Co-Amorphous Formulations of Furosemide with Arginine and P-Glycoprotein Inhibitor Drugs.

Marika Ruponen,Konsta Kettunen,Riikka Laitinen,Monica Santiago Pires

doi:10.3390/pharmaceutics13020171

Marika Ruponen, Konsta Kettunen + Show 2 more

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https://doi.org/10.3390/pharmaceutics13020171

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Abstract

In this study, the amino acid arginine (ARG) and P-glycoprotein (P-gp) inhibitors verapamil hydrochloride (VER), piperine (PIP) and quercetin (QRT) were used as co-formers for co-amorphous mixtures of a Biopharmaceutics classification system (BCS) class IV drug, furosemide (FUR). FUR mixtures with VER, PIP and QRT were prepared by solvent evaporation, and mixtures with ARG were prepared by spray drying in 1:1 and 1:2 molar ratios. The solid-state properties of the mixtures were characterized with X-ray powder diffraction (XRPD), Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) in stability studies under different storage conditions. Simultaneous dissolution/permeation studies were conducted in side-by-side diffusion cells with a PAMPA (parallel artificial membrane permeability assay) membrane as a permeation barrier. It was observed with XRPD that ARG, VER and PIP formed co-amorphous mixtures with FUR at both molar ratios. DSC and FTIR revealed single glass transition values for the mixtures (except for FUR:VER 1:2), with the formation of intermolecular interactions between the components, especially salt formation between FUR and ARG. The co-amorphous mixtures were found to be stable for at least two months under an elevated temperature/humidity, except FUR:ARG 1:2, which was sensitive to humidity. The dissolution/permeation studies showed that only the co-amorphous FUR:ARG mixtures were able to enhance both the dissolution and permeation of FUR. Thus, it is concluded that formulating co-amorphous salts with ARG may be a promising option for poorly soluble/permeable FUR.

Highlights

During drug development, molecules categorized under the Biopharmaceutics classification system (BCS) as class IV, i.e., those compounds that show both insufficient solubility and problems in membrane permeability and/or active cellular efflux across intestinal membranes, are the most difficult from the oral formulation point of view [1]
When selecting the preparation methods for amorphous formulations of FUR, it should be considered that FUR experiences thermal decomposition upon melting [17], it is poorly water soluble [18], and it is degradable upon milling [19,20]
It was observed by differential scanning calorimetry (DSC) that FUR was miscible with verapamil hydrochloride (VER) and PIP with 1:1 and 1:2 molar ratios, showing common and lowered melting temperatures

Summary

Introduction

Molecules categorized under the Biopharmaceutics classification system (BCS) as class IV, i.e., those compounds that show both insufficient solubility and problems in membrane permeability and/or active cellular efflux across intestinal membranes, are the most difficult from the oral formulation point of view [1]. In this study, we aimed to address these challenges from the point of view of formulation in a more widely applicable way, i.e., by synergistically combining solubility/dissolution enhancement with permeation enhancement by adopting a co-amorphous approach to promoting the bioavailability of the most difficult-to-deliver compounds, i.e., class IV drugs. Mixtures of an active molecule and an excipient (e.g., an amino acid) can offer more general formulation options [8,9]. By both approaches, enhanced dissolution properties for poorly soluble drugs, as compared

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