Discovery of dronedarone and its analogues as NLRP3 inflammasome inhibitors with potent anti-inflammation activity.

Inhibiting NLRP3 inflammasome activation is a prospective therapeutic strategy for uncontrolled inflammatory diseases. It is the first time that dronedarone, a multiply ion channel blocker, was identified as a NLRP3-inflammasome inhibitor with an IC50 value of 6.84 µM against IL-1ß release. A series of novel 5-amide benzofuran derivatives were designed and synthesized as NLRP3-inflammasome inhibitors. Compound 8c showed slightly increased activity (IC50 = 3.85 µM) against IL-1ß release. Notably, treatment with 8c could significantly inhibit NLRP3-mediated IL-1ß release and ameliorate peritoneal inflammation in a mouse model of sepsis. Collectively, 8c is a promising lead compound for further chemical development as a NLRP3 inhibitor with anti-inflammation effects.

In vitro behavior of dronedarone hydrochloride loaded pellets using vacuum impregnation technique.

Pharmaceutical pellets are a versatile and adaptable drug carrier system with pharmacological and technological advantages specific to multiparticulate delivery systems. Depending on their porosity and formulation procedure, a controlled drug release pattern can be achieved using a variety of pellet production and drug loading techniques. In the present paper, we have developed microcrystalline cellulose based porous pellets by extrusion/spheronization process. Two types of dronedarone hydrochloride suspensions were prepared in order to load drug onto carrier pellets using vacuum impregnation method. Despite its extensive use in the biomedical field of research, this technique hasn't been applied yet as means of incorporating drugs into inert and porous pellets. In addition, drug release control was tested by spray coating the pellets with hydroxypropyl methylcellulose in a fluidized bed. Pellet morphology, porosity and dissolution behavior were determined and the results indicate that DNR particle size affects the drug incorporation mechanism and, therefore, drug release patterns obtained through in vitro tests. Additionally, it was proven that polymer-based film-coat significantly slows down the drug release from the pellets. In vitro studies of the coated pellets in biorelevant fluids have shown that DNR release profiles are directly related to the type of dissolution media used. Vacuum impregnation was found to be promising technique for incorporation of DNR onto the surface of the porous pellets and into their pores.

An exploratory analysis of effects of poyendarone, a deuterated analogue of dronedarone, on the canine model of paroxysmal atrial fibrillation.

Poyendarone, a deuterated analogue of dronedarone, is expected to reduce the onset of cardiovascular adverse events of dronedarone, including congestive heart failure and excessive QT-interval prolongation. Since information is still lacking on the anti-atrial fibrillatory property of poyendarone, we assessed it along with effects on the inter-atrial conduction time (IACT) and atrial effective refractory period (AERP) using the canine paroxysmal atrial fibrillation model. Poyendarone hydrochloride (n = 4) and dronedarone hydrochloride (n = 4) in intravenous doses of 0.3 and 3 mg/kg/30 s were cumulatively administered. Poyendarone hardly altered sinoatrial rate, but dronedarone decreased it in a dose-related manner, whereas both drugs slightly but significantly reduced idioventricular rate. Poyendarone shortened duration of burst pacing-induced atrial fibrillation, whereas such abbreviation was not observed by dronedarone. Poyendarone and dronedarone similarly prolonged IACT in a frequency-dependent manner, indicating that their INa inhibitory actions may be similar. The high dose of poyendarone prolonged AERP in a reverse frequency-dependent manner, extent of which at basic pacing cycle lengths of 300 and 400 ms was comparable to that of dronedarone. However, the extent at a basic pacing cycle length of 200 ms was tended to be greater in poyendarone than in dronedarone, suggesting greater IKs inhibitory action of poyendarone. The deuteration of dronedarone attenuated the inhibition of sinus automaticity and prolonged the AERP with keeping the blood pressure and ventricular rate stable. Thus, poyendarone may have both more potent anti-atrial fibrillatory action and wider cardiovascular safety margin than dronedarone.

Dronedarone blockage of the tumor-related Kv10.1 channel: a comparison with amiodarone.

Kv10.1 (Eag1, or KCNH1) is a human potassium-selective channel associated with tumor development. In this work, we study the interaction of the drug dronedarone with Kv10.1. Dronedarone presents two chemical modifications aimed to lessen side effects produced by its parent molecule, the antiarrhythmic amiodarone. Hence, our observations are discussed within the framework of a previously reported interaction of amiodarone with Kv10.1. Additionally, we show new data regarding the interaction of amiodarone with the channels. We found that, unexpectedly, the effect of dronedarone on Kv10.1 differs both quantitatively and qualitatively to that of amiodarone. Among other observations, we found that dronedarone seems to be an open-pore blocker, in contrast to the reported behavior of amiodarone, which seems to inhibit from both open and closed states. Additionally, herein we provide evidence showing that, in spite of their chemical similarity, these molecules inhibit the K+ conductance by binding to non-overlapping, independent (non-allosterically related) sites. Also, we show that, while amiodarone inhibits the Cole-Moore shift, dronedarone is unable to inhibit this voltage-dependent characteristic of Kv10.1.

