Evaluation of Emulgel and Nanostructured Lipid Carrier-Based Gel Formulations for Transdermal Administration of Ibuprofen: Characterization, Mechanical Properties, and Ex-Vivo Skin Permeation.

In transdermal applications of nonsteroidal anti-inflammatory drugs, the rheological and mechanical properties of the dosage form affect the performance of the drug. The aim of this study to develop emulgel and nanostructured lipid carrier NLC-based gel formulations containing ibuprofen, evaluate their mechanical properties, bioadhesive value and ex-vivo rabbit skin permeability. All formulations showed non-Newtonian pseudoplastic behavior and their viscosity values are suitable for topical application. The particle size of the nanostructured lipid carrier system was found to be 468 ± 21 nm, and the encapsulation efficiency was 95.58 ± 0.41%. According to the index of viscosity, consistency, firmness, and cohesiveness values obtained as a result of the back extrusion study, E2 formulation was found to be more suitable for transdermal application. The firmness and work of shear values of the E2 formulation, which has the highest viscosity value, were also found to be the highest and it was chosen as the most suitable formulation in terms of the spreadability test. The work of bioadhesion values of NLC-based gel and IBU-loaded NLC-based gel were found as 0.226 ± 0.028 and 0.181 ± 0.006 mJ/cm2 respectively. The percentages of IBU that penetrated through rabbit skin from the Ibuactive-Cream and the E2 were 87.4 ± 2.11% and 93.4 ± 2.72% after 24 h, respectively. When the penetration of ibuprofen through the skin was evaluated, it was found that the E2 formulation increased penetration due to its lipid and nanoparticle structure. As a result of these findings, it can be said that the NLC-based gel formulation will increase the therapeutic efficacy and will be a good alternative transdermal formulation.

Development and pharmacokinetic evaluation of Neusilin® US2-based S-SNEDDS tablets for bosentan: Fasted and fed states bioavailability, IVIS® real-time biodistribution, and ex-vivo imaging.

The study reported here aimed to develop and optimize the S-SNEDDS tablet of bosentan (BOS) and to investigate its pharmacokinetic and biodistribution properties. The BOS-loaded SNEDDS have been developed and characterized in a previous study. The BOS-loaded SNEDDS formulation was converted to S-SNEDDS using Neusilin® US2. The S-SNEDDS tablets were obtained using the direct compression technique, and in vitro dissolution, in vitro lipolysis, and ex-vivo permeability studies of the tablets were performed. The S-SNEDDS tablet and reference tablet (Tracleer®) were administered to male Wistar rats at 50 mg/kg dose by oral gavage in fasted and fed state conditions. The biodistribution of the S-SNEDDS tablet was investigated in Balb/c mice using fluorescent dye. The tablets were dispersed in distilled water before administration to animals. The relationship between in vitro dissolution data and in vivo plasma concentration was examined. The S-SNEDDS tablets showed 2.47, 7.49, 3.70, and 4.39 increases in the percentages of cumulative dissolution in FaSSIF, FeSSIF, FaSSIF-V2, and FeSSIF-V2, respectively, when compared to the reference, and increased the Cmax and AUC 2.65 and 1.28-fold and 4.73 and 2.37-fold in fasted and fed states, respectively, when compared to the reference. S-SNEDDS tablets also significantly reduced interindividual variability in both fasted and fed states (p < 0.05). The XenoLight™ DiR and VivoTag® 680XL labeled S-SNEDDS tablet formulation increased the real-time biodistribution in the body by factors of 2.4 and 3.4 and organ uptake and total emission increased by factors of 2.8 and 3.1, respectively. The IVIVR has been successfully established for S-SNEDDS tablets (R2 > 0.9). The present study confirms the potential of the S-SNEDDS tablet to enhance the in vitro and in vivo performance of BOS.

Formulation development, optimization by Box-Behnken design, characterization, in vitro, ex-vivo, and in vivo evaluation of bosentan-loaded self-nanoemulsifying drug delivery system: A novel alternative dosage form for pulmonary arterial hypertension treatment.

