Formulation and investigation of differently charged β-cyclodextrin-based meloxicam potassium containing nasal powders
Abstract
Introduction
Alternative drug delivery routes have gained attention as the absorption of several orally administered drug may not be satisfying e.g., due to their enzymatic deactivation or as parenteral dosing is inconvenient for the patients and provides a higher risk of infections (Mathias and Hussain, 2010; Mathias and Sridharan, 2017).
The nasal route may be a good alternative to the aforementioned paths. Most commonly, it is used for the treatment of local nasal conditions (e.g., allergic symptoms, rhinitis), even so systemic or central nervous system effects can be also achieved. The relatively large surface area and the high vascularity of the nasal mucosa enable a rapid onset of action of the administered active pharmaceutical ingredients (APIs) while avoiding the first-pass hepatic metabolism. Since, it is a non-invasive, painless administrational route, improved patient compliance can be expected (Laffleur and Bauer, 2021; Mato, 2019; Keller et al., 2022).
Despite the benefits, there are challenges to tackle as well when applying a product in systemic indication. One of the main drawbacks of drug absorption is the selective permeability of the mucosa. Drugs greater than 1 kDa cannot penetrate: on the one hand, they should be water-soluble enough to dissolve in the nasal fluid, on the other hand lipophilic enough to be absorbed (Mato, 2019; Behl et al., 1998). Permeation/solubility enhancers may help to overcome this problem and improve the bioavailability of the APIs (Kaneko et al., 2020).
Cyclodextrins (CDs) are frequently used for this purpose because they affect the membrane fluidity and permeability via their interaction with the components of the biological membranes. β-cyclodextrins – the most popular group of CDs regarding pharmaceutical formulations (Kurkov and Loftsson, 2013) – are said to extract mainly cholesterol from these membranes (Hammoud et al., 2019). They have been applied in a number of studies aimed at the nasal delivery of APIs (Rassu et al., 2021). Baqsimi™, a nasal dry powder formulation has already been marketed, which contains β-CD for the permeation enhancement of glucagon for diabetic patients (Anon). Moreover, CDs are capable of forming inclusion complexes by entrapping drug molecules in their cavities resulting in an increased solubility of the active substances and acceleration of their dissolution (Kim et al., 2020). The charge of the CD and its substrate may have an influence on the complexation. When only one of them has a charge, less stable complexes may be formed. When both of them have a charge, attractive or repulsive forces can appear whether counter ions or oppositely charged molecules are present affecting the strength of interaction (Zia et al., 2001; Jansook et al., 2018; Stella, 1999). Charge might be a remarkable factor to the adhesion of the materials as well, since, among various mechanisms, chemical interactions – including ionic – can facilitate bioadhesion (Palacio and Bhushan, 2012).
Another challenge in nasal systemic drug delivery is the drug residence time prolongation, which is negatively affected by the mucociliary clearance that causes the rejuvenation of the nasal mucus in every 15–20 min (Marttin et al., 1998).
Water soluble or mucoadhesive polymers can extend the contact of the API because they form a viscous gel-like matrix after interacting with the nasal fluid or mucosa slowing the ciliary movement (Javia et al., 2021; Ugwoke et al., 2005). Besides, due to their solubilizing and stabilizing effect, they can enhance the complexation efficiency when they are added to CD-containing systems (Loftsson and Brewster, 2012; Loftsson and Másson, 1999). However, their optimal concentration in the formulations should be considered as disturbing excessively the natural defense mechanism of the nose may result in local pathological conditions and highly viscous environment hinders drug release (Harris et al., 1989). (Polyvinyl)alcohol could be used for these purposes, because it is a water soluble, biodegradable polymer which has been shown to be able to increase the solubilization when applying in CD-containing systems (Soe et al., 2023).
There may be differences in the residence time of dosage forms as well. Powder formulations are forwarded slower towards the nasopharynx than liquid formulations allowing of improved absorption of the active agents. Besides, they are more stable due to their low moisture content therefore there is no need for the use of preservatives during their production which are often irritating (Hussein et al., 2020).
Spray drying is a well-known, common method to obtain dry powders in one step from liquid feed (Malamatari et al., 2020). It permits of producing particles with regulated morphology, flowability and size in the micro- or nano-range. The products may provide an improved and/or controlled dissolution of the incorporated APIs depending on the process parameters and the composition of the initial solution (Baldelli et al., 2022; Gradon and Sosnowski, 2014; Vehring, 2008).
Nasal systemic delivery of nonsteroidal anti-inflammatory drugs (NSAIDs) may be an innovative way of treating acute or chronic, severe pain. Although, currently only one NSAID-containing nasal product is available on the market. Mainly, opioids (e. g., morphine, fentanyl) and triptans (e. g., sumatriptan, zolmitriptan) have been studied for managing cancer pain and migraine, some of them have been marketed in a form of nasal spray or powder formulation (Fortuna et al., 2014; Costantino et al., 2007). In our previous research works, NSAIDs, namely meloxicam and meloxicam potassium monohydrate have been studied extensively. Liquid and powder formulations were prepared for nasal administration with the purpose of delivering the APIs to the systemic circulation or the central nervous system. Different techniques and excipients were applied in order to improve their dissolution and permeability properties (Varga et al., 2021; Bartos et al., 2021; Bartos et al., 2018; Horváth et al., 2016).
This work aimed to produce differently charged β-CD containing meloxicam potassium particles applying a nano spray dryer for systemic pain relieving, which has not been carried out before to the best of our knowledge. Charged CDs may have special complexing properties and may interact with the negatively charged nasal mucosa, therefore they might have a significant impact on the properties of the formulations (Rassu et al., 2020). To study their effect, the physicochemical characterization, mucoadhesivity, in vitro dissolution and permeability of the API through an artificial membrane and RPMI 2650 cells as well were tested. We also intended to observe whether the addition of (polyvinyl)alcohol had any impact on the properties, thus the nasal applicability of the samples.
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Materials
Meloxicam potassium monohydrate (MXP) was obtained from EGIS Ltd. (Budapest, Hungary) and (polyvinyl)alcohol (PVA) was from Sigma Aldrich (Sigma Aldrich Co. LLC, St. Louis, MO, USA). 3 differently charged CDs – neutral beta-cyclodextrin (BCD), anionic sulfobutylated-beta-cyclodextrin sodium salt (SBECD; DS∼6) and cationic (2-hydroxy-3-N,N,N-trimethylamino) propyl-beta-cyclodextrin chloride (QABCD) were from CycloLab Ltd. (Budapest, Hungary).
Patrícia Varga, Anett Németh, Scarlett Zeiringer, Eva Roblegg, Mária Budai-Szűcs, Csilla Balla-Bartos, Rita Ambrus,
Formulation and investigation of differently charged β-cyclodextrin-based meloxicam potassium containing nasal powders, European Journal of Pharmaceutical Sciences, Volume 202, 2024, 106879, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2024.106879.
