A solid solution
Soluplus®, a graft copolymer of PEG comprising polyvinyl acetate and polyvinyl caprolactam (see Figure 1A), was specially designed to solubilize poorly water-soluble drugs. To guarantee appropriate processability (e.g., in melt-extrusion applications), the composition of the polymer was adjusted to optimize its physical properties. With a low glass-transition temperature of around 70 °C, Soluplus® can be processed at low temperatures. Soluplus® shows good stability. Its formulations remain stable so that drugs, especially those that are formulated in an amorphous state, do not show recrystallization. In addition to these composition-related properties, the physical appearance of Soluplus® has been optimized. Using a special drying process, Soluplus® is formulated as free-flowing granules (see Figure 1B) that allow high feed rates and dust-free handling during the feeding process. At the same time the granules can easily be blended with most API crystals without showing segregation in subsequent process steps.
Although the above mentioned study demonstrated the enhanced bioavailability of the investigated drugs, it also compared drug formulations with Soluplus® using only the crystalline form of the API. However, the crystalline form is not an ideal benchmark for comparison, considering that it is not optimized and is not expected to show comparable biovavailability.
Therefore, a new case study was performed by selecting the marketed formulation of a poorly-soluble drug (itraconazole) that had already been optimized with regard to the bioavailabity of the formulated API (2).
Differential scanning calorimetry (DSC) analysis showed the absence of any crystalline substances in the Soluplus® formulation (see Figure 2). Itraconazole in Sempera® seemed mainly amorphous, but an interpretation of the thermograms was impossible due to superimposed peaks from other excipients (PEG, sucrose).
The test formulations were tolerated well and there were no clinical findings. Both formulations, Sempera® and Soluplus® extrudates, achieved a strong increase in bioavailability, compared with crystalline itraconazole (see Figure 4). However, the results from in-vitro dissolution tests and in-vivo plasma concentrations did not really correlate; the observed effect was much higher for the Soluplus®-based extrudate. The corresponding area under the curve (AUC 0-72 h ) increased more than two-fold compared to the Sempera® formulation (8.503 ng*h/mL versus 18.558 ng*h/mL).
This case study confirms the results obtained from previous studies and demonstrates once more that it is possible to achieve a significant increase in oral bioavailability with a Soluplus® formulation. Furthermore, the tested melt-extruded formulation was very easy to formulate and performed significantly better than the more complex marketed formulation. It is the authors' opinion therefore that Soluplus® can therefore help to bring promising new chemical entities to the market and shorten development times by an easy and fast formulation process via melt extrusion.
1. M. Linn et al., "Soluplus as an Effective Absorption Enhancer of Poorly Soluble Drugs In Vitro and In Vivo," Eur. J. Pharm. Sci., 45, 336–343 (2012).
2. F. Guth et al., "Bioavailability Enhancement of Itraconazole with Solid Solutions Based on Soluplus," presented at the 39th Annual Meeting and Exposition of the Controlled Release Society (CRS), Quebéc City, Canada 2012.
3. Rote Liste online, available at http://www.rote-liste.de/Online, accessed July 20, 2012.