Formulation and optimization of intranasal nanolipid carriers of pioglitazone for the repurposing in Alzheimer’s disease using Box-Behnken design

Abstract

Growing evidence suggest that Alzheimer’s disease (AD), the most common cause of dementia among the elderly is a metabolic disorder associated with impaired brain insulin signaling. Hence, the diabetic drug can be a therapeutic option for the management AD. The researches in this area are ongoing and Pioglitazone (PIO) is one of the most investigated diabetic drug in AD. Eventhough PIO treatment was found to improve AD significantly in the preclinical models, the poor blood-brain barrier (BBB) permeability and serious peripheral side effects limited its success in the clinical trials. The objective of the present study was to formulate and optimize intranasal (IN) nano lipid carriers (NLC) of PIO for its targeted delivery to the brain. A Box-Behnken design was employed to optimize the effect of three independent variables on two dependent variables. The optimized formulation had a particle size (PS) of 211.4 ± 3.54 nm and zeta potential of (ZP) of 14.9 ± 1.09 mv. The polydispersibility index (PDI) and entrapment efficiency (EE) was found to be 0.257 ± 0.108 and 70.18 ± 4.5% respectively. Storage stability studies performed has confirmed the stability of NLCs at 4 °C and 25 °C. The in-vitro drug release study has exhibited a sustained release of drug from the NLC. The formulation was observed to improve the nasal permeability of PIO ex-vivo significantly. Toxicity studies were performed to confirm the safety of formulation for the in-vivo administration. In-vivo biodistribution study in rats has shown a direct transport of drug from the nose to brain from the IN-NLC.

Keywords:

• Intranasal route
• pioglitazone
• nanolipid carriers
• Box-Behnken design
• Alzheimer’s disease

Disclosure statement

The authors report no conflict of interest.

Acknowledgment

The authors would like to thank the Department of Science and Technology–Fund for Improvement of Science and Technology Infrastructure in Universities and Higher Educational Institutions (DST_FIST), New Delhi for their infrastructure support to our department.

Additional information

Funding

This work was financially supported by the University Grants Commission (UGC), Government of India, under the scheme of the UGC-MANF Fellowship. The author, Ms Gifty M Jojo wishes to express his gratitude to the University Grants Commission (UGC), New Delhi, India for the award of the UGC-MANF Fellowship [2016–17/MANF-2015–17-KER-54943].