Fabrication of TPGS-Grafted Polyamidoamine Dendrimer for Enhanced Piperine Brain Delivery and Pharmacokinetics

Piperine (PIP) is a neuroprotective phytomedicine that has profound acetylcholine esterase and reactive oxygen species inhibition effect in Alzheimer's disease (AD) model. However, the oral delivery of PIP is limited by poor aqueous solubility and low bioavailability in systemic circulation. To improve the PIP bioavailability, the polyamidoamine (PAMAM) G4 dendrimer is grafted with tocopheryl polyethylene glycol succinate-1000 (TPGS) through carbodiimide chemistry to form TPGS-PAMAM conjugate. The TPGS-PAMAM coupling was confirmed through proton NMR and FTIR techniques. PIP was encapsulated in the TPGS-PAMAM through solvent diffusion method to form PIP-TPGS-PAMAM. The particle size for PIP-TPGS-PAMAM found the less than 50 nm, whereas entrapment efficiency found to 87 +/- 3.5% and 10.6 +/- 2.9% drug loading. The powder differential scanning calorimetry and powder X-ray diffraction characterization were employed to evaluate the amorphous encapsulation of the PIP in TPGS-PAMAM. The PIP-TPGS-PAMAM stability was studied in the gastric fluids which showed no drastic difference in particle size and encapsulation efficiency compared to PIP-PAMAM. The in vitro release analysis revealed 37 +/- 4.1% PIP release from the PIP-TPGS-PAMAM matrix, and 71 +/- 4.9% PIP release from the PIP-PAMAM dendrimer was observed in 48 h. The single-dose oral gavage to Wistar rats of PIP-TPGS-PAMAM showed the AUC(0-infinity )14.38 mu g/mL.h, C-max 7.77 +/- 1.65 mu g/mL, T-max, 1.6 +/- 0.18 h, and half-life 3.47 +/- 0.64 h for PIP in systemic circulation. PIP-PAMAM and free PIP showed significantly poor AUC(0)(-infinity) compared to PIP-TPGS-PAMAM. The brain uptake studies revealed PIP-TPGS-PAMAM treated group showed 2.2 +/- 0.37 mu g/g PIP content compared to free PIP administered group which was 0.4 +/- 0.10 mu g/g. Therefore, PIP-TPGS-PAMAM can offer excellent prospect for the delivery hydrophobic drugs to brain in AD.

Automated summary

Piperine (PIP) is a neuroprotective phytomedicine that inhibits acetylcholine esterase and reactive oxygen species in Alzheimer's disease (AD) model. To improve its bioavailability, researchers encapsulated PIP in polyamidoamine (PAMAM) G4 dendrimer, grafted with tocopheryl polyethylene glycol succinate-1000 (TPGS) through carbodiimide chemistry. The resulting PIP-TPGS-PAMAM showed good stability and release profile, and demonstrated higher bioavailability and brain uptake compared to free PIP and PIP-PAMAM. This suggests that PIP-TPGS-PAMAM could be a promising delivery system for hydrophobic drugs in AD.