Enteric Polymer–Based Amorphous Solid Dispersions Enhance Oral Absorption of the Weakly Basic Drug Nintedanib via Stabilization of Supersaturation

Abstract

The pH–induced crystallization of weakly basic drugs in the small intestine limits oral bioavailability. In this study, we investigated the solubilization and inhibitory effects on nintedanib in the presence of enteric polymers (HPMCAS LG, HPMCAS MG, Eudragit L100 55, and Eudragit L100). These polymers provided maintenance of supersaturation by increasing the solubility of nintedanib in PBS 6.8 in a concentration–dependent manner, and the improved ranking was as follows: Eudragit L100 > Eudragit L100 55 > HPMCAS MG > HPMCAS LG. After being formulated into amorphous solid dispersions (ASDs) by a solvent evaporation method, the drug exhibited an amorphous state. The pH shift dissolution results of polymer–ASDs demonstrated that four polymers could effectively maintain the drug supersaturation even at the lowest ratio of nintedanib and polymer (1:1, w/w). Eudragit L100–ASD could provide both acid resistance and the favorable mitigation of crystallization in GIF. In comparison to the coarse drug, the relative bioavailability of Eudragit L100–ASD was 245% after oral administration in rats, and Tmax was markedly delayed from 2.8 ± 0.4 h to 5.3 ± 2.7 h. Our findings indicate that enteric ASDs are an effective strategy to increase the intestinal absorption of nintedanib by improving physiologically generated supersaturation and subsequent crystallization.

Hot-Melt Extrusion as an Effective Technique for Obtaining an Amorphous System of Curcumin and Piperine with Improved Properties Essential for Their Better Biological Activities

“…Furthermore, after oral administration, systems demonstrated higher AUC and Cmax than the raw drug. Qin et al then used a solvent evaporation method to create amorphous dispersions of nintedanib [29]. Their work showed that the addition of a polymer to amorphous systems delays or inhibits precipitation and crystallization, thus contributing to the remaining supersaturation.…”

Effect of Drug–Polymer Interaction in Amorphous Solid Dispersion on the Physical Stability and Dissolution of Drugs: The Case of Alpha-Mangostin

“…AM was used as a model of a poorly water-soluble drug because it is a potentially active compound used as an antitumor treatment which has a low water solubility, leading to low oral bioavailability. Meanwhile, polyvinylpyrrolidone (PVP) [ 20 , 21 ] and eudragit were used as polymers because they have been widely utilized in ASD and showed good ability in drug crystallization inhibition either after storage or dispersion in water [ 22 , 23 ]. Lehmkemper et al reported that the presence of PVP can improve the physical stability of amorphous naproxen and acetaminophen [ 20 ].…”

Solubility Enhanced Formulation Approaches to Overcome Oral Delivery Obstacles of PROTACs

“…It is well-known that the polymer-induced solubility enhancement and supersaturation stabilization of an API depend on intermolecular interactions between the API and the polymer. Therefore, functional groups of the polymers play a key role in maintaining the supersaturated state [ 39 ]. For cellulose derivatives, it has been reported that a moderate level of hydrophobicity provides optimal polymer properties, as hydrophobic interactions are decisive for precipitation inhibition [ 26 , 40 ].…”