Dronedarone Hydrochloride Research Articles

Dronedarone hydrochloride (DH) induces pancreatic cancer cell death by triggering mtDNA-mediated pyroptosis

Pancreatic cancer is one of the leading causes of cancer-associated mortality, with a poor treatment approach. Previous study has shown that inducing pyroptosis in pancreatic ductal adenocarcinoma (PDAC) slows the growth of PDACs, implying that pyroptosis inducers are potentially effective for PDAC therapy. Here, we found that Dronedarone hydrochloride (DH), an antiarrhythmic drug, induces pyroptosis in pancreatic cancer cells and inhibits PDAC development in mice. In PANC-1 cells, DH caused cell death in a dosage- and time-dependent manner, with only pyroptosis inhibitors and GSDMD silencing rescuing the cell death, indicating that DH triggered GSDMD-dependent pyroptosis. Further work revealed that DH increased mitochondrial stresses and caused mitochondrial DNA (mtDNA) leakage, activating the cytosolic STING-cGAS and pyroptosis pathways. Finally, we assessed the anti-cancer effects of DH in a pancreatic cancer mouse model and found that DH treatment suppressed pancreatic tumor development in vivo. Collectively, our investigation demonstrates that DH triggers pyroptosis in PDAC and proposes its potential effects on anti-PDAC growth.

Koncept ekološki prihvatljivih hromatografskih metoda - studija slučaja na primeru razdvajanja dronedaron hidrohlorida i njegovih degradacionih proizvoda

Recently, concern about the environmental impact of drug analysis methods has increased significantly. Reversed-phase high-performance liquid chromatography (RP-HPLC), the predominant technique in drug analysis, relies heavily on organic solvents such as acetonitrile, which is known for its chromatographic efficiency, but also for its toxicity and flammability. To address these concerns, it is essential to minimize the use of toxic organic solvents. The aim of this study is to explore greener RP-HPLC modifications and evaluate their applicability in the pharmaceutical industry. Methods were developed for the separation of dronedarone hydrochloride and its degradation products based on experimental design, including micellar liquid chromatography (MLC), b-cyclodextrin (CD) modified RP-HPLC and ultra-high performance liquid chromatography (UHPLC). The eco-friendliness of these methods was assessed using the analytical eco-scale score, green analytical procedure index (GAPI) and analytical greenness (AGREE). AGREE appears to be the most suitable, as it revealed the greatest differences between the compared methods, as well as insights into critical aspects of the methods. UHPLC and b-CD modified RP-HPLC have been shown to be superior to MLC, and both methods can be a good choice, depending on whether the ease of implementation or energy efficiency is considered to be a more important criterion.

Ion-Triggered In Situ Gelling Intranasal Spray of Dronedarone Hydrochloride Nanocarriers: In Vitro Optimization and In Vivo Pharmacokinetic Appraisal.

The current study aims to develop niosomal nanocarriers for intranasal delivery of dronedarone hydrochloride to ameliorate its limited bioavailability. Niosomes were prepared by ethanol injection method and optimized using 3² full factorial experimental design. Both Span® type (X1) and Span®: cholesterol ratio (X2) were set as independent variables. Vesicle size (Y1), polydispersity index (Y2), zeta potential (Y3), and entrapment efficiency (Y4) were set as responses. The optimal formula was further incorporated into an ion-sensitive in situ gelling polymer for intranasal delivery. Optimal formula (N7), which is composed of Span® 80: cholesterol (1:1), was of the least vesicle size (121.27 ± 13.31 nm), least polydispersity index (0.43 ± 0.073), highest zeta potential (-22.23 ± 2.84 mV) and highest entrapment efficiency (73.44 ± 2.8%). About 75.86% and 60.29% of dronedarone hydrochloride were released from N7 dispersion and in situ gel, respectively, within 12 h, compared to only 13.3% released from a drug-free suspension. In vivo pharmacokinetic study on male New Zealand rabbits resulted in significantly higher Cmax, AUC0-72, and AUC0-∞ of intranasal niosomal in situ gel compared to oral suspension. Almost twofold amplification of relative bioavailability was obtained after intranasal administration of niosomal in situ gel (195.7%) compared to oral suspension.

Dronedarone hydrochloride enhances the bioactivity of endothelial progenitor cells via regulation of the AKT signaling pathway.

