Development of Oral Tablets of Nebivolol with Improved Dissolution Properties, Based on Its Combinations with Cyclodextrins
Abstract
Introduction
Hypertension is considered as a major public health concern, being one of the leading causes of morbidity and mortality in the current world population [1]. The effective control of blood pressure is fundamental in hypertension management, to decrease the risks of hypertension-related pathologies and death [2]. Nebivolol hydrochloride (NEB) is a third-generation highly-selective β1-adrenergic receptor antagonist particularly recommended in the treatment of hypertension [3,4,5,6] and it is available on the market as tablets. Beneficial effects of NEB in the prevention and treatment of diabetic neuropathy have also been reported [7]. NEB has been classified as a Class II drug according to the biopharmaceutical classification system (BCS), and it is characterized by a high membrane permeability but a poor solubility and dissolution rate. Unfortunately, despite its favorable partition coefficient value, it presents problems of poor and variable oral bioavailability, mainly related to its low aqueous solubility [5,8].
A variety of formulation approaches has been explored to improve NEB solubility, and then enhance its clinical efficacy, including the development of solid dispersions with hydrophilic polymers [9,10] nanosuspension tablets [11], immediate-release tablets [12], nanofibrous sheets [13], solidified self-nanoemulsions [14], cocrystals [15], microemulsions [16] and liquisolid compacts [17]. Cyclodextrin (CD) complexation is another method widely applied to enhance the solubility and bioavailability of poorly soluble drugs [18,19]. CDs are cyclic oligosaccharides characterized by their particular structure composed by an internal hydrophobic cavity and an external hydrophilic surface, enabling them to form stable complexes with a variety of hydrophobic molecules [20]. Natural and chemically modified CDs have been largely used in the pharmaceutical field in virtue of their ability to form inclusion complexes with hydrophobic drug molecules, improving their water solubility, stability and bioavailability and decreasing their side effects [21,22]. However, the effectiveness of such a strategy towards NEB has been very scarcely explored to date [23,24], and the design and development of dosage forms containing NEB as CD complex has never yet been investigated. On the contrary, also considering its low daily dosage, NEB appears as an ideal candidate for such a strategy, which is also applicable to conventional dosage forms, without requiring the development of appropriate delivery systems, thus further being particularly attractive to reduce time and production costs.
Therefore, the purpose of this study was to exploit CD complexation to develop more effective conventional oral tablets of NEB, endowed with improved drug dissolution properties. With this aim, an initial screening based on phase-solubility studies was performed to evaluate the solubilizing and complexing power towards the drug of native βCD and some highly-soluble βCD-derivatives, in order to select the most effective partner for NEB. Native βCD was selected, since, despite the limits due to its relatively low water solubility, it is until now the most largely used CD, its cavity being suitable for accommodating a large variety of drugs. As for the hydrosoluble βCD-derivatives, methyl-βCD was selected for its highest aqueous solubility, while hydroxypropyl-βCD and particularly sulfobutylether-βCD were chosen considering not only their good water solubility, but also their complete absence of toxicity, being the only βCD-derivatives also allowed for parenteral use [25,26].
Solid drug–CD binary systems were then prepared with the selected CDs, evaluating and comparing the efficacy of different preparation methods (grinding, kneading and coevaporation). The solid-state features of the various binary systems were investigated by differential scanning calorimetry and X-ray powder diffraction analyses and their dissolution performance was compared to that of the simple physical mixtures and the pure drug. The best product was finally selected for the development of conventional tablets, which were characterized for technological properties according to the Eur. Pharmacopoeia tests, and tested for dissolution properties in comparison with an NEB commercial tablet.
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Materials
Nebivolol HCl (NEB) (2,2′-Azanediylbis(1-(6-fluorochroman-2-yl) ethanol) hydrochloride) was a kind gift from Menarini S.p.a. (L’Aquila, Italy). Beta-cyclodextrin (βCD) was from Sigma (St. Louis, MO, USA). Hydroxypropyl-βCD (HPβCD, average substitution degree 0.62) was kindly supplied by Roquette (Lestrem, France), and sulfobutylether-βCD (Dexolve®) (SBEβCD, average substitution degree 6.5) was a kind gift from Cyclolab Ltd. (Budapest, Hungary). Randomly substituted methyl-βCD (RAMEB, average substitution degree 1.8) was from Wacker Chemie (München, Germany). Explotab® (sodium starch glycolate) was from JRS Pharma (Rosenberg, Germany), and Mg stearate, polyvinylpyrrolidone (PVP) K90, mannitol and CaHPO4 were from Sigma (St. Louis, MO, USA). All other chemicals and solvents were of analytical reagent grade.
Maestrelli, F.; Cirri, M.; Mennini, N.; Fiani, S.; Stoppacciaro, B.; Mura, P. Development of Oral Tablets of Nebivolol with Improved Dissolution Properties, Based on Its Combinations with Cyclodextrins. Pharmaceutics 2024, 16, 633. https://doi.org/10.3390/pharmaceutics16050633
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