Fixed dose combinations of an Organic Anion Transporter Polypeptide activator with a statin drug to reduce statin induced myopathy

The goal of the project is to enable statin-based therapy with a superior safety profile as compared to existing statin based dosing regimens. Our hypothesis is that the combination of an OATP activator with a statin will lead to higher statin levels in the liver. Due to lower systemic statin levels, myopathy will be reduced and patients can be treated for a longer period of time with statins.

A number of compounds such as domperidone, tangeritin, etc… have been identified as potent OATP activators. In a first step we will select the OATP activators and the statins, based on their physicochemical properties, to include in this project. In order to have a reasonable number of both type of compounds, 3 OATP activators and 3 statins will be selected.

Next to the active pharmaceutical ingredients (API), the functional excipients have to be selected. Excipients will be selected based on i) their permeability for a given statin, ii) the extent to which they can dissolve a given statin or an OATP activator in the solid state and iii) the potential to maintain the supersaturated state of a dissolved statin or OATP in gastrointestinal fluids. The first criterion is necessary to assure the desired statin release kinetics and prevention of premature statin release, whereas the second one assures adequate solid state stability, apparent solubility and dissolution rate of poorly soluble statins and OATP activators. Finally, precipitation of poorly soluble statins and OATP activators after release from their dosage form in the GI tract will limit the driving force (diffusion) for absorption in the blood circulation. Hence excipients that are able to maintain a sufficient degree of supersaturation to assure adequate absorption are required.

The third step in this project is the development of the core of the dosage form which will contain the statin. Two challenging hurdles to take are the low solubility of the statins and obtaining a delayed and either slightly sustained or pulsed but reproducible release of a poorly soluble compound. The first hurdle will be tackled by two different approaches. A first approach will be the formulation of the statin as an amorphous solid dispersion (ASD), which will be applied as a layer on top of a neutral core (pellet or bead made up of sucrose or microcrystalline cellulose). A fluid bed process will be applied for this purpose. A second approach will be loading of the statin in either mesoporous silica particles or cellulose particles by using a fluid bed process. Experimental design will be used to determine formulation -and process parameters.

Integration of the OATP activator in the dosage form will be accomplished by applying it as a layer on the statin based core by using a fluid bed process. Depending on the solubility properties of the selected compounds, this layer will be a stabilized ASD or a simple solid dispersion. The process and formulation will be optimized to obtain immediate and complete OATP activator release. 

The pharmaceutical performance of the developed dosage forms will be tested by evaluating the in vitro release kinetics of the OATP activator and the statin. These tests will be performed in biorelevant media that mimic the GI conditions. Drug quantification will be done with HPLC with UV detection. Stability will be studied after storage of the dosage forms during 1, 3, 6 and 12 months in conditions of elevated temperature and relative humidity.