A Win–Win Solution in Oral Delivery of Lipophilic Drugs: Supersaturation via Amorphous Solid Dispersions Increases Apparent Solubility without Sacrifice of Intestinal Membrane Permeability

Abstract

Recently, we have revealed a trade-off between solubility increase and permeability decrease when solubility-enabling oral formulations are employed. We have shown this trade-off phenomenon to be ubiquitous, and to exist whenever the aqueous solubility is increased via solubilizing excipients, regardless if the mechanism involves decreased free fraction (cyclodextrins complexation, surfactant micellization) or simple cosolvent solubilization. Discovering a way to increase drug solubility without concomitant decreased permeability represents a major advancement in oral delivery of lipophilic drugs and is the goal of this work. For this purpose, we sought to elucidate the solubility-permeability interplay when increased apparent solubility is obtained via supersaturation from an amorphous solid dispersion (ASD) formulation. A spray-dried ASD of the lipophilic drug progesterone was prepared in the hydrophilic polymer hydroxypropyl methylcellulose acetate succinate (HPMC-AS), which enabled supersaturation up to 4× the crystalline drug's aqueous solubility (8 μg/mL). The apparent permeability of progesterone from the ASD in HPMC-AS was then measured as a function of increasing apparent solubility (supersaturation) in the PAMPA and rat intestinal perfusion models. In contrast to previous cases in which apparent solubility increases via cyclodextrins, surfactants, and cosolvents resulted in decreased apparent permeability, supersaturation via ASD resulted in no decrease in apparent permeability with increasing apparent solubility. As a result, overall flux increased markedly with increasing apparent solubility via ASD as compared to the other formulation approaches. This work demonstrates that supersaturation via ASDs has a subtle yet powerful advantage over other solubility-enabling formulation approaches. That is, increased apparent solubility may be achieved without the expense of apparent intestinal membrane permeability. Thus, supersaturation via ASDs presents a markedly increased opportunity to maximize overall oral drug absorption.

Dissolution behavior of co-amorphous amino acid-indomethacin mixtures: The ability of amino acids to stabilize the supersaturated state of indomethacin

“…Converting a crystalline material into an amorphous form is one of the most promising ways to improve apparent solubility, since the maximum concentrations in solution achieved with the amorphous form may be significantly higher due to its higher internal energy than with its crystalline counterpart [9][10][11][12]. Furthermore, the increased apparent solubility does not decrease the drug's permeability through intestinal wall [13][14][15]. Unfortunately, the greater internal energy and molecular movement of the amorphous form may also cause the material to convert spontaneously back to its crystalline form during processing, storage or dissolution.…”

Stabilisation of amorphous furosemide increases the oral drug bioavailability in rats

“…In the literature, it is reported that a glass solution will not influence on the permeability properties of a drug (Miller et al, 2012), and therefore it is believed that the in vivo data can be interpreted based on the dissolution data. Figure 5 shows the mean plasma concentration versus time profiles for the two ASSF formulations, and the noncompartmental pharmacokinetic parameters are provided in Table 2.…”

Regional-Dependent Intestinal Permeability and BCS Classification: Elucidation of pH-Related Complexity in Rats Using Pseudoephedrine

“…The equilibrium solubility of the drug was determined at both 37°C and at room temperature (25°C), in phosphate buffer at pH 7.5, acetate buffer at pH 4.5, and maleate buffer at pH 1.0, using the shake-flask method, as previously reported (15)(16)(17). Briefly, excess amounts of pseudoephedrine were added to glass vials containing the different buffers.…”