Interplay of Drug-Polymer Interactions and Release Performance for HPMCAS-Based Amorphous Solid Dispersions.

The interplay between drug and polymer chemistry and its impact on drug release from an amorphous solid dispersion (ASD) is a relatively underexplored area. Herein, the release rates of several drugs of diverse chemistry from hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based ASDs were explored using surface area normalized dissolution. The tendency of the drug to form an insoluble complex with HPMCAS was determined through coprecipitation experiments. The role of pH and the extent of drug ionization were probed to evaluate the role of electrostatic interactions in complex formation. Relationships between the extent of complexation and the drug release rate from an ASD were observed, whereby the drugs could be divided into two groups. Drugs with a low extent of insoluble complex formation with HPMCAS tended to be neutral or anionic and showed reasonable release at pH 6.8 even at higher drug loadings. Cationic drugs formed insoluble complexes with HPMCAS and showed poor release when formulated as an ASD. Thus, and somewhat counterintuitively, a weakly basic drug showed a reduced release rate from an ASD at a bulk solution pH where it was ionized, relative to when unionized. The opposite trend was observed in the absence of polymer for the neat amorphous drug. In conclusion, electrostatic interactions between HPMCAS and lipophilic cationic drugs led to insoluble complex formation, which in turn resulted in ASDs with poor release performance.

Does Media Choice Matter When Evaluating the Performance of Hydroxypropyl Methylcellulose Acetate Succinate-Based Amorphous Solid Dispersions?

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is a weakly acidic polymer that is widely used in the formulation of amorphous solid dispersions (ASDs). While the pH-dependent solubility of HPMCAS is widely recognized, the role of other solution properties, including buffer capacity, is less well understood in the context of ASD dissolution. The goal of this study was to elucidate the rate-limiting steps for drug and HPMCAS release from ASDs formulated with two poorly water soluble model drugs, indomethacin and indomethacin methyl ester. The surface area normalized release rate of the drug and/or polymer in a variety of media was determined. The HPMCAS gel layer apparent pH was determined by incorporating pH sensitive dyes into the polymer matrix. Water uptake extent and rate into the ASDs were measured gravimetrically. For neat HPMCAS, the rate-limiting step for polymer dissolution was observed to be the polymer solubility at the polymer-solution interface. This, in turn, was impacted by the gel layer pH which was found to be substantially lower than the bulk solution pH, varying with medium buffer capacity. For the ASDs, the HPMCAS release rate was found to control the drug release rate. However, both drugs reduced the polymer release rate with indomethacin methyl ester having a larger impact. In low buffer capacity media, the presence of the drug had less impact on release rates when compared to observations in higher strength buffers, suggesting changes in the rate-limiting steps for HPMCAS dissolution. The observations made in this study can contribute to the fundamental understanding of acidic polymer dissolution in the presence and absence of a molecularly dispersed lipophilic drug and will help aid in the design of more in vivo relevant release testing experiments.

Exploring the Role of Surfactants in Enhancing Drug Release from Amorphous Solid Dispersions at Higher Drug Loadings.

To reduce the dosage size of amorphous solid dispersion (ASD)-based formulations, it is of interest to devise formulation strategies that allow increased drug loading (DL) without compromising dissolution performance. The aim of this study was to explore how surfactant addition impacts drug release as a function of drug loading from a ternary ASD, using felodipine as a model poorly soluble compound. The addition of 5% TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate, a surfactant) to felodipine-polyvinylpyrrolidone/vinyl acetate ASDs was found to facilitate rapid and congruent (i.e., simultaneous) release of drug and polymer at higher DLs relative to binary ASDs (drug and polymer only). For binary ASDs, good release was observed for DLs up to <20% DL; this increased to 35% DL with surfactant. Microstructure evolution in ASD films following exposure to 100% relative humidity was studied using atomic force microscopy coupled with nanoscale infrared imaging. The formation of discrete, spherical drug-rich domains in the presence of surfactant appeared to be linked to systems showing congruent and rapid release of drug and polymer. In contrast, a contiguous drug-rich phase was formed for systems without surfactant at higher DLs. This study supports the addition of surfactant to ASD formulations as a strategy to increase DL without compromising release. Furthermore, insights into the potential role of surfactant in altering ASD release mechanisms are provided.

Tocophersolan stabilized lipid nanocapsules with high drug loading to improve the permeability and oral bioavailability of curcumin.

The present investigation highlights the development of D-α-Tocopheryl polyethylene glycol 1000 succinate (Tocophersolan; TPGS) stabilized lipid nanocapsules for enhancing the oral bioavailability and permeability of curcumin (CUR). Lipid nanocapsules were optimized for different lipids, different concentrations of TPGS and different drug: lipid ratio and were further lyophilized. Subsequently, they were characterized by powder X-ray diffraction, Transmission electron microscopy and also evaluated for in vitro release study, Caco-2 cell uptake study, ex vivo intestinal permeability and in vivo pharmacokinetic performance. Optimized lipid nanocapsules exhibited desirable quality attributes (average particle size of 190 nm, polydispersity index of 0.240 and average % entrapment efficiency of 51.06 ±â€¯7.27) employing Maisine™ 35-1 as a lipid carrier, 0.05% TPGS and CUR: lipid ratio of 5:10 and showed sustained release biphasic pattern. They showcased excellent stability in simulated gastrointestinal fluids and storage stability. The CUR nanocapsules exhibited ∼14-fold higher Caco-2 cell uptake and ∼12.8-fold increased ex vivo intestinal permeability. Also, the AUC of CUR nanocapsules in Sprague Dawley rats was increased by ∼12 folds and MRT ∼2.47-folds as compared to aqueous CUR suspension. Thus, lipid nanocapsules possessed a positive impact on improving the permeability and oral bioavailability of CUR.