Preparation of Filaments and the 3D Printing of Dronedarone HCl Tablets for Treating Cardiac Arrhythmias.

The production of 3D-printed dosage forms requires the preparation of high-quality filaments containing an active pharmaceutical ingredient (API). The objective of this research is to prepare filaments containing dronedarone hydrochloride, a drug used in the treatment of cardiac arrhythmias. Filaments and 3D-printed tablets were subjected to characterization methods in order to prove and ensure the stability of the API and preservation of the drug content. Blends containing different proportions of dronedarone hydrochloride (DNR), polyethylene glycol (PEG), and polyvinyl alcohol filament (PVA) were prepared in two forms: as a powder mixture and as a solid dispersion. Thermogravimetric analysis was conducted, and the thermal properties of the components and polymer blends were tested using differential scanning calorimetry. Hot melt extrusion at 170 °C was used to prepare the filaments, and the fused deposition modeling technique was employed to print tablets. Drug release profiles were obtained by in vitro tests. The results indicate that the mixture containing 10 wt.% of polyethylene glycol prepared as a solid dispersion exhibits the most straightforward structure and shows only the slightest deviation from the target filament diameter. The compact structure of the tablet obtained from the filament provides a uniform in vitro drug release over a 24-h period. It also shows the smallest aberration from the expected DNR content in the tablet. The paper demonstrates that a blend containing 10 wt.% of PEG, 10 wt.% of DNR, and 80 wt.% of PVA filament is the most appropriate formula for extrusion and tablet printing.

Solid Lipid Nanoparticles of Dronedarone Hydrochloride for Oral Delivery: Optimization, In Vivo Pharmacokinetics and Uptake Studies.

BACKGROUND: Dronedarone HCl (DRD), owing to its poor aqueous solubility and extensive presystemic metabolism shows low oral bioavailability of about 4% without food, which increases to approximately 15% when administered with a high fat meal. OBJECTIVE: Solid lipid nanoparticles (SLN) were designed with glyceryl monstearate (GMS) in order to improve oral bioavailability of DRD. METHODS: Hot homogenization followed by probe sonication was used to prepare SLN dispersions. Box-Behnken design was used to optimize manufacturing conditions. SLN were characterized for particle size, zeta potential, entrapment efficiency, physical state and in vitro drug release. Pharmacokinetics and intestinal uptake study of dronedarone HCl loaded solid lipid nanoparticles (DRD-SLN) in the presence and absence of endocytic uptake inhibitor, chlorpromazine (CPZ) was performed with conscious male Wistar rats. RESULTS: Optimized formulation of SLN showed particle size of 233 ± 42 nm and entrapment efficiency of 87.4 ± 1.29%. Results of pharmacokinetic studies revealed enhancement of bioavailability of DRD by 2.68 folds from SLN as compared to DRD suspension. Significantly reduced bioavailability of DRD-SLNs in the presence of chlorpromazine, demonstrated the role of endocytosis in uptake of SLN formulation. CONCLUSION: These results indicated that dronedarone HCl loaded SLN could potentially be exploited as a delivery system for improving oral bioavailability by minimizing first pass metabolism.

Formulation of Dronedarone Hydrochloride-Loaded Proliposomes: In Vitro and In Vivo Evaluation Using Caco-2 and Rat Model.

The objective of the present study was to develop a proliposomal formulation to increase the oral bioavailability of dronedarone hydrochloride (dronedarone HCl) by enhancing solubility, dissolution, and/or intestinal absorption. Proliposomes were prepared by using solvent evaporation method. In this process, different ratios of drug, phospholipids, such as soy phosphatidylcholine (SPC), Phospholipon 90H, hydrogenated egg phosphatidylcholine (HEPC), and dimyristoyl phosphatidylglycerol (DMPG), and cholesterol were used. Physical characterization and in vitro dissolution studies were evaluated for the prepared formulations. In vitro transport across the membrane was carried out using Caco-2 cells. Among all the formulations, the amount of drug released in dissolution was higher with DPF8 formulation (drug:DMPG Na:cholesterol:::1:2:0.2) compared to the pure drug. Also, Caco-2 cell permeability studies resulted in 2.6-fold increase in apparent permeability. Optimized formulation was evaluated in vivo in male Sprague-Dawley rats. After single oral administration of optimized formulation (DPF8), a relative bioavailability of 148.36% was achieved compared to the pure drug. Improved oral bioavailability of dronedarone could be provided by an optimized proliposomal formulation with enhanced solubility, permeability, and oral absorption.

