Interaction of Polymers with Enzalutamide Nanodroplets-Impact on Droplet Properties and Induction Times.

Amorphous solid dispersions (ASDs), which consist of a drug dispersed in a polymeric matrix, are increasingly being applied to improve the in vivo performance of poorly water-soluble drugs delivered orally. The polymer is a critical component, playing several roles including facilitating drug release from the ASD, as well as delaying crystallization from the supersaturated solution generated upon dissolution. Certain ASD formulations dissolve to produce amorphous drug-rich nanodroplets. The interaction of the polymer with these nanodroplets is poorly understood but is thought to be important for inhibiting crystallization in these systems. In this study, the impact of ionic polymers on the crystallization kinetics of enzalutamide from supersaturated solutions containing different amounts of amorphous nanodroplets was evaluated by determination of nucleation induction times. The amount of the polymer associated with the drug nanodroplets was also determined. When comparing two polymers, hydroxypropylmethyl cellulose acetate succinate (HPMCAS) and Eudragit E PO, it was found that the crystallization tendency and physical properties of the drug nanodroplets varied in the presence of these two polymers. Both polymers distributed between the aqueous phase and the drug-rich nanodroplets. A greater amount of Eudragit E PO was associated with the drug-rich nanodroplets. Despite this, Eudragit E PO was a less-effective crystallization inhibitor than HPMCAS in systems containing nanodroplets. In conclusion, in supersaturated solutions containing amorphous nanodroplets, the extent of association of a polymer with the drug nanodroplet does not solely predict crystallization inhibition.

Influence of Polymer and Drug Loading on the Release Profile and Membrane Transport of Telaprevir.

During the dissolution of amorphous solid dispersions (ASDs), various phase transformations can occur, which will ultimately impact the degree of supersaturation. This study employed dissolution and diffusion measurements to compare the performance of various ASD formulations based on the maximum amount of free drug in the solution that was able to permeate through a cellulose-based membrane. Telaprevir (TPV) was used as the model drug compound, and ASDs were prepared with different drug loadings and with four different polymers. Four possible scenarios that can influence TPV mass flow rates upon ASD dissolution were described and supported with experimental data: (1) a system dissolves readily and completely undergoes phase separation via glass-liquid phase separation (GLPS), forming drug-rich aggregates, and reaches the maximum anticipated mass flow rate; (2) where the maximum mass flow rate decreases due to substantial mixing of the polymer into the drug-rich phase, and/or due to the formation of soluble polymer-drug complexes; (3) a system does not undergo GLPS due to slow drug release and/or matrix crystallization; and (4) a system does not undergo GLPS due to rapid crystallization from the supersaturated solution generated during dissolution. The results described herein support the importance of the combined use of the dissolution-diffusion measurements to determine the maximum level of supersaturation achievable for diverse drug formulations.

Amorphous solid dispersions of enzalutamide and novel polysaccharide derivatives: investigation of relationships between polymer structure and performance.

Amorphous solid dispersion (ASD) is a widely employed formulation technique for drugs with poor aqueous solubility. Polymers are integral components of ASDs, but mechanisms by which polymers lead to the generation and maintenance of supersaturated solutions, which enhance oral absorption in vivo, are poorly understood. Herein, a diverse group of newly synthesized cellulose derivatives was evaluated for their ability to inhibit crystallization of enzalutamide, a poorly soluble compound used to treat prostate cancer. ASDs were prepared from selected polymers, specifically a somewhat hydrophobic polymer that was extremely effective at inhibiting drug crystallization, and a less effective, but more hydrophilic, crystallization inhibitor, that might afford better release. Drug membrane transport rate was evaluated in vitro and compared to in vivo performance, following oral dosing in rats. Good correlation was noted between the in vitro diffusion cell studies and the in vivo data. The ASD formulated with the less effective crystallization inhibitor outperformed the ASD prepared with the highly effective crystallization inhibitor in terms of the amount and rate of drug absorbed in vivo. This study provides valuable insight into key factors impacting oral absorption from enabling ASD formulations, and how best to evaluate such formulations using in vitro approaches.