In chronic atrioventricular block dogs, SEA-0400 treatment is effective against TdP. Unlike specific inhibition of LTCC, combined NCX and LTCC inhibition has no negative effects on cardiac hemodynamics.

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The unique requirements of poorly water-soluble drug delivery have driven a great deal of research into new formulations and routes of administration. This study investigates the use of nanosuspensions for solubility enhancement and drug delivery. Simple methods were used to prepare nasal formulations of loratadine based on nanosuspension pre-dispersion with sodium hyaluronate as a mucoadhesive agent. The nanosuspension was prepared by antisolvent precipitation method followed by ultrasonication and characterized for particle size, polydispersity index, zeta potential, morphology, and structure. Moreover, the nasal formulations were characterized for drug loading, pH, particle size, viscosity, bioadhesive viscosity parameter, and were evaluated for in vitro dissolution and diffusion, in addition to in vivo studies in a rat model. Loratadine nanosuspension displayed a particle size of 311 nm, a polydispersity index of 0.16, and zeta potential of -22.05 mV. The nanosuspension preserved the crystalline status of the raw drug. The addition of sodium hyaluronate exhibited an increase in the mean particle size and zeta potential of the nanoparticles. The nasal formulations showed enhanced bioadhesive properties compared to the unprocessed loratadine in the reference samples. The nanosuspension based-formulation that contained 5 mg mL −1 sodium hyaluronate and 2.5 mg mL −1 loratadine (NF4) showed a significant enhancement of flux and permeability coefficient through a synthetic membrane. NF4 exhibited 24.73 µg cm −2 h −1 and 0.082 cm h −1 , while the reference sample showed 1.49 µg cm −2 h −1 and 0.017 cm h −1 , for the flux and the permeability coefficient, respectively. Nasal administration of NF4 showed a bioavailability of 5.54-fold relative to the oral administration. The results obtained in this study indicate the potential of the nasal route and the nanosuspension for loratadine delivery. The relative bioavailability of NF4 was 1.84-fold compared to unprocessed loratadine in the reference sample. Therefore, the nanosized loratadine could be suggested as a practical and simple nanosystem for the intranasal delivery with improved bioavailability.

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The aim of this article was to study the trans-epithelial absorption to reach the blood and to target the brain by axonal transport using nasal formulations with nanonized meloxicam (nano MEL spray) and its salt form known as meloxicam potassium monohydrate (MELP spray). The physicochemical properties and the mucoadhesivity of nasal formulations were controlled. In vitro and in vivo studies were carried out. These forms were first investigated in “nose-to-brain” relation. It was found that the in vitro study and in vivo study did not show any significant correlation. In vitro experiments demonstrated faster dissolution rate and higher diffusion of MELP from the spray compared with the nano MEL spray. The administration of the nano MEL spray resulted in faster absorption and constant plasma concentration of the drug after five minutes of administration as compared to MELP. The axonal transport of the drug was justified. MEL appeared in the brain tissues after the first five minutes of administration in the case of both spray forms, but its amount was too small in comparison with the total plasma concentration. The application of the nano MEL spray resulted in the same AUC in the brain as the intravenous injection. The “nose-to-blood” results predicted the nasal applicability of MEL and MELP in pain management. The “nose-to-brain” pathway requires further study.

The aim of this study was to optimize the formulation of meloxicam (MEL)-containing human serum albumin (HSA) nanoparticles for nose-to-brain via a quality by design (QbD) approach. Liquid and dried formulations of nanoparticles containing Tween 80 and without the surfactant were investigated. Various properties, such as the Z-average, zeta potential, encapsulation efficacy (EE), conjugation of MEL and HSA, physical stability, in vitro dissolution, in vitro permeability, and in vivo plasma and brain distribution of MEL were characterized. From a stability point of view, a solid product (Mel-HSA-Tween) is recommended for further development since it met the desired critical parameters (176 ± 0.3 nm Z-average, 0.205 ± 0.01 PdI, −14.1 ± 0.7 mV zeta potential) after 6 months of storage. In vitro examination showed a significantly increased drug dissolution and permeability of MEL-containing nanoparticles, especially in the case of applying Tween 80. The in vivo studies confirmed both the trans-epithelial and axonal transport of nanoparticles, and a significantly higher cerebral concentration of MEL was detected with nose-to-brain delivery, in comparison with intravenous or per os administration. These results indicate intranasal the administration of optimized MEL-containing HSA formulations as a potentially applicable “value-added” product for the treatment of neuroinflammation.

Besides the opioids the standard management of the World Health Organization suggests NSAIDs (non-steroidal anti-inflammatory drugs) alone or in combination to enhance analgesia in malignant and non-malignant pain therapy. The applicability of NSAIDs in a nasal formulation is a new approach in pharmaceutical technology. In order to enhance the nasal absorption of meloxicam (MX) as an NSAID, its salt form, meloxicam potassium monohydrate (MXP), registered by Egis Plc., was investigated in comparison with MX. The physico-chemical properties of the drugs (structural analysis, solubility and dissolution rate) and the mucoadhesivity of nasal formulations were controlled. In vitro and in vivo studies were carried out to determine the nasal applicability of MXP as a drug candidate in pain therapy. It can be concluded that MX and MXP demonstrated the same equilibrium solubility at the pH5.60 of the nasal mucosa (0.017mg/ml); nonetheless, MXP indicated faster dissolution and a higher permeability through the synthetic membrane. The animal studies justified the short T value (15min) and the high AUC of MXP, which is important in acute pain therapy. It can be assumed that the low mucoadhesivity of MXP spray did not increase the residence time in the nasal cavity, and the elimination from the nasal mucosa was therefore faster than in the case of MX. Further experiments are necessary to prove the therapeutic relevance of this MXP-containing innovative intranasal formulation.