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Nose-To-Brain Delivery of PLGA-Diazepam Nanoparticles

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Abstract

The objective of the present investigation was to optimize diazepam (Dzp)-loaded poly(lactic-co-glycolic acid) nanoparticles (NP) to achieve delivery in the brain through intranasal administration. Dzp nanoparticles (DNP) were formulated by nanoprecipitation and optimized using Box-Behnken design. The influence of various independent process variables (polymer, surfactant, aqueous to organic (w/o) phase ratio, and drug) on resulting properties of DNP (z-average and drug entrapment) was investigated. Developed DNP showed z-average 148–337 d.nm, polydispersity index 0.04–0.45, drug entrapment 69–92%, and zeta potential in the range of −15 to −29.24 mV. Optimized DNP were further analyzed by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), ex-vivo drug release, and in-vitro cytotoxicity. Ex-vivo drug release study via sheep nasal mucosa from DNP showed a controlled release of 64.4% for 24 h. 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay performed on Vero cell line showed less toxicity for DNP as compared to Dzp suspension (DS). Gamma scintigraphy and biodistribution study of DNP and DS was performed on Sprague-Dawley rats using technetium-99m-labeled (99mTc) Dzp formulations to investigate the nose-to-brain drug delivery pathway. Brain/blood uptake ratios, drug targeting efficiency, and direct nose-to-brain transport were found to be 1.23–1.45, 258, and 61% for 99mTc-DNP (i.n) compared to 99mTc-DS (i.n) (0.38–1.06, 125, and 1%). Scintigraphy images showed uptake of Dzp from nose-to-brain, and this observation was in agreement with the biodistribution results. These results suggest that the developed poly(D,L-lactide-co-glycolide) (PLGA) NP could serve as a potential carrier of Dzp for nose-to-brain delivery in outpatient management of status epilepticus.

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Acknowledgments

The authors would like to thank the Department of Biotechnology, Government of India for providing financial support to conduct the research work (DBT project No. BT/PR1891/MED/30/626/2011). The authors are grateful to the Jaypee Institute of Information Technology, Noida, UP (India), for the infrastructural support, Director of INMAS and Dr. Aseem Bhatnagar, Nuclear Medicine Department, for providing nuclear scintigraphy facility, and Dr. A. K. Panda from the National Institute of Immunology, New Delhi (India), for providing the facility for particle size analysis and zeta potential.

Conflict of Interest

The authors declare that this paper content has no conflict of interests.

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Authors and Affiliations

  1. Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector 62, Noida, UP, 201307, India

    Deepak Sharma, Reema Gabrani, Sanjeev K. Sharma & Shweta Dang

  2. Division of CBRN Defence, Institute of Nuclear Medicine and Allied Sciences, Brig SK Mazumdar Marg, Delhi, 110054, India

    Rakesh Kumar Sharma & Navneet Sharma

  3. Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi, 110062, India

    Javed Ali

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  1. Deepak Sharma
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Correspondence to Shweta Dang.

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Sharma, D., Sharma, R.K., Sharma, N. et al. Nose-To-Brain Delivery of PLGA-Diazepam Nanoparticles. AAPS PharmSciTech 16, 1108–1121 (2015). https://doi.org/10.1208/s12249-015-0294-0

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