Cardiovascular disease (CVD) and its complications are the leading cause of morbidity and mortality in the world. Because of the side effects and incomplete recovery from current therapy, stem cell therapy emerges as a potential therapy for CVD treatment, and endothelial progenitor cell (EPC) is one of the key stem cells used for therapeutic applications. The effect of this therapy required the expansion of EPC function. To enhance the EPC activation, proliferation, and angiogenesis using dronedarone hydrochloride (DH) is the purpose of this study. DH received approval for atrial fibrillation treatment and its cardiovascular protective effects were already reported. In this study, DH significantly increased EPC proliferation, tube formation, migration, and maintained EPCs surface marker expression. In addition, DH treatment up-regulated the phosphorylation of AKT and reduced the reactive oxygen species production. In summary, the cell priming by DH considerably improved the functional activity of EPCs, and the use of which might be a novel strategy for CVD treatment.

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.

Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-CoV-2.

COVID-19 pandemic has infected millions of people with mortality exceeding >1 million. There is an urgent need to find therapeutic agents that can help clear the virus to prevent severe disease and death. Identifying effective and safer drugs can provide more options to treat COVID-19 infections either alone or in combination. Here, we performed a high throughput screening of approximately 1,700 US FDA-approved compounds to identify novel therapeutic agents that can effectively inhibit replication of coronaviruses including SARS-CoV-2. Our two-step screen first used a human coronavirus strain OC43 to identify compounds with anti-coronaviral activities. The effective compounds were then screened for their effectiveness in inhibiting SARS-CoV-2. These screens have identified 20 anti-SARS-CoV-2 drugs including previously reported compounds such as hydroxychloroquine, amlodipine besylate, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, mefloquine, and thioridazine hydrochloride. Five of the newly identified drugs had a safety index (cytotoxic/effective concentration) of >600, indicating a wide therapeutic window compared to hydroxychloroquine which had a safety index of 22 in similar experiments. Mechanistically, five of the effective compounds (fendiline HCl, monensin sodium salt, vortioxetine, sertraline HCl, and salifungin) were found to block SARS-CoV-2 S protein-mediated cell fusion. These FDA-approved compounds can provide much needed therapeutic options that we urgently need during the midst of the pandemic.

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 10wt.% 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 10wt.% of PEG, 10wt.% of DNR, and 80wt.% of PVA filament is the most appropriate formula for extrusion and tablet printing.

ATOMIC ABSORPTION SPECTROPHOTOMETER – A VERSATILE TOOL FOR THE ESTIMATION OF NICKEL CONTENT IN DRONEDARONE

Objective: The present investigation is to develop a validated analytical method for the determination of nickel content in dronedarone hydrochloride bulk drug by atomic absorption spectrophotometer (AAS).
 Methods: Samples were analyzed after a preparation of sample solution by dissolving in suitable diluents of nitric acid and perchloric acid. In the present method, AAS with 0.2 nm slit width, nickel hollow cathode lamp with a wavelength of 232 nm has been employed.
 Results: The system suitability parameters were performed to assess the system performance. The limit of detection and limit of quantification (LOQ) were found to be 0.051 ppm and 0.15 ppm, respectively. The percentage recovery at LOQ, 50%, 100%, and 150% levels of nickel in dronedarone was found to be 95.55, 109.33, 96, and 97.55, respectively.
 Conclusion: With the developed method, the nickel content in dronedarone bulk sample was found to be 3.0 ppm.

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.

Design and 3D printing of multi-compartmental PVA capsules for drug delivery

3D printing is predicted to play a significant role in the future of the pharmaceutical industry. Personalized drug delivery, which includes personalizing dosage forms, drug content and release has become a new, promising and effective way in the treatment of patients. This paper provides a contribution to the development of personalized oral dosage forms based on the design and production of modular capsules. Fused deposition modeling was utilized to produce a polyvinyl alcohol concentrically compartmental Can-capsule and modular Super-H capsule with different membrane thicknesses. Dronedarone hydrochloride and ascorbic acid in powdery form were filled into the printed capsules and used to test the rate of dissolution. In vitro studies were performed at different pH to investigate capsule performance. Lag time of the Super-H capsules in an acidic medium (0.1 M HCl) was correlated to membrane thickness. The inner part of the Can-capsule is gastro-resistant, resistant to an acid medium (0.1 M HCl) for 2 h, and is suitable for delivery of drugs to the small intestine. The results show that the Super-H and Can-capsule can be used as modular devices for administering drugs when a postponed release is required or for the delivery of two different active ingredients.

