In vitro & in vivo evaluations of PLGA nanoparticle based combinatorial drug therapy for baclofen and lamotrigine for neuropathic pain management

Abstract

Aim

Baclofen and Lamotrigine via PLGA nanoparticles were developed for nose-to-brain delivery for the treatment of Neuropathic pain.

Methods

Nanoparticles were prepared using the modified nano-precipitation method. The prepared NPs were characterised and further in vitro and in vivo studies were performed.

Results

The Bcf-Ltg-PLGA-NPs were ∼177.7 nm with >75%(w/w) drugs encapsulated. In vitro dissolution studies suggested zero-order release profiles following the Korsmeyer-Peppas model. In vitro cytotoxicity and staining studies on mammalian cells showed dose dependant cytotoxicity where nanoparticles were significantly less toxic (>95% cell-viability). ELISA studies on RAW-macrophages showed Bcf-Ltg-PLGA-NPs as a potential pro-inflammatory-cytokines inhibitor. In vivo gamma-scintigraphy studies on rats showed intra-nasal administration of ^99mTc-Bcf-Ltg-PLGA-NPs showed C_max 3.6%/g at T_max = 1.5h with DTE% as 191.23% and DTP% = 38.61% in brain. Pharmacodynamics evaluations on C57BL/6J mice showed a significant reduction in licks/bites during inflammation-induced phase II pain.

Conclusion

The findings concluded that the combination of these drugs into a single nanoparticle-based formulation has potential for pain management.

Highlights

• Baclofen and Lamotrigine loaded PLGA nanoparticles were prepared with a size of 177.7nm, PDI 0.057 and Zeta Potential −15.8 mV

• In vitro cell lines based studies showed dose dependant cytotoxicity and Bcf-Ltg-PLGA-NPs were found to be pro-inflammatory cytokines inhibitors

• In vivo Pharmacokinetic studies showed C_max 3.6%/g at T_max = 1.5 h with Drug Targeting Efficiency 191.23% and Drug Target Organ Transport 38.61% in the brain for prepared nanoparticles

• In vivo pharmacodynamics studies showed a significant reduction in licks/bites during inflammation-induced phase II pain

Keywords:

• Baclofen
• lamotrigine
• PLGA
• nanoparticles
• neuropathic pain

Acknowledgement

This work has been carried out with fellowship grant support from CSIR, India (File No. 09/1132(0006)/19-EMR-I). The authors would like to thank the institutes/organizations: Jaypee Institute of Information Technology, NOIDA, Institute of Nuclear Medicine & Allied Sciences, DRDO, Delhi and Sophisticated Analytical Instrumentation Facility, AIIMS, Delhi for providing the essential infrastructural support. Authors extend their humble thanks to Dr. A. K. Panda, NII, Delhi and Dr. M. Kalia, THSTI, Faridabad for their support in the completion of this work.

Ethics approval and consent to participate

Institutional ethical committee approval was taken from Jaypee Institute of Information Technology, Noida. Animal experiments were performed in Institute of Nuclear and Applied Medicine, Defence Research and Development Organisation, Delhi with prior ethical clearance from Institutional Animal Ethics Committee (IAEC vide number INM/IAEC/16/10).

Consent for publication

The publication of this article is consented to by respective departments/institutions.

Competing interests

The authors declare that they have no competing interests.

Author contributions

Kuldeep Nigam: Conceptualisation, Methodology, Investigation, Visualisation, Writing – Original Draft; Atinderpal Kaur: Visualisation, Methodology; Amit Tyagi: Methodology, Resources, Project administration; Kailash Manda: Methodology, Visualisation, Resources; Nidhi Goswami: Methodology, Formal analysis; Md Nematullah: Resources, Formal analysis; Farah Khan: Resources, Formal analysis; Reema Gabrani: Resources, Writing – Review & Editing; Pammi Gauba: Resources, Writing – Review & Editing; Shweta Dang: Conceptualisation, Methodology, Visualisation, Supervision, Project administration, Writing – Review & Editing.

Disclosure statement

The authors declare that this paper content has no conflict of interest in publication.

Data availability statement

All the data and material used in this work were available. Also, no data has been either fabricated or manipulated including images to support the conclusions.

Additional information

Funding

This work has been carried out with fellowship grant support from CSIR, India (File No. 09/1132(0006)/19-EMR-I).