Therapeutic Availability Research Articles

Aerosol-based efficient delivery of azithromycin to alveolar macrophages for treatment of respiratory infections

The efficacy of aerosol-based delivery of azithromycin (AZM) for the treatment of respiratory infections caused by pathogenic microorganisms infected in alveolar macrophages (AMs) was evaluated by comparison with oral administration. The aerosol formulation of AZM (0.2 mg/kg) was administered to rat lungs using a Liquid MicroSprayer®. The oral formulation of AZM (50 mg/kg) was used for comparison. Time-courses of concentrations of AZM in AMs following administration were obtained, and then the therapeutic availability (TA) was calculated. In addition, the area under the concentrations of AZM in AMs – time curve/minimum inhibitory concentration at which 90% of isolates ratio (AUC/MIC90) were calculated to estimate the antibacterial effects in AMs. The TA of AZM in AMs following administration of aerosol formulation was markedly greater than that following administration of oral formulation. In addition, the AUC/MIC90 of AZM in AMs was markedly higher than the effective values. This indicates that the aerosol formulation could be useful for the treatment of respiratory infections caused by pathogenic microorganisms infected in AMs. This study suggests that aerosolized AZM is an effective pulmonary drug delivery system for the treatment of respiratory infections.

Albumin coupled lipid nanoemulsions of diclofenac for targeted delivery to inflammation

Diclofenac lipid nanoemulsions (DLNEs) were prepared with different compositions. Based on size, PDI, zeta potential, and in vitro drug release, the optimized DLNEs (DLNE-4 and DLNE-7) were developed and evaluated for drug content, entrapment efficiencies, and stability in comparison to the control formulation (DLNE-1). The albumin was coupled to DLNE-7 globules (DLNE-8) by water soluble carbodiimide (EDC) method, purified, and quantified by modified Bradford method. The pharmacokinetic study was conducted in inflammation (granuloma air pouch model) induced rats. The maximum peak concentration of DLNE-8 was almost fourfold to fivefold in comparison to drug solution in granuloma air pouch fluid (GAPF). The therapeutic availability (TA) of DLNE-8 was 2.89, 2.34, and 1.66 times that of drug solution, DLNE-4 and DLNE-7, respectively. The GAPF/serum ratio of diclofenac from DLNE-8 was above one at all time points indicating the targeting potential of albumin ligated LNEs to inflammatory sites. From the Clinical EditorThis study demonstrates targeted delivery of diclofenac to an inflammatory environment using the granuloma air pouch model and diclofenac nanoemulsions with different compositions.

Brain delivery of transferrin coupled indinavir submicron lipid emulsions—Pharmacokinetics and tissue distribution

Indinavir, an antiretroviral protease inhibitor used in treatment of HIV infection has limited penetration into brain due to efflux of P-glycoprotein. The aim of this work was to develop transferrin coupled submicron lipid emulsions (SLEs) containing indinavir for delivery to brain. Stearylamine containing SLEs were prepared, characterized, tested for stability and optimized formulation (SLE-4) was developed. Transferrin was coupled to get SLE-6 by water soluble EDC method and purified by gel filtration. The coupled transferrin was quantified by modified Bradford dye assay method. The fluorescent dye (DiD oil) incorporated SLEs were used to check the brain specific delivery of SLEs. The in vivo pharmacokinetic and tissue distribution were conducted in mice. During pharmacokinetic studies, there was no significant difference in the serum levels of indinavir from SLE-1, SLE-4 and SLE-6 formulations at all time points. In tissue distribution studies the therapeutic availability (TA) of indinavir in brain from SLE-6 was 4.69, 3.1 and 1.7 times higher than drug solution, SLE-1 and SLE-4 respectively whereas, the TA of indinavir from SLE-4 was 2.76 and 1.82 times the drug solution and SLE-1. The brain to serum ratios with SLE-6 were above one indicates the brain specific delivery. The brain delivery of indinavir was improved with transferrin ligand attachment to SLEs by receptor mediated transcytosis.

Development of Indinavir Submicron Lipid Emulsions Loaded with Lipoamino Acids—In Vivo Pharmacokinetics and Brain-Specific Delivery