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 β‑cyclodextrin (β-CD) and 2‑hydroxypropil‑β‑CD (HP-β-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 β-CD and HP-β-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 β-CD and HP-β-CD may be potentially useful in the preparation of novel pharmaceutical formulations containing dronedarone hydrochloride.

Establishment of a stability indicating HPLC method for dronedarone hydrochloride in tablets and in cyclodextrin inclusion complexes: application to degradation kinetic studies

The stability indicating HPLC method for the determination of dronedarone (DRO) hydrochloride in tablets and in inclusion complexes with cyclodextrin was carried out on a C18 column using a buffer solution (0.3% glacial acetic acid; pH 4.9) and acetonitrile (35:65, v/v) as mobile phase. The method validation according to ICH guidelines demonstrated acceptable results. Dronedarone was exposed to stress conditions, and drug-degradation kinetics was studied. Additionally, the degraded samples were analyzed by mass spectrometry and the preliminary toxicity against 3T3 cells was also determined. The results obtained evidenced that dronedarone degradation kinetics in alkaline conditions followed first-order reaction and that inclusion complexation with cyclodextrin reduced its chemical degradation. Among the samples exposed to stress conditions, only the photodegraded samples presented cytotoxic effects. Moreover, assay results were compared to a previously validated micellar electrokinetic chromatography method, showing non-significant difference (p > 0.05). The combination of HPLC, mass spectrometry and cytotoxicity study could be an important tool for the screening of DRO pharmaceutical forms, improving quality and safety in the development of novel drug delivery systems.

Prediction of particle size distribution of dronedarone hydrochloride in spiral jet mill using design of experiments

ABSTRACTIn pharmaceutical industry, micronization is used to achieve solubility enhancement through the increase in specific surface area, and finally improving the dissolution rate of the drug. Industrial application of micronization is mostly based on experience and trial and error method. This research deals with the micronization of dronedarone hydrochloride and the path for evaluation of characteristics of micronized drug. Micronization was performed in laboratory spiral jet mill and the samples were analyzed to determine particle size distribution, span of distribution, sphericity, shape, and specific surface area. Results were analyzed using analysis of variance and in terms of specific energy consumption. Paths for evaluation of particle size and span of distribution were proposed and good correlation between experimental and model results was achieved.

Bioanalytical Method Validation for Dronedarone and Duloxetine in Blood Serum

The present work relates to the development and validation of reversed-phase HPLC-UV-photodiode array methods for the estimation of two drugs in blood serum: dronedarone hydrochloride (DDN), a class III antiarrhythmic drug, and duloxetine hydrochloride (DLX), an antidepressant. Chromatographic analysis of DLX was carried out on a Nucleodur C18 column (250 × 4.6 mm, 5 μm) using ammonium acetate buffer (32 mM, pH 5.5) and acetonitrile (40 + 60, v/v; flow rate of 1.0 mL/min; detection wavelength of 290 nm) as the mobile phase. A Waters XTerra C18 column (250 × 4.6 mm, 5 μm) was used for the chromatographic analysis of DDN using an acetonitrile-ammonium formate buffer (20 mM, pH 3.0, with formic acid; 45 + 55, v/v; flow rate 1.0 mL/min) as the mobile phase. Pentazocine and bupropion HCl were used as the internal reference standards for DLX and DDN, respectively. Excellent linearity was observed for DLX (r2 = 0.9996; concentration range 0.2-10.0 μg/mL) and DDN (r2 = 0.9997; concn. range 2.0-50.0 μg/mL). The LODs for DLX and DDN were 0.022 and 0.78 μg/mL, respectively, and the LOQs 0.066 and 2.4 μg/mL, respectively.

Development and Validation of Stability-Indicating Derivative Spectrophotometric Methods for Determination of Dronedarone Hydrochloride

Rapid, sensitive, cost effective and reproducible stability-indicating derivative spectrophotometric methods have been developed for the estimation of dronedarone HCl employing peak–zero (P–0) and peak–peak (P–P) techniques, and their stability-indicating potential assessed in forced degraded solutions of the drug. The methods were validated with respect to linearity, accuracy, precision and robustness. Excellent linearity was observed in concentrations 2–40 μg/ml (r 2 = 0.9986). LOD and LOQ values for the proposed methods ranged from 0.42–0.46 μg/ml and 1.21–1.27 μg/ml, respectively, and excellent recovery of the drug was obtained in the tablet samples (99.70 ± 0.84%).

