Advantageous Solubility-Permeability Interplay When Using Amorphous Solid Dispersion (ASD) Formulation for the BCS Class IV P-gp Substrate Rifaximin: Simultaneous Increase of Both the Solubility and the Permeability

Abstract

Rifaximin is a BCS class IV (low-solubility, low-permeability) drug and also a P-gp substrate. The aims of this work were to assess the efficiency of different rifaximin amorphous solid dispersion (ASDs) formulations in achieving and maintaining supersaturation and to investigate the consequent solubility-permeability interplay. Spray-dried rifaximin ASDs were prepared with different hydrophilic polymers and their ability to achieve and maintain supersaturation was assessed. Then, rifaximin's apparent intestinal permeability was investigated as a function of increasing supersaturation both in vitro using the parallel artificial membrane permeability assay (PAMPA) and in vivo using the single-pass rat intestinal perfusion (SPIP) model. The efficiency of the different ASDs to achieve and maintain supersaturation of rifaximin was found to be highly polymer dependent, and the copovidone/HPC-SL formulation was found to be superior to the other two, allowing supersaturation of 200× that of the crystalline solubility for 20 h. In vitro, rifaximin flux was increased and the apparent permeability was constant as a function of increasing supersaturation level. In vivo, on the other hand, absorption rate coefficient (k ) was first constant as a function of increasing supersaturation, but at 250×, the crystalline solubility k was doubled, similar to the k in the presence of the strong P-gp inhibitor GF120918. In conclusion, a new and favorable nature of solubility-permeability interplay was revealed in this work: delivering high supersaturation level of the BCS class IV drug rifaximin via ASD, thereby saturating the drugs' P-gp-mediated efflux transport, led to the favorable unique win-win situation, where both the solubility and the permeability increased simultaneously.

Mechanistic Physiologically Based Pharmacokinetic Modeling of the Dissolution and Food Effect of a Biopharmaceutics Classification System IV Compound—The Venetoclax Story

“…12 Therefore, if GLPS can be maintained in vivo, it may also represent the concentrations that will help overcome other barriers that might be present (e.g., efflux) or represent concentrations that will be available to be taken up by intestinal uptake transporters. 11 Therefore, it is imperative to appropriately account for the maximum available concentrations that can be reached in the GI tract. For venetoclax, the amorphous solubility in pure aqueous conditions was the most relevant measurement to use in the PBPK model for this particular type of clinical/commercial formulation (ASD).…”

“…9,10 The increased solution concentration of the drug provided via its amorphous solubility has been demonstrated to drive flux through epithelial barriers present in the gastrointestinal (GI) tract, typically resulting in higher overall exposures. 11,12 A key factor limiting the utilization of ASDs is physical stability and the potential for crystallization of the drug upon generation of the metastable, supersaturated state in aqueous solution. Drugs with higher molecular weight (such as venetoclax), tend to be slow crystallizers and can remain in the supersaturated state at the amorphous solubility across physiologically relevant time frames in the presence of amorphous drug-rich particles, which serve as reservoirs of absorbable drug.…”

Mechanisms of increased bioavailability through amorphous solid dispersions: a review

“…It can be hypothesized, that by removing the drug-rich particles, the molecularly dispersed concentration dropped to the level of the crystalline solubility, as the increased chemical potential of the amorphous form was missing to maintain the amorphous solubility. In addition to progesterone, a similar study was also carried out with rifaximin, a P-gp substrate, and different polymers (Beig et al, 2017). The authors found that with increasing apparent solubility, the absorption rate constant in vivo only increased only after passing a certain solubility threshold.…”

Segmental-Dependent Intestinal Drug Permeability: Development and Model Validation of In Silico Predictions Guided by In Vivo Permeability Values

“…An interplay between the 2 parameters determines whether the drug moiety will undergo absorption or not. [58][59][60][61][62] Knowing the range of Log p values where the drug is lipophilic enough, but still gets dissolved in the GIT is crucial for absorption. Hence, Log p or some other representation of lipophilicity is included in practically any drug absorption model.…”