This study aimed to develop and optimize a self-nanoemulsifying drug delivery system (SNEDDS) of bosentan (BOS) to solve its poor oral bioavailability due to low water solubility. A pseudo-ternary phase diagram was created based on the solubility and emulsification studies. The major components of the formulation were selected as glyceryl monolinoleate (lipid), polyoxyl 40 hydrogenated castor oil (surfactant), and caprylocaproyl polyoxyl-8 glycerides (co-surfactant). The composition of BOS-SNEDDS was optimized using the Box-Behnken design (BBD) and then was characterized for various physicochemical properties. The in vitro dissolution, in vitro lipolysis, and ex-vivo permeability studies were performed and compared to SNEDDS and reference tablets. The fasted and fed state bioavailability of BOS-loaded SNEDDS was evaluated in Wistar rats (n = 6) compared to the reference. The prepared SNEDDS were thermodynamically stable with a droplet size of 17.11 nm, a polydispersity index of 0.180, and an emulsification time of <1 min. The BOS-loaded SNEDDS showed 3.0, 7.97, 4.23, and 4.94-fold increases in the percentages of cumulative dissolution compared to reference tablets in FaSSIF, FeSSIF, FaSSIF-V2, and FeSSIF-V2, respectively. The permeation study showed that the SNEDDS increased the drug permeation by 3.36, 19.2, 16.4, and 16.6-fold in FaSSIF, FeSSIF, FaSSIF-V2, and FeSSIF-V2, respectively. The enhancement of in vitro dissolution, in vitro lipolysis, and ex-vivo permeability was found significant (p < 0.05). SNEDDS was increased the Cmax and AUC 1.67 and 2.12-fold and 5.15 and 1.84-fold in fasted and fed state compared to the reference, respectively. The in vitro-in vivo relationship has been successfully performed for SNEDDS. These results indicated that the SNEDDS formulation could be a promising delivery system that enhances the absorption and oral bioavailability of BOS.

Development and Validation of an HPLC Method Using an Experimental Design for Analysis of Amlodipine Besylate and Enalapril Maleate in a Fixed-dose Combination

Objectives: The aim of this study was to develop and optimize a simple, cost-effective, and robust high-performance liquid chromatography (HPLC) method by taking an experimental design approach to the assay and dissolution analysis of amlodipine besylate and enalapril maleate from a fixed-dose combination tablet. Materials and Methods: The chromatographic analysis was performed on a C18 column (4.6x250 mm id., particle size of 5 µm). The injection volume was 5 µL, and the detection wavelength was 215 nm. A Box-Behnken design was used to test the robustness of the method. The flow rate (1, 1.2, and 1.4 mL/min), column temperature (25°C, 30°C, and 35°C), methanol ratio of the mobile phase (5, 10, and 15%), and pH of the mobile phase (2.8, 3, and 3.2) were selected as independent variables. The method was validated according to International Conference on Harmonization guidelines. Dissolution of the tablets was performed by using USP apparatus 2 and analyzed using the optimized HPLC method. Multivariate linear regression analysis and ANOVA were used in the statistical evaluation. Results: Linear models were fitted for all variables. The flow rate was the most significant factor affecting the APIs' concentrations. The optimized method included the following parameters: Column temperature of 25°C, 10% methanol as the mobile phase, pH of 2.95, and flow rate of 1.205 mL/min. Retention times were 3.8 min and 7.9 min for enalapril and amlodipine, respectively. The method was found to be linear in the range of 0.8-24 µg/mL (R2 >0.999) and 1.6-48 µg/mL (R2 >0.999) for amlodipine and enalapril, respectively. Both APIs were dissolved more than 85% within 10 min. Conclusion: The experimental design was proved as a useful tool for the determination and separation of enalapril maleate and amlodipine besylate in dosage forms. The optimized method can be used for in vitro performance and quality control tests of fixed-dose tablet combinations containing enalapril maleate and amlodipine besylate.

Preparation of ritonavir nanosuspensions by microfluidization using polymeric stabilizers: I. A Design of Experiment approach.

The objective of this study was to prepare ritonavir (RTV) nanosuspensions, an anti-HIV protease inhibitor, to solve its poor water solubility issues. The microfluidization method with a pre-treatment step was used to obtain the nanosuspensions. Design of Experiment (DoE) approach was performed in order to understand the effect of the critical formulation parameters which were selected as polymer type (HPMC or PVP), RTV to polymer ratio, and number of passes. Interactions between the formulation variables were evaluated according to Univariate ANOVA. Particle size, particle size distribution and zeta potential were selected as dependent variables. Scanning electron microscopy, X-ray powder diffraction, and differential scanning calorimetry were performed for the in vitro characterization after lyophilization of the optimum nanosuspension formulation. The saturation solubility was examined in comparison with coarse powder, physical mixture and nanosuspension. In vitro dissolution studies were conducted using polyoxyethylene 10 lauryl ether (POE10LE) and biorelevant media (FaSSIF and FeSSIF). The results showed nanosuspensions were partially amorphous and spherically shaped with particle sizes ranging from 400 to 600nm. Moreover, 0.1-0.4 particle size distribution and about -20mV zeta potential values were obtained. The nanosuspension showed a significantly increased solubility when compared to coarse powder (3.5 fold). Coarse powder, physical mixture, nanosuspension and commercial product dissolved completely in POE10LE; however, cumulative dissolved values reached ~20% in FaSSIF for the commercial product and nanosuspension. The nanosuspension showed more than 90% drug dissolved in FeSSIF compared to the commercial product which showed ~50% in the same medium. It was determined that RTV dissolution was increased by nanosuspension formulation. We concluded that DoE approach is useful to develop nanosuspension formulation to improve solubility and dissolution rate of RTV.