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Enhanced biopharmaceutical performance of brick dust molecule nilotinib via stabilized amorphous nanosuspension using a facile acid–base neutralization approach

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Abstract

“Brick dust” compounds have high lattice energy as manifested by the poor aqueous solubility and suboptimal bioavailability. Nilotinib being a weakly basic brick dust molecule exhibits erratic and limited absorption during gastrointestinal transit, attributed to pre-absorptive factors like pH-dependent solubility, poor dissolution kinetics, and post-absorptive factors including P-gp-mediated drug efflux. In our study, these problems are addressed holistically by the successful fabrication of amorphous nanosuspension by an acid–base neutralization approach. The nanosuspension was obtained via rapid precipitation of nilotinib in an amorphous form and the generated in situ sodium chloride salt assisted in stabilizing the drug-loaded nanosuspension in a cage of salt and micellar stabilizer. Soluplus® and hypromellose acetate succinate (HPMCAS) were employed as a novel combination of stabilizers. Systematic optimization was carried out by employing the I-optimal method using Design Expert® software with a concentration of HPMCAS and Soluplus® as independent variables and evaluating them for responses viz particle size, polydispersity index (PDI), and zeta potential. The resultant nanosuspension showed a mean particle size of 130.5 ± 1.22 nm with a PDI value of 0.27 ± 0.01, and a zeta potential of − 5.21 ± 0.91 mV. The nanosuspension was further characterized for morphology, dissolution, and in vivo pharmacokinetics study. X-ray powder diffraction study of the nano-formulation displayed a halo pattern revealing the amorphous form. Stability studies showed that the nanosuspension remained stable at 40 °C ± 2 °C and 75% RH ± 5% RH for a period of three months. In vitro drug release and solubility study showed threefold and 36-fold enhancement in dissolution and solubility of the nanosuspension. Furthermore, an in vivo pharmacokinetic study in Sprague–Dawley rats following oral administration displayed a 1.46-fold enhancement in the relative bioavailability of the nanosuspension in contrast to neat nilotinib.

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Availability of data and materials

All data generated or analyzed during this study are provided in this published article and supplementary information.

Abbreviations

Nil:

Nilotinib

Nil-NS:

Nilotinib nanosuspension

CMC:

Critical micelle concentration

PDI:

Polydispersity index

PVP-VA:

Poly vinyl pyrrolidone-vinyl acetate

HPMCAS:

Hydroxypropylmethylcellulose acetate succinate

SLS:

Sodium lauryl sulfate

TPGS:

Tocopherol polyethylene glycol succinate

RDI:

Redispersibility index

DLS:

Dynamic light scattering

SEM:

Scanning electron microscopy

TEM:

Transmission electron microscopy

FTIR:

Fourier-transform infrared spectroscopy

PXRD:

Powder X-ray diffraction

FaSSIF:

Fasted state simulated intestinal fluid

FeSSIF:

Fed state simulated intestinal fluid

FaSSGF:

Fasted state simulated gastric fluid

GI:

Gastrointestinal

SGF:

Simulated gastric fluid

UWL:

Unstirred water layer

PSA:

Parameter sensitivity analysis

AUC:

Area under curve

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Acknowledgements

The authors would like to acknowledge Dr. Reddy’s Laboratories (Hyderabad, India) for providing the gift samples. Support provided by the Director, NIPER S.A.S Nagar regarding the necessary facilities and infrastructure is also highly acknowledged. We also gratefully acknowledge lab members Karan Jadhav, Nandini Savardekar, and Manasi Pawar for their technical support during this project.

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  1. Mahendra Chougule and Arvind Sirvi are first authors.

Authors and Affiliations

  1. Department of Pharmaceutical Technology and Formulations, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, 160062, India

    Mahendra Chougule

  2. Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab, 160062, India

    Arvind Sirvi, Vanshul Saini, Mahesh Kashyap & Abhay T. Sangamwar

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Contributions

Mahendra Chougule: conceptualisation, methodology, investigation, data curation, and validation. Arvind Sirvi: conceptualization, investigation, formal data analysis, and writing—review and editing. Vanshul Saini: manuscript writing (original draft), methodology, and data curation. Mahesh Kashyap: methodology (pharmacokinetic study). Abhay T. Sangamwar: conceptualisation, data review, project administration, supervision, and writing—review and editing.

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Correspondence to Abhay T. Sangamwar.

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All the animal handling, care, and experiments are carried out in compliance with ARRIVE guidelines and were carried out in accordance with the UK Animals (Scientific Procedures) Act, 1986, associated guidelines and EU Directive 2010/63/EU for animal experiments. The protocol mandatory to conduct pharmacokinetic study on laboratory animals was approved by Institutional Animal Ethics Committee (IAEC, NIPER S.A.S. Nagar, India) with the Protocol approval number: IAEC/22/ 07.

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Abhay T. Sangamwar, corresponding author for this research article, on behalf of all the other respected authors (Mahendra Chougule, Arvind Sirvi, Vanshul Saini, and Mahesh Kashyap) hereby affirms that this article is in original form and does not violate any copyright. This research article has not been published earlier, and not under consideration in any other journal.

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Chougule, M., Sirvi, A., Saini, V. et al. Enhanced biopharmaceutical performance of brick dust molecule nilotinib via stabilized amorphous nanosuspension using a facile acid–base neutralization approach. Drug Deliv. and Transl. Res. 13, 2503–2519 (2023). https://doi.org/10.1007/s13346-023-01334-7

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