Development of an oral solid dispersion formulation for use in low-dose metronomic chemotherapy of paclitaxel

Johannes Moes, Stijn Koolen, Alwin Huitema, Jan Schellens, Jos Beijnen, Bastiaan Nuijen

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

68 Citaten (Scopus)


For the clinical development of low-dose metronomic (LDM) chemotherapy of paclitaxel, oral administration is vital. However, the development of an oral formulation is difficult due to paclitaxel's low oral bioavailability, caused by its low permeability and low solubility. We increased the oral bioavailability of paclitaxel by combining a pharmacokinetic booster, ritonavir, with a new oral solid dispersion formulation of paclitaxel. The combined use of Hansen solubility parameters and dissolution experiments resulted in the development of a solid dispersion formulation containing 1/11 w/w paclitaxel, 9/11 w/w polyvinylpyrrolidone (PVP) K30, and 1/11 w/w sodium lauryl sulfate (SLS). Analysis of the solid dispersion formulation by X-ray diffraction, Fourier transform infrared (FT-IR) spectroscopy, and modulated differential scanning calorimetry (mDSC) confirmed the amorphous nature of paclitaxel and the fine dispersion of paclitaxel in the matrix of PVP-K30 and SLS. Furthermore, in vitro tests showed a major increase in the apparent solubility and dissolution rate of paclitaxel. To test the clinical significance of these findings, the solid dispersion formulation of paclitaxel (ModraPac001 10 mg capsule) was compared to the paclitaxel premix solution in four patients with advanced cancer. Although the mean systemic exposure to paclitaxel after oral administration of the solid dispersion formulation was slightly lower compared to the paclitaxel premix solution (190 ± 63.1 ng/mL h for vs. 247 ± 100 ng/mL h), the systemic exposure to paclitaxel is clinically relevant [1,2]. In addition to this, the favorable pharmaceutical characteristics, for example, neutral taste, dosing accuracy, and the 2-year ambient shelf life, make the ModraPac001 10 mg capsule an attractive candidate for oral paclitaxel chemotherapy. Currently, the ModraPac001 formulation is applied in the first clinical trial with oral LDM chemotherapy of paclitaxel.

Originele taal-2Engels
Pagina's (van-tot)87-94
Aantal pagina's8
TijdschriftEuropean Journal of Pharmaceutics and Biopharmaceutics
Nummer van het tijdschrift1
StatusGepubliceerd - jan. 2013
Extern gepubliceerdJa


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