Solubility of dronedarone hydrochloride in six pure solvents at the range of 298.15 to 323.15 K

The aim of this study was to measure the mole fraction solubility of dronedarone hydrochloride in six pure solvents across a temperature range of 298.15–323.15K. The experimental solubility of dronedarone hydrochloride correlated with the Apelblat equation. The maximum mole fraction solubility of dronedarone hydrochloride was observed to be 0.119 in methanol at 323.15K followed by ethanol (3.62×10−2 at 323.15K), 1-propanol (1.59×10−2 at 323.15K), 1-butanol (8.05×10−3 at 323.15K), 2-propanol (2.93×10−3 at 323.15K), and water (6.11×10−5 at 323.15K). Based on these results, dronedarone hydrochloride can be considered freely soluble in methanol, soluble in ethanol, and slightly soluble in 1-propanol, 2-propanol, 1-butanol, and water. These data could be important for the recrystallization and formulation development of dronedarone hydrochloride.

Identification and characterization of stress degradation products of dronedarone hydrochloride employing LC-UV/PDA, LC–MS/TOF and MSn studies

Dronedarone HCl was subjected to forced decomposition conditions of hydrolysis (neutral, acidic and alkaline), oxidation, photolysis and thermal stress, as suggested in the ICH guideline Q1A(R2). The drug showed significant degradation under alkaline hydrolytic and alkaline photolytic conditions while it remained stable in neutral, acidic, thermal and oxidative conditions. In total, six degradation products (I–VI) were formed, which could be separated by chromatography on C18 (250mm×4.6mm; 5μ, Xterra) column using isocratic elution method. Detection wavelength was selected as 288nm. Multi-stage (MSn) and MS/TOF accurate mass studies were carried out to establish the complete fragmentation pathway of the drug which in turn was utilized in characterization of the products. The degradation pathway of the drug leading to generation of products I–VI was postulated and this has not been reported so far.

Enhanced Dissolution Rate of Dronedarone Hydrochloride via Preparation of Solid Dispersion using Vinylpyrrolidone‐Vinyl Acetate Copolymer (Kollidone® VA 64)

Solid dispersion (SD) systems have been widely used to increase the dissolution rate and oral absorption of poorly water‐soluble compounds. In order to enhance the dissolution rate of dronedarone hydrochloride (DRN), a recent antiarrhythmic agent, SDs of DRN were formulated using conventional solvent evaporation method with amorphous polymers including hydroxypropyl methyl cellulose (HPMC), poly(vinyl pyrrolidone) (PVP), and vinylpyrrolidone‐vinyl acetate copolymer (VA64). The prepared SDs were characterized in terms of drug crystallinity, morphology, and in vitro dissolution profile in aqueous medium. The physical characterization using differential scanning calorimetry and X‐ray powder diffraction revealed that the active compound was molecularly dispersed in all polymeric carriers tested, in a stable amorphous form in drug to polymer ratios ranging from 1:0.5 to 1:2. The dissolution rates of DRN in all SDs were much higher than those from the corresponding physical mixture and drug powder alone. In particular, the greatest dissolution enhancement was obtained from the VA64‐based SD in a drug to polymer weight ratio of 1:1, achieving almost complete drug release after 120 min at pH 1.2. Thus, VA64‐based SD with higher drug dissolution rate along with a simple preparation process is suggested as an alternative for the oral formulation of the benzofuran derivative.

Synthesis and characterization of new related substances of the antiarrhythmic drug dronedarone hydrochloride

Two new potential impurities of antiarrhythmic drug substance Dronedarone Hydrochloride together with debutyldronedarone were detected by LC–MS analysis during process development. A successful synthetic strategy for the synthesis of these potential impurities was developed facilitating the access to new impurity reference standards. Their synthesis and characterization are discussed in detail. The availability of these impurity standards allowed cost reduction through the increase of process control.

Stability Indicating RP-HPLC Assay Method for Estimation of Dronedarone Hydrochloride in Tablet

Development and validation of dissolution proceduresBhavesh Vaghela, Rajan Kayastha, Nayana Bhatt, Nimish Pathak, Dashrath Rathod