Combinations of Freeze-Dried Amorphous Vardenafil Hydrochloride with Saccharides as a Way to Enhance Dissolution Rate and Permeability.

Gabriela Wiergowska,Andrzej Miklaszewski,Kamil Wdowiak,Dominika Ludowicz,Judyta Cielecka-Piontek,Kornelia Lewandowska

doi:10.3390/ph14050453

Abstract

To improve physicochemical properties of vardenafil hydrochloride (VAR), its amorphous form and combinations with excipients—hydroxypropyl methylcellulose (HPMC) and β-cyclodextrin (β-CD)—were prepared. The impact of the modification on physicochemical properties was estimated by comparing amorphous mixtures of VAR to their crystalline form. The amorphous form of VAR was obtained as a result of the freeze-drying process. Confirmation of the identity of the amorphous dispersion of VAR was obtained through the use of comprehensive analysis techniques—X-ray powder diffraction (PXRD) and differential scanning calorimetry (DSC), supported by FT-IR (Fourier-transform infrared spectroscopy) coupled with density functional theory (DFT) calculations. The amorphous mixtures of VAR increased its apparent solubility compared to the crystalline form. Moreover, a nearly 1.3-fold increase of amorphous VAR permeability through membranes simulating gastrointestinal epithelium as a consequence of the changes of apparent solubility (Papp crystalline VAR = 6.83 × 10−6 cm/s vs. Papp amorphous VAR = 8.75 × 10−6 cm/s) was observed, especially for its combinations with β-CD in the ratio of 1:5—more than 1.5-fold increase (Papp amorphous VAR = 8.75 × 10−6 cm/s vs. Papp amorphous VAR:β-CD 1:5 = 13.43 × 10−6 cm/s). The stability of the amorphous VAR was confirmed for 7 months. The HPMC and β-CD are effective modifiers of its apparent solubility and permeation through membranes simulating gastrointestinal epithelium, suggesting a possibility of a stronger pharmacological effect.

Highlights

Vardenafil hydrochloride (VAR) is a selective phosphodiesterase V (PDE-5) inhibitor that exhibits vasodilatory activity [1,2]
In order to assess the impact of physical modification of vardenafil hydrochloride (VAR) form, we estimated the changes in physicochemical properties such as dissolution rate and permeability in regards to the crystalline form of the drug
The amorphous VAR was obtained using freeze-drying, and its amorphous character was confirmed by X-ray powder diffraction (PXRD) and differential scanning calorimetry (DSC), supported by FT-IR spectroscopy, coupled with density functional theory (DFT) calculations

Summary

Introduction

Vardenafil hydrochloride (VAR) is a selective phosphodiesterase V (PDE-5) inhibitor that exhibits vasodilatory activity [1,2]. VAR has a comparable but slightly prolonged duration of pharmacological effect with regards to sildenafil—the first PDE-5 inhibitor used to treat erectile dysfunction. It is recommended to take VAR about one hour before intercourse, but patients can use it from 30 min to 2 h before sexual activity, as the medication requires sexual stimulation for effectiveness [5]. VAR is reported to be a very potent and highly selective inhibitor of PDE-5, which inhibits. This selectivity prevents adverse effects, which sometimes occur with sildenafil, and ensures no VAR impact on visual acuity and color perception [6]

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Conclusion