Comparative evaluation of the hepatotoxicity, phototoxicity and photosensitizing potential of dronedarone hydrochloride and its cyclodextrin-based inclusion complexes.

In this study, the hepatotoxicity, phototoxicity and photosensitizing potential of free dronedarone (DRO) and its inclusion complexes with ß-cyclodextrin (ß-CD) and 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD), prepared by different methods, were investigated by using in vitro cell-based approaches. The results of the 3T3 NRU phototoxicity assay showed that free DRO and the CD-based inclusion complexes did not present any substantial phototoxic potential. The photosensitizing potential was assessed by using THP-1 cells and IL-8 as a biomarker, and the experimental data confirmed that both the free drug and the inclusion complexes are likely to cause skin photosensitization, as they were able to induce IL-8 release after irradiation. Nevertheless, the inclusion complexes obtained by kneading followed by spray-drying induced a lower IL-8 release and also presented a smaller stimulation index in comparison with free DRO, suggesting a reduction in the photosensitizing potential. Finally, the free drug and inclusion complexes were also tested for hepatotoxicity using HepG2 cells. Even though lower IC50 values were found for the inclusion complexes prepared by kneading followed by spray-drying, there was no significant difference, indicating that the complexation of dronedarone did not induce hepatotoxicity. Overall, the obtained data confirmed that the inclusion complexes prepared by kneading followed by spray-drying, especially those based on HP-ß-CD, appeared to be the most promising formulations and, therefore, could be encouragingly explored in the development of novel pharmaceutical dosage forms containing DRO, presumably with reduced side effects and improved safety profile.

Preparation, characterization and in vitro cytotoxicity study of dronedarone hydrochloride inclusion complexes.

Dronedarone is a new antiarrhythmic drug for the treatment of atrial fibrillation. This study investigated the complexation of dronedarone hydrochloride with ß­cyclodextrin (ß-CD) and 2­hydroxypropil­ß­CD (HP-ß-CD) using three different techniques. The complexes in the solid state were characterized by DSC, TGA, PXRD, FT-IR, SEM and 1H NMR, demonstrating the formation of the inclusion complexes and exhibiting different properties from the pure drug. Its aqueous solubility increased about 4.0-fold upon complexation with ß-CD and HP-ß-CD. The dissolution rate of the drug was notably improved in all tested physiological pH values from 1.2 to 6.8 in the presence of both cyclodextrins. Furthermore, an in vitro cytotoxic assay revealed that the inclusion complexes could reduce the cytotoxic effects of the drug on 3T3 cells. The overall results suggest that the inclusion complexes with ß-CD and HP-ß-CD may be potentially useful in the preparation of novel pharmaceutical formulations containing dronedarone hydrochloride.

Dose proportionality and pharmacokinetics of dronedarone following intravenous and oral administration to rat.

The aim of this study was to investigate the pharmacokinetic properties of dronedarone by using noncompartmental analysis and modeling approaches after intravenous and oral administration of dronedarone to rats. Twenty-eight male Sprague-Dawley rats were randomly divided into four groups, and dronedarone was administered intravenously (1 mg/kg) and orally (5, 10 and 40 mg/kg) based on a parallel design. Blood samples were collected before and 0.083 (intravenous administration only), 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12 and 24 h after drug administration. The plasma concentration of dronedarone was determined by using LC-MS/MS. The oral bioavailability of dronedarone was evaluated as approximately 16% in rats, similar to that in humans. The assessment of dose proportionality by using the power model showed that AUCinf increased in a dose-proportional manner, whereas AUC24h and Cmax exhibited a lack of dose proportionality over the dose range between 5 and 40 mg/kg. The two-compartment model, with first-order absorption and elimination rate constants, was sufficient to explain the pharmacokinetics of dronedarone with biexponential decay. These findings will help to understand the pharmacology of dronedarone to develop the new formulation and therapeutics optimization linked to pharmacokinetic/pharmacodynamic study.

A short synthesis of Dronedarone.

A modification of the Nenitzescu reaction was used to obtain Dronedarone from quinonimine 20 and 1,3-diketone 14 (R = CH2CH2CH2NBu2) in a two-stage process in almost 55% overall yield. Our results represent significant improvement over other state-of-the-art methods as no extra steps for the decoration of the benzofuran core are required.