The aim of our present work was to develop indinavir O/W submicron lipid emulsions (SLEs) loaded with lipoamino acids for specific delivery to brain. Tetradecyl aspartic acid (A) and decyl glutamic acid (G) loaded stable SLEs of indinavir having a mean size range of 210-220 nm and average zeta potential of -23.54±1.2 mV were developed using homogenization and ultrasonication. The cumulative % drug release from different SLEs varied in between 26% and 85%. The formulations, SLE, SLE-A3, and SLE-G3 were stable to the centrifugal stress, dilution stress, and storage at RT. The total drug content and entrapment efficiency were determined by HPLC method. During pharmacokinetic studies in male Wistar rats there was no significant difference in the serum levels of indinavir for SLE, SLE-A3 and SLE-G3 formulations at all time points. In tissue distribution studies, the therapeutic availability (TA) of indinavir in brain and kidneys for SLE-A3 were 4.27- and 2.66-fold whereas for SLE-G3 were 2.94 and 2.12 times, respectively, higher than that of indinavir solution. But when compared with that of SLE, in brain tissue the levels of indinavir from SLE-G3 and SLE-A3 varied in between 2.5- and 3.38-fold. While in case of the kidney, it was between 1.23- and 1.54-fold only. However, the TA is not significantly different in tissues like the heart, liver, and spleen. Thus, brain-specific delivery of indinavir was improved by including tetradecyl aspartic acid and decyl glutamic acid in submicron lipid emulsions.

Brain specific delivery of pegylated indinavir submicron lipid emulsions

The aim of this study was to develop stable parenteral pegylated indinavir submicron lipid emulsions (SLEs) for improving brain specific delivery. The O/W SLEs were prepared by homogenization and ultra sonication process. The sizes of oil globules varied from 241.5 to 296.4 nm and zeta potential from −26.6 to −42.4 mV. During in vitro drug release studies the cumulative amount of drug released within 12 h from SLE-5, DSP2-3 and DPP5-3 was 71.8 ± 0.76, 66.09 ± 1.45 and 68.33 ± 1.29, respectively. The total drug content and entrapment efficiencies were determined. The optimized formulations were stable for the effect of centrifugal stress, thermal stress, dilution stress and storage. In vivo pharmacokinetic and tissue distribution studies were performed in Swiss albino mice, the therapeutic availability (TA) of DSP2-3 was 3.59 times and 2.36 times in comparison to drug solution and SLE-5 respectively, where as DPP5-3 showed TA 2.8 and 1.84 times the drug solution and SLE-5, respectively. The brain to serum ratio of indinavir from DSP2-3 and DPP5-3 varied between 0.4 and 0.7 at all time points indicated the preferential accumulation of drug in brain. In conclusion, pegylated SLEs improved brain specific delivery of indinavir and will be useful in treating chronic HIV infection.

Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. V. Biological disposition and targeting characteristics of osteotropic estradiol.

An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug has been developed for 17 beta-estradiol (E2) to improve patient compliance in estrogen replacement therapy of postmenopausal osteoporosis. The biological disposition and the targeting efficiency of a bisphosphonic prodrug of E2, disodium [17 beta-(3'-hydroxy-1',3',5'-estratrienyloxy)carbonylpropyl carboxamidomethylene]bisphosphonate (E2-BP), was investigated in ovariectomized rats. After intravenous injection, E2-BP was rapidly taken up into the bone and subsequently cleared from the bone at a half-life of 13.5 d. The bone concentration of regenerated E2 was maintained throughout 28 d. In contrast, E2 injected intravenously showed extremely low bone distribution and rapid clearance from the bone, and E2 administered orally showed even lower bone distribution. Therapeutic availability (TA) and drug targeting index (DTI), which were calculated on the basis of the AUCs for E2 in the bone and plasma after injection of E2-BP and E2, were 64.6 and 451, respectively. These results suggest that ODDS has a potential to improve not only the apparent potency but also the therapeutic index of E2. As compared with the conventional estrogenic products, E2-BP should improve patient compliance with lower adverse effects and less frequent medication in long-term estrogen replacement therapy.

Osteotropic drug delivery system (ODDS) based on bisphosphonic prodrug. III: Pharmacokinetics and targeting characteristics of osteotropic carboxyfluorescein.

An osteotropic drug delivery system (ODDS) based on a bisphosphonic prodrug has been developed as a novel method for site-specific and controlled delivery of drugs to the bone. The pharmacokinetics and the targeting efficiency of a bisphosphonic prodrug of carboxyfluorescein (CF), disodium (fluorescein-6-carbonyloxy) acetoaminomethylene bisphosphonate (CF-BP), was investigated in rats. After intravenous injection, CF-BP was rapidly taken up into the skeleton, and subsequently cleared from the bone by hydrolysis of its ester linkage at a half-life of 3.2 days. On the other hand, the bone concentration of regenerated CF gradually increased to reach the maximum at 14 days and slowly decreased up to 56 days. Kinetical analysis revealed that bone tissue acts as a reservoir of regenerated CF to supply the parent compound into the systemic circulation. In contrast with CF-BP, CF injected intravenously showed rapid clearance from the plasma and extremely low bone distribution. Therapeutic availability (TA) and drug targeting index (DTI), which were calculated on the basis of the AUCs for CF in the bone and plasma after injection of CF-BP and CF, were 1551 and 6689, respectively. These results suggest that ODDS has a potential to improve not only apparent potency but also therapeutic index of the drugs which exhibit their pharmacological effects in the bone.