools to Drive Efficient Oral Product Design

Abstract

Abstract. Modeling and simulation of drug dissolution and oral absorption has been increasingly used over the last decade to understand drug behavior in vivo based on the physicochemical properties of Active Pharmaceutical Ingredients (API) and dosage forms. As in silico and in vitro tools become more sophisticated and our knowledge of physiological processes has grown, model simulations can provide a valuable confluence, tying-in in vitro data with in vivo data while offering mechanistic insights into clinical performance. To a formulation scientist, this unveils not just the parameters that are predicted to significantly impact dissolution/absorption, but helps probe explanations around drug product performance and address specific in vivo mechanisms. In formulation, development, in silico dissolutionabsorption modeling can be effectively used to guide: API selection (form comparison and particle size properties), influence clinical study design, assess dosage form performance, guide strategy for dosage form design, and breakdown clinically relevant conditions on dosage form performance (pH effect for patients on pH-elevating treatments, and food effect). This minireview describes examples of these applications in guiding product development including those with strategies to mitigate observed clinical exposure liability or mechanistically probe product in vivo performance attributes.

From Bench to Humans: Formulation Development of a Poorly Water Soluble Drug to Mitigate Food Effect

“…The aqueous solubility is almost eight times higher at neutral pH than at pH in the range of 1.2-6. The pK a and logD values are 4.85 and 5.09, respectively (25). The P eff value is 5,000 cm/s.…”

“…When kinetic biorelevant media solubility, i.e., FaSSIF and FeSSIF, was included in the model, the model predicted the fasted-state clinical data but not the fed-state data. Solubility experiments showed that the drug was very soluble in digestible lipids and subsequent experiments, where additional lipid was included in the FeSSIF, indicated a greater than tenfold increase in drug solubility from 109 μg/ml in FaSSIF media to 1,340 μg/ml in FeSSIF+Microlipid media (all adjusted to pH 6.3) (25). The model was run using FeSSIF+ Microlipid media, assuming a 1 h gastric emptying T 50 (as is typically observed with a highfat meal).…”

“…The API has high solubility in oils and lipids. The API is classified as BCS Class II displaying poor aqueous solubility across the physiological pH range and high permeability based on clinical data (25).…”

“…The logD, pH-solubility profile, and solubility in dietary lipids were determined experimentally, and the aqueous diffusivity was estimated based on molecular weight. To simulate the fed-state condition, the peak kinetic solubility in FeSSIF with added 10% microlipid (surrogate for high-fat meal media) media was used as the model input (25).…”

“…Such a strong positive food effect can be attributed to several factors: physicochemically based (solubilization of the drug, sensitivity to GI pH), altered permeability (bile and lipid-influenced influx or efflux), reduced GI emptying and transit, or other physiological changes such as increased spanchnic blood flow or altered gut metabolism (25). In order to devise a strategy to mitigate this food effect, it was necessary to investigate the key rate-limiting factors.…”