Clozapine-laden carbon dots delivered to the brain via an intranasal pathway: Synthesis, characterization, ex vivo , and in vivo studies

Clozapine, which is widely used to treat schizophrenia, shows low bioavailability due to poor solubility and high first -pass metabolism. The study aimed to design clozapine-loaded carbon dots (CDs) to enhance availability of the clozapine to the brain via intranasal pathway. The CDs were synthesized by pyrolysis of citric acid and urea at 200 degrees C by hydrothermal technique and characterized by photoluminescence, transmission electron microscopy (TEM), X-ray Photoelectron Spectrometer (XPS), and Fourier transform infrared spectrum (FTIR). The optimized clozapine-loaded CDs (CLZ-CDs-1:3 - 200) showed a quasi -spherical shape (9 - 12 nm) with stable blue fluorescence. The CDs showed high drug solubilization capacity (1.5 mg drug in 1 mg/ml CDs) with strong electrostatic interaction with clozapine (drug loading efficiency = 94.74%). The ex vivo release study performed using nasal goat mucosa showed sustained release of clozapine (43.89%) from CLZ-CDs-1:3 - 200 for 30 h. The ciliotoxicity study (histopathology) confirmed no toxicity to the nasal mucosal tissues using CDs. In the rat model ( in vivo pharmacokinetic study), when CDs were administrated by the intranasal route, a significantly higher concentration of clozapine in the brain tissue (C max = 58.07 +/- 5.36 mu g/g and AUC t ( mu g/h*g) = 105.76 +/- 12.31) was noted within a short time (t max =1 h) compared to clozapine suspension administered by intravenous route (C max = 20.99 +/- 3.91 mu g/g, AUC t ( mu g/h*g) = 56.89 +/- 12.31, and t max = 4 h). The high value of drug targeting efficiency (DTE, 486%) index and direct transport percentage (DTP, 58%) indicates the direct entry of clozapineCDs in the brain via the olfactory route. In conclusion, designed CDs demonstrated a promising dosage form for targeted nose -to -brain delivery of clozapine for the effective treatment of schizophrenia.