Solid dispersions in oncology: a solution to solubility-limited oral drug absorption

Abstract

This thesis discusses the formulation method solid dispersion and how it works to resolve solubility-limited absorption of orally dosed anticancer drugs. Dissolution in water is essential for drug absorption because only dissolved drug molecules are absorbed. The problem is that half of the arsenal of orally dosed anticancer drugs are poorly soluble in water, resulting in incomplete bioavailability and high variability in blood concentrations. This ultimately can result in under- or overdosing. Dissolution-limited absorption can be addressed with the pharmaceutical formulation. A promising formulation method is the solid dispersion technique. In a solid dispersion the drug is finely dispersed in a hydrophilic excipient. The hydrophilic excipient, decreased particle size and close integration of drug-excipient increase drug dissolution, allowing higher in-vivo absorption. There are currently 27 commercially available solid dispersions, 3 of them are oral anticancer formulations, highlighting the feasibility and success. For example, vemurafenib solid dispersion formulation Zelboraf® results in 30 times increased dissolution and 5 times increased bioavailability compared to a crystalline physical mixture formulation. For this thesis, oral formulations for three different drugs were developed by using the solid dispersion technique: elacridar hydrochloride, docetaxel and paclitaxel. Elacridar hydrochloride is intensively studied in oncology because of its boosting effect on the oral bioavailability and brain penetration of many anticancer drugs. The boost is caused by inhibition of drug-efflux pumps P-glycoprotein (PgP) and Breast Cancer Resistance Protein (BCRP) which are expressed in cells such as in the gastrointestinal tract, blood-brain barrier and limit oral bioavailability and drug uptake in the central nervous system. Previous clinical trials with elacridar hydrochloride already confirmed this boosting effect. However, further commercial development of elacridar hydrochloride is stopped, possibly due to its challenging pharmaceutical properties: it is practically insoluble in water and the previously used clinical formulation results in poor and unpredictable absorption. This thesis describes the development and clinical evaluation of a novel oral formulation containing an elacridar hydrochloride solid dispersion. Docetaxel and paclitaxel are widely used against many cancer types. The oral bioavailability of these drugs is low (<10%) because of their poor solubility in water and presystemic metabolism. This explains why they are administered only intravenously. Intravenous administration of docetaxel and paclitaxel is burdening for the patient because hospitalization is required and dosing schedules are intensive, resulting often in toxicity. An oral formulation of docetaxel and paclitaxel has been developed previously by us. The solubility is enhanced by capsules containing a freeze dried solid dispersion of docetaxel or paclitaxel. The formulation is co-administered with presystemic metabolism inhibitor ritonavir and this results in promising clinical outcome. However, freeze drying is slow and non-continuous and results in a powder with poor flow properties, as a consequence capsules are filled manually. This production method is not suitable for further larger clinical studies with docetaxel and paclitaxel. Spray drying is a fast and continuous production process and allows better particle engineering, making it suitable for upscaling and improving powder mechanics. The pharmaceutical development and clinical evaluation of the spray dried solid dispersion for docetaxel and paclitaxel is described in this thesis.