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

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Abstract

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 AUC0-∞ 14.38 µg/mL.h, Cmax 7.77 ± 1.65 µg/mL, Tmax, 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 AUC0-∞ compared to PIP-TPGS-PAMAM. The brain uptake studies revealed PIP-TPGS-PAMAM treated group showed 2.2 ± 0.37 µg/g PIP content compared to free PIP administered group which was 0.4 ± 0.10 µg/g. Therefore, PIP-TPGS-PAMAM can offer excellent prospect for the delivery hydrophobic drugs to brain in AD.

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Data Availability

All experimental or analysis data of this study are reported in manuscript tables and figures.

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Acknowledgements

The authors acknowledge the Department of Pharmaceuticals under the Ministry of Chemicals and Fertilizers, Government of India, for research facility. We also acknowledge the Animal Ethics Committee of NIPER-R for allowing the animal experiments having no. NIPER/RBL/IAEC/80/August 2021. The NIIPER communication no. is 317.

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Authors and Affiliations

  1. Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER-Raebareli), Near CRPF Base Camp, Bijnor-Sisendi Road, Sarojini Nagar, Lucknow, (UP)-226002, India

    Ajit Singh, Akshada Mhaske & Rahul Shukla

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  1. Ajit Singh
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Contributions

Dr. Rahul Shukla, supervision, conceptualization, methodology, and investigation. Ajit Singh, validation, visualization, data curation, analysis, data interpretation, and investigation. Akshada Mhaske, review and editing.

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Correspondence to Rahul Shukla.

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Singh, A., Mhaske, A. & Shukla, R. Fabrication of TPGS-Grafted Polyamidoamine Dendrimer for Enhanced Piperine Brain Delivery and Pharmacokinetics. AAPS PharmSciTech 23, 236 (2022). https://doi.org/10.1208/s12249-022-02393-8

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