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Utilization of Lipophilic Salt and Phospholipid Complex in Lipid-Based Formulations to Modulate Drug Loading and Oral Bioavailability of Pazopanib

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Abstract

Pazopanib hydrochloride (PAZ) displays strong intermolecular interaction in its crystal lattice structure, limiting its solubility and dissolution. The development of lipid-based formulations (LbFs) resulted in reduced PAZ loading due to solid-state mediated low liposolubility. This study aims to enhance our understanding of PAZ crystallinity by synthesizing a lipophilic salt and phospholipid complex and investigating its impact on the drug loading in LbFs. The synthesized pazopanib lipophilic salt and phospholipid complex were extensively characterized. The solid form of pazopanib docusate (PAZ-DOC) and pazopanib phospholipid complex (PAZ-PLC) indicates a reduction in characteristic diffraction peaks of crystalline PAZ. The lipid formulations were prepared using synthesized PAZ-DOC and PAZ-PLC, where PAZ-DOC demonstrated six fold higher drug solubility than the commercial salt form and twice that of the PAZ-PLC due to differences in the crystallinity. Further, the impact of salt and complex formation was assessed on the aqueous drug solubilization using lipolysis and multimedia dissolution experiments. Moreover, the LbFs showed notably faster dissolution compared to the crystalline PAZ and marketed tablet. In terms of in vivo pharmacokinetics, the PAZ-DOC LbF exhibited a remarkable 11-fold increase in AUC value compared to the crystalline PAZ and a 2.5-fold increase compared to Votrient®. Similarly, PAZ-PLC LbF showed an approximately nine fold increase in drug exposure compared to the crystalline PAZ, and a 2.2-fold increase compared to Votrient®. These findings suggest that disrupting the crystallinity of drugs and incorporating them into LbF could be advantageous for enhancing drug loading and overcoming limitations related to drug absorption.

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Data Availability

Data will be made available on request.

Abbreviations

AUC:

Area under the curve

BCS:

Biopharmaceutical classification system

DOC:

Docusate

DLS:

Dynamic light scattering

FTIR:

Fourier transform infrared

GI:

Gastrointestinal

GRAS:

Generally recognized as safe

HRMS:

High-resolution mass spectrometry

HTP:

High throughput

LbFs:

Lipid-based formulations

1H-NMR:

Nuclear magnetic resonance

PAZ:

Pazopanib hydrochloride

PAZ-DOC:

Pazopanib docusate

PAZ-PLC:

Pazopanib phospholipid complex

PDGFR:

Platelet-derived growth factor receptors

PLC:

Phospholipid complex

SEM:

Scanning electron microscopy

PDI:

Polydispersity index

PLM:

Polarized light microscopy

TEM:

Transmission electron microscopy

VEGFR:

Vascular endothelial growth factor receptors

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Acknowledgements

The authors are thankful to the Director of NIPER S.A.S. Nagar for providing the infrastructure and amenities required to undertake the experimental investigations.

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Authors and Affiliations

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

    Karan Jadhav, Arvind Sirvi, Akash Janjal, Mahesh C. Kashyap & Abhay T. Sangamwar

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  1. Karan Jadhav
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  2. Arvind Sirvi
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Contributions

KJ: conceptualization, methodology, investigation, visualization, writing—original draft. AS: conceptualization, investigation, writing—original draft, writing—review and editing. AJ: methodology, data curation. MCK: methodology (pharmacokinetic study) ATS: conceptualization, funding acquisition, project administration, resources, writing—review, and editing.

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Correspondence to Abhay T. Sangamwar.

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All aspects of animal handling, care, and experimentation adhere to the ARRIVE guidelines and comply with the UK Animals (Scientific Procedures) Act, 1986, along with associated guidelines and the EU Directive 2010/63/EU for animal experiments. The protocol necessary for conducting a pharmacokinetic study on laboratory animals received approval from the Institutional Animal Ethics Committee, NIPER S.A.S. Nagar, India.

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Jadhav, K., Sirvi, A., Janjal, A. et al. Utilization of Lipophilic Salt and Phospholipid Complex in Lipid-Based Formulations to Modulate Drug Loading and Oral Bioavailability of Pazopanib. AAPS PharmSciTech 25, 59 (2024). https://doi.org/10.1208/s12249-024-02780-3

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