The Twofold Advantage of the Amorphous Form as an Oral Drug Delivery Practice for Lipophilic Compounds: Increased Apparent Solubility and Drug Flux Through the Intestinal Membrane

Abstract

Abstract. The purposes of this study were to assess the efficiency of different nifedipine amorphous solid dispersions (ASDs) in achieving and maintaining supersaturation and to investigate the solubilitypermeability interplay when increasing the apparent solubility via ASD formulations. Spray-dried ASDs of nifedipine in three different hydrophilic polymers, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), copovidone, and polyvinylpyrrolidone (PVP), were prepared and characterized by powder X-ray diffraction and differential scanning calorimetry. The ability of these formulations to achieve and maintain supersaturation over 24 h was assessed. Then, nifedipine's apparent intestinal permeability was investigated as a function of increasing supersaturation in the parallel artificial membrane permeability assay model and in the single-pass rat intestinal perfusion model. The efficiency of the different ASDs to achieve and maintain supersaturation of nifedipine was found to be highly polymer dependent; while a dispersion in HPMC-AS enabled supersaturation 20× that of the crystalline aqueous solubility, a dispersion in copovidone enabled 10×, and PVP allowed supersaturation of only 5× that of the crystalline solubility. Nifedipine flux across the intestine from supersaturated solutions was increased, and the apparent intestinal permeability was constant, irrespective of the degree of supersaturation or the polymer being used. In conclusion, while with other solubility-enabling approaches (e.g., surfactants, cyclodextrins, cosolvents), it is not enough to increase the apparent solubility, but to strike the optimal solubility-permeability balance, which limits the chances for successful drug delivery, the amorphous form emerges as a more advantageous strategy, in which higher apparent solubility (i.e., supersaturation) will be readily translated into higher drug flux and overall absorption.

Oral Delivery of Lipophilic Drugs: The Tradeoff between Solubility Increase and Permeability Decrease When Using Cyclodextrin-Based Formulations

“…These opposing effects on apparent solubility and permeability must be taken into account in order to fully understand the impact on the overall fraction of drug absorbed when solubility-enabling formulations are employed to enhance the oral exposure of a poorly soluble drug. We have recently revealed that the solubility-permeability tradeoff can be circumvented by using amorphous solid dispersions that increase the apparent solubility of the drug by supersaturation (and not solubilization), provided substantial supersaturation can be achieved and maintained [39], [40]. However, the development and manufacture of these solubility enabling formulations are much more challenging.…”

Enhancements and Limits in Drug Membrane Transport Using Supersaturated Solutions of Poorly Water Soluble Drugs

“…Although most of the studies on the relationship between membrane transport and supersaturation have been in the context of transdermal delivery, there is an increasing interest in exploiting supersaturated solutions to enhance oral absorption. Recent studies have demonstrated enhanced flux across intestinal membranes when perfused with supersaturated solutions . However, the impact of the colloidal species generated in highly supersaturated solutions has not been fully evaluated to date.…”

Head-To-Head Comparison of Different Solubility-Enabling Formulations of Etoposide and Their Consequent Solubility–Permeability Interplay

“…This solubility–permeability tradeoff was shown in several settings, including cases in which the increased solubility is accompanied by decreased free fraction that can explain the decreased permeability, but also in cases that do not involve decreased free fraction of the drug . It was recently discovered that this tradeoff can be overcome by using the amorphous form of the drug for solubility enhancement via supersaturation …”