In vivo brain microdialysis as a formulation-screening tool for a poorly soluble centrally acting drug.

OBJECTIVE: Efficacy of a formulation of a poorly soluble centrally acting drug was evaluated by measuring dopamine responses using in vivo brain microdialysis. METHODS: Co-crystals (1:1) of carbamazepine and nicotinamide (CBZ-NCT) were complexed with cyclodextrins (γ-CDs) using supercritical fluid processing. Phase solubility and intrinsic dissolution were studied. Pharmacodynamic studies were performed on rats divided into three groups getting either CBZ-NCT in CD (20 mg/kg CBZ), pure CBZ solution or vehicle. A guide cannula was implanted to attach the microdialysis probe. Dialysate samples were analyzed for dopamine levels, which were compared between groups. RESULTS: The optimized CBZ formulation (5% w/w in γ-CD) with solubility - 10 mg/mL showed stepwise increase in dopamine response (maximum 250% of baseline) compared to neat CBZ or vehicle (p < 0.05). The pharmacokinetics of the drug required 30 min to elicit CNS response, which peaked at about 1.5-2 h. CONCLUSION: Hence, brain microdialysis was successfully used to evaluate a dissolution rate enhancing formulation.

In vivo brain microdialysis to evaluate FITC-dextran encapsulated immunopegylated nanoparticles.

CONTEXT: Delivery of drugs and dyes through intact blood-brain barrier (BBB) is extremely sought-after. A safe and reliable measurement of delivery efficacy in live animals is necessary. OBJECTIVE: To investigate the brain uptake of FITC-dextran MW 4000 (FD4) by CD71/OX-26 coated nanoparticles by microdialysis sampling and fluorescence/confocal microscopy. MATERIALS AND METHODS: Methoxy-poly(ethylene glycol)-poly(lactide) (Met-PEG-PLA) and maleimide-poly(ethylene glycol)-poly(lactide) (Mal-PEG-PLA) nanoparticles were prepared by nanoprecipitation. The surfaces of the prepared nanoparticles were embellished with CD-71/OX-26 antibodies for brain targeting. Male Sprague Dawley rats received 0.4 mg/kg FD4 and equivalent nanoparticulate formulation through lateral tail vein. Animals were euthanized 24 h postadministration, after which the tissues were harvested and analyzed for FD4 concentrations. Tissues were fixed with paraformaldehyde, cryotomed to 20 µm sections, and analyzed by Total Internal Reflection microscopy. RESULTS: Particle sizes of 200 ± 25 nm and zeta potentials of -18 ± 1 mV were obtained. FD4 concentrations, determined using in vivo brain microdialysis, were high on the first day (~360 ng/mL) compared to 60 ng/mL on the following 2 days. The nanoparticle treated animals showed significantly higher (p < 0.05) FD4 concentrations in the brain than pure-FD4 treated animals. Immunopegylated nanoparticles sustained and enhanced Central nervous system (CNS) concentration of hydrophilic dye for at least 3 days. CONCLUSION: Immunopegylated nanoparticles produce enhanced and sustained uptake of brain permeability marker FD4 relative to controls.

Efficacy of surface charge in targeting pegylated nanoparticles of sulpiride to the brain.

The objective of the study was to formulate sulpiride-loaded nanoparticles (NPs) that can improve bioretention and achieve dose reduction by passively targeting the drug near the site of action. Methoxy PEG-PLA and maleimide PEG-PLA were synthesized via ring opening polymerization of L-lactide and used to prepare pegylated nanoparticles (NPs) loaded with sulpiride by emulsification and solvent evaporation method. Thiolated cationized bovine serum albumin (CBSA) was conjugated through the maleimide function to the NPs. Rhodamine B and Alexa Fluor 488 were used as fluorescent markers for nanoparticle uptake studies. The nanoparticles were characterized for particle size, zeta potential and drug loading. Sprague Dawley rats were administered with each of CBSA-NPs, BSA-NPs and uncoated NPs (10mg/kg) via tail vein; plasma and urine concentrations were measured and tissue sections were observed under fluorescence microscope. Characterized particles (mean particle size 329+/-44 nm) indicated the conjugation of cationic albumin to NPs (zeta potential shift from -39 mV to -19 mV). Fluorescence showed a high accumulation of CBSA-NPs in brain compared to that of BSA-NPs and uncoated NPs supported by plasma and urine profile. The significant results proved that CBSA-NPs could be a promising brain drug delivery for sulpiride.