Development and characterization of orally disintegrating films of Nebivolol as complex with Sulfobutylether-β-cyclodextrin

Abstract

Low water solubility and extensive hepatic first-pass metabolism limit oral bioavailability of Nebivolol hydrochloride (NEB), a new-generation β-blocker agent effective in hypertension treatment. To overcome such issues, a combined strategy was applied, based on the development of orally disintegrating films (ODFs) loaded with NEB as SBEβCD complex. This approach exploits both the SBEβCD solubilizing power and the fast drug dissolution in the oral cavity provided by ODF. Preformulation studies allowed to select the best combinations of film-forming polymers (PVA in mixture with Na alginate or HPMC) and plasticizer (PEG 400) to obtain ODFs with the desired properties. Loading of selected ODF formulations with NEB-SBEβCD complex significantly increased its dissolution rate: > 50% drug dissolved in simulated saliva after 5’ and 100% in simulated gastric medium within 30’. In contrast, the plain drug achieved only 30% and 70% dissolution, respectively.

This should enhance the drug fraction absorbed in the pre-gastric tract, limiting hepatic first-pass metabolism. Moreover, SBEβCD caused a significant reduction of the film disintegration time, due to the higher water-affinity of the drug-CD complex than free drug. Finally, the drug entrapment within the CD cavity should prevent palatability problems related to drug bitter taste, avoiding addition of flavoring agents.

Introduction

Cardiovascular diseases, and particularly hypertension, currently are among the leading causes of morbidity and mortality worldwide. An efficient monitoring and control of blood pressure is essential in reducing risks and problems related to hypertension and connected diseases or events such as heart attack and stroke (Volpe et al., 2018). Nebivolol hydrochloride (NEB), a new-generation β-blocker drug with high selectivity for β1adrenoceptors, is recognized as particularly effective and well tolerated in hypertension management of patients with heart diseases, reducing blood pressure and improving cardiac function (Fongemie & Felix-Getzik, 2015; Hilas & Ezzo, 2009; Olawi et al., 2019). Nevertheless NEB, available on the market as conventional tablets, exhibits a low/variable oral bioavailability, due to its low water solubility and extensive hepatic first-pass metabolism (Gielen et al., 2006).

Several strategies have been investigated to enhance NEB solubility and consequently its bioavailability. These include solid dispersions (Mude et al., 2021; Raj & Kumar, 2018; Swamiappan & Shaikh, 2023), nanosuspensions (Kiran et al., 2015) , nano- and micro-emulsions (G. Kaur et al., 2021; Sabri & Hussien, 2020), cocrystals (Nikam & Patil, 2020), liquisolid formulations(Sura et al., 2022), micellar solubilization by nonionic surfactants (Keleshovska et al., 2022) or complexation with cyclodextrins (Bhopate & Dhole, 2015; Zhou et al., 2018). This last approach has the advantage of being directly applicable to conventional dosage forms, without the need to develop an appropriate delivery system. This reduces time and production costs, and is particularly attractive in the case of NEB, given its low daily-dose. We recently successfully developed oral conventional tablets of NEB as complex with Sulfobutylether-β-cyclodextrin (SBEβCD) (Maestrelli et al., 2024). Phase solubility studies indicated SBEβCD as the most effective solubilizing/complexing agent for the drug, among the various natural and derivative cyclodextrins tested, showing an AL- type diagram, indicative of the formation of a soluble 1:1 mol:mol complex with a stability constant of 2306 mM-1. The developed tablets allowed to reach 100% dissolved drug at 60 min, compared to 64% of a commercial tablet.

However, despite their widespread use, due to numerous advantages, including manufacture simplicity and low cost, high versatility, ease of administration, good patient acceptance, higher stability and more accurate dosing than oral liquid formulations, conventional tablets also present some drawbacks, such as delayed onset of action, variable/low bioavailability for drugs with extensive first-pass metabolism, and swallowing difficulties. This last issue is particularly important for pediatric and elderly patients, or patients suffering from Parkinson’s disease, dysphasia or mentally disabled or unconscious (Salunke & Tuleu, 2014).

In recent years, to overcome these disadvantages, alternative formulations to conventional tablets have been explored, such as the disintegrating granules (ODGs), multi-particulate dosage forms containing the drug dose fractionated into multiple small granules and packaged into single-dose sachets (Kean & Adeleke, 2023), and the orally disintegrating tablets (ODTs) (Comoglu & Dilek Ozyilmaz, 2019). Both these new dosage forms are characterized by rapid dispersibility within the oral cavity, without the need of water ingestion. Thus, they join the benefits of conventional tablets, i.e. accurate dosing, good stability and high patient compliance, with those of liquid formulations, i.e. simpler administration, shorter onset of action and absence of swallowing issues or choking hazards (Ghourichay et al., 2021). Moreover, their fast dispersion into the oral cavity allows for a partial drug absorption through the oral and pre gastric mucosa, thus enabling a reduction in hepatic first-pass metabolism effects (Comoglu & Dilek Ozyilmaz, 2019; Ghourichay et al., 2021)].

