Compromised in vitro dissolution and membrane transport of multidrug amorphous formulations

Abstract

Herein, the thermodynamic properties of solutions evolving from the non-sink dissolution of amorphous solid dispersions (ASDs) containing two or more drugs have been evaluated, focusing on the maximum achievable supersaturation and tendency of the system to undergo liquid-liquid phase separation (LLPS). Ritonavir (RTV) and atazanavir (ATV) were co-formulated with polyvinylpyrrolidone to produce ASDs with different molar ratios of each drug, and the dissolution profile of each drug was studied under non-sink conditions. The phase behavior of the supersaturated solutions generated by ASD dissolution was compared to that of supersaturated solutions generated by antisolvent addition. Dissolution of an ASD containing RTV, ATV and lopinavir (LPV) was also investigated. A thermodynamic model was used to predict the maximum achievable supersaturation for ASDs containing two and three drugs. In addition, a transport study with Caco-2 cells was conducted to evaluate the impact of co-addition of drugs on membrane transport. It was found that the formulation containing a 1:1 molar ratio of RTV and ATV achieved only 50% of the supersaturation attained by dissolution of the single drug systems. The maximum achievable concentration of ATV decreased linearly as the mole fraction of ATV in the formulation decreased and a similar trend was observed for RTV. For the dispersion containing a 1:1:1 molar ratio of RTV, ATV and LPV, the maximum concentration of each drug was only one third of that achieved for the single drug formulations. The decrease in the achievable supersaturation was well-predicted by the thermodynamic model for both the binary and ternary drug combinations. These observations can be explained by a decrease in the concentration at which the drugs undergo LLPS in the presence of other miscible drugs, thereby reducing the maximum achievable supersaturation of each drug. The reduced free drug concentration was reflected by a decreased flux across Caco-2 cells for the drug combinations compared to drug alone. This study sheds light on the complex dissolution and solution phase behavior of multicomponent amorphous dosage forms, in particular those containing poorly water soluble drugs, which may undergo supersaturation in vivo.

Supersaturating drug delivery systems: The potential of co-amorphous drug formulations

“…Although the reduced maximum achievable supersaturation can be considered a drawback, it may, on the other hand, be advantageous in reducing the driving force for crystallization and thus both of these effects should be considered when evaluating implications for bioavailability. Similar results were obtained for ASDs containing ritonavir and atazanavir and ritonavir, atazanavir and lopinavir at different molar ratios (Alhalaweh et al, 2016). A formulation containing a 1:1 molar ratio of ritonavir and atazanavir achieved only half of the supersaturation attained by dissolution of the single drug systems and, for the ternary dispersion, the maximum concentration of each drug was only one third of that achieved for the single drug ASD formulations.…”

“…This, in turn, decreased the observed flux across Caco-2 cells for the drug combinations compared to drug alone. From these studies it can be concluded that a decrease in maximum achievable supersaturation is likely to be of importance for the dissolution and absorption of multicomponent amorphous dosage forms, particularly those containing combinations of poorly water soluble drugs, which may undergo supersaturation in vivo (Alhalaweh et al, 2016;Trasi and Taylor, 2015b).…”

Impact of Endogenous Bile Salts on the Thermodynamics of Supersaturated Active Pharmaceutical Ingredient Solutions

“…This presumably stems from the mixing of STCDC into the telaprevir drug-rich phase upon GLPS, leading to a reduced activity of telaprevir in the drug-rich phase. 28,29,38,39 For SGCDC (Figure 11d), the maximum achievable supersaturation also decreases in the presence of both monomeric and micellar bile salts, indicating mixing of SGCDC and the telaprevir drug-rich phase. …”

Low Energy Nanoemulsions as Templates for the Formulation of Hydrophobic Drugs

“…It should be noted that amorphous form of a poorly soluble API has higher apparent solubility and improved dissolution rate as compared to its crystalline form since no crystal lattice has to be broken down for dissolution to take place . Though the amorphous form of APIs represents another promising technique to improve the bioavailability of poorly water‐soluble drugs, their stabilization is a major concern . However, in this study, the ibuprofen amorphous particles encapsulated inside the ionic polymer (alginate) hydrogel matrix remain stable for at least 4 months at 25 °C and 60% relative humidity (see the DSC/XRD results in the Supporting Information).…”

“…This is particularly useful since it might be desirable to have a faster dissolution of a particular drug and a slower release of another, or to have faster release of both drugs to optimize the therapeutic efficacy. In fact reports indicate an increasing demand in dosage forms that carry multiple APIs in fixed dose combination . We also build a physical model that successfully explains the dependence of release rate on API nanoparticle size and hydrogel bead size, providing us with a rationale to design systems.…”