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Nose-to-brain delivery of lamotrigine-loaded PLGA nanoparticles

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Abstract

Direct nose-to-brain delivery of drugs and faster onset of action have made intra-nasal route a much sought-after alternative to conventional routes of drug delivery to the brain. Lamotrigine is used for the treatment and management of neuropathic pain, and in the present work, lamotrigine (LTG)-PLGA nanoparticles were developed for intra-nasal delivery. The LTG-PLGA nanoparticles were prepared using modified nanoprecipitation method via high-speed homogenization and ultra-sonication techniques. Entrapment efficiency (EE%) of developed LTG-PLGA-NPs was found to be 84.87 ± 1.2% with drug loading of 10.21 ± 0.89%. The particle size of developed nanoparticles was found to be 184.6 nm with PDI value of 0.082 and zeta potential of − 18.8 mV. Dissolution profiles were studied in PBS (pH 7.4), simulated nasal fluid, and simulated cerebrospinal fluid where almost complete release was observed within 5 h in CSF. In vitro, cytotoxicity was analyzed using MTT assay where dose-dependent cytotoxicity was observed for developed LTG-PLGA-NPs. In vitro cytokine analysis showed positive effects of LTG-PLGA-NPs as pro-inflammatory cytokine suppressors. Further, in vivo studies were performed for radiolabeled formulation and drug (99mTc-LTG-PLGA-NPs and 99mTc-LTG-aqueous) using Sprague Dawley rats where with the help of gamma scintigraphy studies, various routes of administration viz. oral, intra-nasal, and intra-venous were compared. Various pharmacokinetic parameters were evaluated using biodistribution studies to estimate the drug levels in blood and brain. For 99mTc-LTG-PLGA-NPs via intra-nasal route, drug targeting efficiency (DTE%) was found to be 129.81% and drug target organ transport (DTP%) to be 22.81% in brain with Cmax of 3.82%/g within Tmax 1.5 h. Thus, the developed PLGA nanoparticles for intra-nasal delivery provide a possible alternative for existing available drug formulation for neuropathic pain management.

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Abbreviations

AEDs:

Antiepileptic drugs

IL:

Interleukin

I.N:

Intra-nasal

I.V.:

Intra-venous

LTG:

Lamotrigine

PLGA:

(Poly(lactic-co-glycolic acid)

NPs:

Nanoparticles

DTE:

Drug target efficiency

DTP:

Drug transport percentage

TNF-α:

Tumor necrosis factor alpha

IFN-γ:

Interferon gamma

99mTc:

Technetium-99m

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Acknowledgements

The authors would like to acknowledge Jaypee Institute of Information Technology, Noida, and Institute of Nuclear Medicine & Allied Sciences, Delhi, for providing basic infrastructural support to carry out the project. The authors would like to thank Dr. A. Panda, National Institute of Immunology, Delhi, and Dr. M. Kalia, Translational Health Science And Technology Institute, Faridabad, for providing required resources for completion of this work.

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Authors and Affiliations

  1. Department of Biotechnology, Jaypee Institute of Information Technology, A-10, Sector-62, Noida, 201309, India

    Kuldeep Nigam, Atinderpal Kaur, Reema Gabrani & Shweta Dang

  2. Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organisation, Timarpur, Delhi, 110054, India

    Amit Tyagi

  3. Department of Biochemistry, Faculty of Science, Jamia Hamdard, New Delhi, 110062, India

    Md Nematullah & Farah Khan

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  1. Kuldeep Nigam
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  2. Atinderpal Kaur
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  4. Md Nematullah
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The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

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Correspondence to Shweta Dang.

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Fig S1

Particle size distribution of developed LTG-PLGA-NPs. (PNG 19 kb)

High resolution image (TIFF 27 kb)

Fig S2

Zeta potential distribution of developed LTG-PLGA-NPs (PNG 15 kb)

High resolution image (TIFF 20 kb)

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Nigam, K., Kaur, A., Tyagi, A. et al. Nose-to-brain delivery of lamotrigine-loaded PLGA nanoparticles. Drug Deliv. and Transl. Res. 9, 879–890 (2019). https://doi.org/10.1007/s13346-019-00622-5

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