Ketan Hippalgaonkar

Injectable Lipid Emulsions—Advancements, Opportunities and Challenges

Injectable lipid emulsions, for decades, have been clinically used as an energy source for hospitalized patients by providing essential fatty acids and vitamins. Recent interest in utilizing lipid emulsions for delivering lipid soluble therapeutic agents, intravenously, has been continuously growing due to the biocompatible nature of the lipid-based delivery systems. Advancements in the area of novel lipids (olive oil and fish oil) have opened a new area for future clinical application of lipid-based injectable delivery systems that may provide a better safety profile over traditionally used long- and medium-chain triglycerides to critically ill patients. Formulation components and process parameters play critical role in the success of lipid injectable emulsions as drug delivery vehicles and hence need to be well integrated in the formulation development strategies. Physico-chemical properties of active therapeutic agents significantly impact pharmacokinetics and tissue disposition following intravenous administration of drug-containing lipid emulsion and hence need special attention while selecting such delivery vehicles. In summary, this review provides a broad overview of recent advancements in the field of novel lipids, opportunities for intravenous drug delivery, and challenges associated with injectable lipid emulsions.

Indomethacin-Loaded Solid Lipid Nanoparticles for Ocular Delivery: Development, Characterization, and In Vitro Evaluation

PURPOSE The goal of this study was to develop and characterize indomethacin-loaded solid lipid nanoparticles (IN-SLNs; 0.1% w/v) for ocular delivery. METHODS Various lipids, homogenization pressures/cycles, Tween 80 fraction in the mixture of surfactants (Poloxamer 188 and Tween 80; total surfactant concentration at 1% w/v), and pH were investigated in the preparation of the IN-SLNs. Compritol(®) 888 ATO was selected as the lipid phase for the IN-SLNs, as indomethacin exhibited a highest distribution coefficient and solubility in this phase. RESULTS Homogenization at 15,000 psi for 6 cycles resulted in the smallest particle size. Increase in the Poloxamer 188 fraction resulted in decrease in the entrapment efficiency (EE). The mean particle size, polydispersity index, zeta-potential, and EE of the optimized formulation were 140 nm, 0.16, -21 mV, and 72.0%, respectively. IN-SLNs were physically stable post-sterilization and on storage for a period of 1 month (last timepoint tested). A dramatic increase in the chemical stability and in vitro corneal permeability of indomethacin was observed with the IN-SLN formulation in comparison to the indomethacin solution- (0.1% w/v) and indomethacin hydroxypropyl-beta-cyclodextrin-based formulations (0.1% w/v). CONCLUSION Results from this study suggest that topical IN-SLNs could significantly improve ocular bioavailability of indomethacin.

Interaction between Topically and Systemically Coadministered P-Glycoprotein Substrates/Inhibitors: Effect on Vitreal Kinetics

The objective of the present study was to investigate the effect of topically coadministered P-glycoprotein (P-gp) substrates/inhibitors on the vitreal kinetics of a systemically administered P-gp substrate. Anesthetized male rabbits were used in these studies. The concentration-time profile of quinidine in the vitreous humor, after intravenous administration, was determined alone and in the presence of topically coadministered verapamil, prednisolone sodium phosphate (PP), and erythromycin. The vitreal pharmacokinetic parameters of quinidine in the presence of verapamil [apparent elimination rate constant (λz), 0.0027 ± 0.0002 min−1; clearance (CL_F), 131 ± 21 ml/min; area under the curve (AUC0–∞), 39 ± 7.0 μg · min/ml; and mean residence time, 435 ± 20 min] were significantly different from those of the control (0.0058 ± 0.0006 min−1, 296 ± 46 ml/min, 17 ± 3 μg · min/ml, and 232 ± 20 min, respectively). A 1.7-fold decrease in the vitreal λz and a 1.5-fold increase in the vitreal AUC of quinidine were observed in the presence of topical PP. Statistically significant differences between the vitreal profiles of the control and erythromycin-treated group were also observed. Plasma concentration-time profiles of quinidine, alone or in the presence of the topically instilled compounds, remained unchanged, indicating uniform systemic quinidine exposure across groups. This study demonstrates an interaction between topically and systemically coadministered P-gp substrates, probably through the modulation of P-gp on the basolateral membrane of the retinal pigmented epithelium, leading to changes in the vitreal kinetics of the systemically administered agent.

Vitreal Kinetics of Quinidine in Rabbits in the Presence of Topically Coadministered P-Glycoprotein Substrates/Modulators

The purpose of this study was to investigate whether topically administered P-glycoprotein (P-gp) substrates/modulators can alter vitreal kinetics of intravitreally administered quinidine. Male New Zealand rabbits were used under anesthesia. Vitreal kinetics of intravitreally administered quinidine (0.75-μg dose) was determined alone and in the presence of verapamil (coadministered topically/intravitreally) or prednisolone hemisuccinate sodium (PHS) (coadministered topically). In the presence of topically instilled verapamil (1% w/v), elimination half-life (t1/2) (176 ± 7 min), apparent elimination rate constant (λz) (0.0039 ± 0.0001 min–1), and mean retention time (MRT) (143 ± 30 min) of intravitreally administered quinidine were significantly different from those of the control (105 ± 11 min, 0.0066 ± 0.0007 min–1, and 83 ± 13 min, respectively). A 2-fold increase in the t1/2 with a corresponding decrease in λz and a 1.5-fold increase in the MRT of quinidine were observed in the presence of topically coadministered 2% w/v PHS. Intravitreal coadministration of quinidine and verapamil resulted in a significant increase in t1/2 (159 ± 9 min) and a decrease in λz (0.0043 ± 0.0002 min–1) of quinidine. The vitreal pharmacokinetic parameters of sodium fluorescein, alone or in the presence of topically instilled verapamil, did not show any statistically significant difference, indicating that ocular barrier integrity was not affected by topical verapamil administration. Results from this study suggest that topically applied P-gp substrates/modulators can alter vitreal pharmacokinetics of intravitreally administered P-gp substrates, possibly through the inhibition of P-gp expressed on the basolateral membrane of the retinal pigmented epithelium.

Intravitreal kinetics of hesperidin, hesperetin, and hesperidin G: effect of dose and physicochemical properties.

Hesperidin, a flavanone glycoside, and its aglycone hesperetin are potential candidates for the treatment of diabetic retinopathy and macular edema. The objective of this study was to delineate vitreal pharmacokinetics of hesperidin and hesperetin and the hydrophilic derivative glucosyl hesperidin (hesperidin G) following intravitreal administration in anaesthetized rabbits. Concentration changes in vitreous humor were monitored using microdialysis sampling procedure. All three molecules were administered intravitreally at three dose levels (50 µL injection volume containing 1.5, 4.5, and 15 µg of the drug, resulting in a final vitreal concentration of 1, 3, and 10 µg/mL). Vitreal microdialysis samples were collected every 20 min over a period of 10 h. All three molecules exhibited linear pharmacokinetics within the dose range tested because area under the curve and maximum concentration (C(max) ) increased linearly with increasing dose and a significant difference in the elimination parameters such as clearance or half-life was not observed. The vitreal elimination half-life of these three compounds was observed to correlate with the molecular weight and lipophilicity of the molecules. The findings from this study provide practical information that will be useful in the future design of ocular drug delivery strategies for bioflavonoids.

Evaluation of the Intravenous and Topical Routes for Ocular Delivery of Hesperidin and Hesperetin

PURPOSE The objective of this study was to determine the ocular bioavailability of hesperidin and hesperetin, especially with respect to their distribution into the posterior segment of the eye, following systemic and topical administration in rabbits. METHODS Hesperidin and hesperetin were administered either intravenously or topically to male New Zealand white (NZW) rabbits. Vitreous humor and plasma samples were collected after intravenous administration and analyzed to estimate the concentrations of the parent compounds and their metabolites. Ocular tissue concentrations, obtained on topical administration of hesperidin and hesperetin, were also determined. RESULTS In the systemic circulation, hesperidin and hesperetin were rapidly metabolized into their glucuronides, which are extremely hydrophilic in nature. Vitreal samples did not demonstrate any detectable levels of hesperidin/hesperetin following intravenous administration. Topical administration produced significant concentrations of hesperidin/hesperetin in all the ocular tissues tested at the 1 and 3 hours time points postdosing, with hesperetin showing higher levels compared to hesperidin. However, only low levels were generated in the vitreous humor. Inclusion of a penetration enhancer, benzalkonium chloride (BAK), improved the back-of-the-eye hesperetin levels. CONCLUSIONS Ocular delivery of hesperidin/hesperetin via the systemic route does not seem to be feasible considering the rapid generation of the hydrophilic metabolites. Topical application appears to be more promising and needs to be further developed/refined.