Brain targeting of chitosan-based diazepam mucoadhesive microemulsions via nasal route: formulation optimization, characterization, pharmacokinetic and pharmacodynamic evaluation.

OBJECTIVE: The aim of present investigation was to develop microemulsions (MEs) and mucoadhesive microemulsions (MME) of diazepam for brain uptake through nasal administration for the treatment of seizure emergency. SIGNIFICANCE: Status epilepticus (SE) is a medical emergency, requires intravenous administration of diazepam which requires hospitalization of patient. Initiation of therapy at home via nasal administration of diazepam could prevent the damage of brain due to delay of therapy initiation. METHODS: Diazepam MEs were prepared by phase titration method, optimized by using Box-Behnken design. The influence of independent variables oleic acid, surfactant mixture (tween 80:propylene glycol), and water on dependent variables size, flux, and zeta potential was investigated. Optimized MEs, MMEs, and Calmpose (i.v route) were evaluated for pharmacokinetic and pharmacodynamic studies on rats. RESULTS: MME2 composed of oleic acid (5), surfactant mixture (50), water (45), and chitosan (0.5) showed size of 96.45 nm, PDI 0.21 and zeta potential 13.52 mV. MME2 showed significantly high flux of 846.96 ± 34 µg/cm2/h and AUCbrain 1206.49 ± 145.8. The drug targeting efficiency (314%) and direct nose-to-brain transport (68.1%) of MME2 were significantly high compared to Calmpose (i.v) and ME. The latency periods of minimal clonal seizures and generalized tonic-clonic seizures of MME2 was significantly increased (p < 0.0001) compared to drug solution and Calmpose (i.v). CONCLUSION: The brain uptake of diazepam from chitosan-based MMEs via nasal route is significantly high compared to i.v route.

Formulation and pharmacokinetics of diclofenac lipid nanoemulsions for parenteral application.

The objective of the present study was to formulate and determine the pharmacokinetics of stable o/w parenteral lipid nanoemulsions (LNEs) of diclofenac acid used to treat arthritic conditions. The LNEs of diclofenac acid with a mean size ranging from 200 to 240 nm and a zeta potential of -29.4 ± 1.04 mV (negatively charged LNEs) and 62.1 ± 3.5 (positively charged LNEs) emulsions were prepared by hot homogenization and ultrasonication process. The influence of formulation variables, such as the change in proportion of cholesterol, was studied, and optimized formulations were developed. The optimized formulations were relatively stable during centrifugal stress, dilution stress, and storage. The drug content and entrapment efficiency were determined using high-performance liquid chromatography. The in vitro drug release was carried out in phosphate-buffered saline pH 7.4 and cumulative amount of drug released was estimated using a UV-visible spectro-photometer. During in vivo pharmacokinetic studies in male Wistar rats, diclofenac serum concentration from LNEs was higher than that of Voveran injection and was detectable up to 12 h. Diclofenac in LNEs showed improved pharmacokinetic profile with increase in area under the curve, elimination half-life and mean residence time in comparison to Voveran. LAY ABSTRACT: Our aim was to prepare and determine the pharmacokinetics of injectable lipid nanoemulsions of diclofenac acid for treating arthritic conditions by reducing the frequency of dosing and pain at site of injection. The nanoemulsions of diclofenac acid were prepared by homogenization and ultrasonication process. The sizes and charges of oil globules were determined. The effect of cholesterol on stability of emulsion was studied, and an optimized preparation was developed. The optimized formulations were stable during centrifugation, dilution, and storage. The total amount of drug in emulsion and percentage amount of drug present in emulsion globules were determined using high-performance liquid chromatography. The drug release from preparation was carried out in phosphate-buffered saline pH 7.4. The cumulative amount of drug released was estimated using a spectrophotometer. The time course of the released drug in rat serum was determined. Diclofenac concentrations from lipid nanoemulsions were higher than that of Voveran injection (solution form) in serum.