In Vitro-In Vivo Evaluation of Novel Co-spray Dried Rifampicin Phospholipid Lipospheres for Oral Delivery.

The objective of this study comprises of developing novel co-spray dried rifampicin phospholipid lipospheres (SDRPL) to investigate its influence on rifampicin solubility and oral bioavailability. Solid-state techniques were employed to characterize the liposphere formulation. SDRPL solubility was determined in distilled water. BACTEC 460TB System was employed to evaluate SDRPL antimycobacterial activity. The oral bioavailability of the lipospheres was evaluated in Sprague Dawley rats. Lipospheres exhibited amorphous, smooth spherical morphology with a significant increase (p < 0.001) in solubility of SDRPL (2:1), 350.9 ± 23 versus 105.1 ± 12 µg/ml and SDRPL (1:1) 306.4 ± 20 versus 105.1 ± 12 µg/ml in comparison to rifampicin (RMP). SDRPL exhibited enhanced activity against Mycobacterium tuberculosis, H37Rv strain, with over twofolds less minimum inhibitory concentration (MIC) than the free drug. Lipospheres exhibited higher peak plasma concentration (109.92 ± 25 versus 54.31 ± 18 µg/ml), faster T max (two versus four hours), and enhanced area under the curve (AUC0-∞) (406.92 ± 18 versus 147.72 ± 15 µg h/L) in comparison to pure RMP. Thus, SDRPL represents a promising carrier system exhibiting enhanced antimycobacterial activity and oral bioavailability of rifampicin.

Phytotoxic effects of invasive Ageratina adenophora on two native subtropical shrubs in Nepal.

The response of native plants to allelopathic interference of invasive species may differ from species to species. In this study, the phytotoxic effects of Ageratina adenophora were tested on two native shrubs (Osbeckia stellata and Elsholtzia blanda) of Nepal. Both the shrubs were grown in pots under treatments of A. adenophora fresh leaves and root leachates, and litter. Then, the seedling length and biomass were compared among the treatments. The results show that A. adenophora litter has stimulatory effects but the leachates from fresh leaves and root are phytotoxic to the growth and development of native shrubs. Infrared Spectroscopy (IR) analysis confirmed the presence of O-H (Hydroxyl), N-H (Amines), C≡C (Alkynes), and C-H stretching (Aromatic) or C-O-C stretching (Ethers) in the leachates representing harmful allelochemicals. The invaded soil by A. adenophora had low pH and a high amount of organic matter, total nitrogen, phosphorus, and potassium than the uninvaded soil. The results indicate that the native O. stellata and E. blanda are harmed by A. adenophora in nature by leaching of allelochemicals and probably by reducing the soil pH. Overall, this study has provided valuable insights regarding the effects of A. adenophora invasion on native shrubs and revealing the potential mechanism of its invasiveness.

Potential of aerosolized rifampicin lipospheres for modulation of pulmonary pharmacokinetics and bio-distribution.

The aim of the present study was to establish the potential of rifampicin loaded phospholipid lipospheres carrier for pulmonary application. Lipospheres were prepared with rifampicin and phospholipid in the ratio of 1:1 using spray drying method. Further, lipospheres were evaluated for flow properties and surface area measurement. The formulated lipospheres were evaluated in vitro for aerodynamic characterization and in vivo for lung pharmacokinetics and biodistribution studies in Sprague Dawley rats. Powder flow properties finding suggested the free flowing nature of the lipospheres. In-vitro aerosol performance study indicated more than 80±5% of the emitted dose (ED) and 77.61±3% fine particles fraction (FPF). Mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were found to be 2.72±0.13 µm and 3.28±0.12, respectively. In-vitro aerosol performance study revealed the higher deposition at 3, 4 and 5 stages which simulates the trachea-primary bronchus, secondary and terminal bronchus of the human lung, respectively. The drug concentration from nebulized lipospheres in the non-targeted tissues was lesser than from rifampicin-aqueous solution. The pulmonary pharmacokinetic study demonstrated improved bioavailability, longer residence of drug in the lung and targeting factor of 8.03 for lipospheres as compared to rifampicin-aqueous solution. Thus, the results of the study demonstrated the potential of rifampicin lipospheres formulation would be of use as an alternative to existing oral therapy.

Novel rifampicin-phospholipid complex for tubercular therapy: synthesis, physicochemical characterization and in-vivo evaluation.

To enhance the oral bioavailability of rifampicin (RMP), the newly emerging phospholipid complexation technique was employed. Rifampicin-phospholipid complex (RMP-PC) was prepared by solvent-evaporation method. Infrared spectroscopy (IR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), powder X-ray diffraction (PXRD) and hot stage microscopy (HSM) analysis were employed to confirm the formation of phospholipid complex. The results reveal hydrogen bond formation and electrostatic interaction between RMP and phospholipid molecule play an important role in the formation of RMP-PC without the formation of a new compound. In comparison with the physical mixture and RMP, solubility studies indicated an enhancement in the aqueous solubility of RMP-PC. Stability studies of RMP-PC in presence of isoniazid showed a remarkable improvement of the stability of the phospholipid complex in comparison to free RMP. Oral bioavailability of RMP-PC was evaluated in Sprague-Dawley (SD) rats and plasma rifampicin estimated by LCMS. RMP-PC exhibited higher peak plasma concentration (54.3 vs. 48.5 µg/mL), increased AUC0-∞ (472.4 vs. 147.71 5.812 ± 0.49 µg h/mL), increased T1/2 (8.3 vs. 1.5h) when compared to free RMP implying improved bioavailability of the drug. This enhancement can be attributed to the improvement of the aqueous solubility of rifampicin-phospholipid complex. Hence, phospholipid complexation holds a promising potential for increasing oral bioavailability of poorly water soluble drugs.

Hepatoprotective agent tethered isoniazid for the treatment of drug-induced hepatotoxicity: Synthesis, biochemical and histopathological evaluation.

The aim of the study was to investigate the protective effect of isoniazid-curcumin conjugate (INH-CRM) in INH-induced hepatic injury by biochemical analysis and histology examination of liver in Wistar rats. The biochemical analysis included determination of the levels of plasma cholesterol, triglycerides (TG), albumin content, and lipid peroxidation (MDA). INH-CRM administration resulted in a significant decrease in plasma cholesterol, TG, and MDA levels in the liver tissue homogenate with an elevation in albumin level indicating its hepatoprotective activity. Histology of the liver further confirmed the reduction in hepatic injury. The hepatoprotective with INH-CRM can be attributed to the antioxidant activity of curcumin. The conjugate probably stabilizes the curcumin molecule, preventing its presystemic metabolism thereby enhancing its bioavailability and therefore, its hepatoprotective activity. Thus, the novel INH-CRM has the potential to alleviate INH-induced liver toxicity in antitubercular treatment.