An interesting emerging alternative to ODGs and ODTs is represented by the orally dispersible films (ODFs), consisting of single or multilayered flexible sheets of suitable materials, quickly dissolving/disintegrating in saliva when put in the mouth, resulting in a fast delivery of the drug (Jacob et al., 2023). ODFs are more stable and resistant than ODTs, which have problems of hardness, fragility and friability during production, storage and use and require special packaging for transportation (Cupone et al., 2020; Lee et al., 2017). A further advantage they present with respect to ODGs and ODTs is represented by the large surface area of the film and the presence in their formulation of a mucoadhesive polymer, which provides a more intimate contact with the highly-vascularized oral mucosa. This enhances their ability in favoring the direct drug oromucosal absorption, resulting particularly attractive for drugs presenting high first-pass metabolism (Kaur et al., 2021; Palezi et al., 2023).

Based on these premises, we thought it very interesting to evaluate the development of ODFs of NEB as complex with SBEβCD. In fact, such a combined strategy should be able to overcome both issues limiting NEB oral bioavailability, by increasing its low solubility in virtue of complexation with SBEβCD and reducing its extensive hepatic first-pass metabolism by the ODF formulation. Moreover, the use of NEB as cyclodextrin complex should also avoid eventual palatability problems related to the drug bitter taste, in virtue of the known taste-masking power of cyclodextrins (Adamkiewicz & Szeleszczuk, 2023; Cirri et al., 2024).

In the first part of this work, we performed preformulation studies to select the most suitable polymers to obtain ODFs with the desired properties. With this aim we evaluated the biocompatible, mucoadhesive, hydrophilic polymer polyvinyl alcohol (PVA) as main film former agent in different w/w combinations with sodium alginate and hydroxypropyl-methylcellulose (HPMC), and with polyethylene glycol 400 (PEG 400), selected as plasticizer.

The prepared formulations were evaluated for physical appearance, smoothness, transparency, thickness, mechanical properties and disintegration time. Selected formulations were then loaded with the drug, as such or as complex with SBEβCD, and, in addition to the above-cited analyses, were also characterized for weight and drug content uniformity, surface pH, morphology, moisture % uptake and % content, drug dissolution profile and storage stability.

Download the full article as PDF here Development and characterization of orally disintegrating films of Nebivolol as complex with Sulfobutylether-β-cyclodextrin

or continue reading here

Materials

Nebivolol hydrochloride (NEB) (2,2′-Azanediylbis(1-(6-fluorochroman-2-yl) ethanol) HCl) was gently gifted by Menarini S.p.a. (L’Aquila, Italy). Sulfobutylether-β-cyclodextrin (Dexolve®) (SBEβCD, average substitution degree 6.5) was a kind gift from Cyclolab Ltd. (Budapest, Hungary). Polyvinyl alcohol (PVA, Gohsenol^TMEG05P) was a gift from Mitsubishi Chemical Corporation (Tokyo, Japan). Hydroxypropylmethylcellulose (HPMC, CAS: 9004-65-3, viscosity: 2.600-5.600 cP, 2 % in H2O at 20°C), Alginic acid sodium salt (CAS: 9005-38-3; viscosity 20.000-40.000 cps; M/G ratio∼1.56; molecular weight (Mw)=80-120 kDa) and polyethylene glycol average M_n 400 (PEG 400) were provided by Sigma-Aldrich Lab & Production Materials (Merk Life Science S.r.l. Milan, Italy). Purified water was obtained by Elix Milli-Q® system (Merck-Millipore, Merk Life Science S.r.l. Milan, Italy) was used. All the other chemicals used were of analytical reagent grade. Simulated saliva (SS) fluid (8.00 g/L of NaCl, 0.19 g/L of KH₂PO₄, and 2.38 g/L of Na₂HPO₄) was prepared according to Marques et al.

Marzia Cirri, Silvia Fiani, Francesca Maestrelli, Natascia Mennini, Maria Cristina Salvatici, Paola Mura, Development and characterization of orally disintegrating films of Nebivolol as complex with Sulfobutylether-β-cyclodextrin, Journal of Drug Delivery Science and Technology, 2026, 108043, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2026.108043.

Read also our introduction article on Orally Disintegrating Tablets (ODTs) here: