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Quality by design–based development and optimization of fourth-generation ternary solid dispersion of standardized Piper longum extract for melanoma therapy

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Abstract

The study aimed to enhance the solubility, dissolution, and oral bioavailability of standardized Piper longum fruits ethanolic extract (PLFEE) via fourth-generation ternary solid dispersion (SD) for melanoma therapy. With the use of solvent evaporation method, the standardized PLFEE was formulated into SD, optimized using Box-Wilson’s central composite design (CCD), and evaluated for pharmaceutical performance and in vivo anticancer activity against melanoma (B16F10)–bearing C57BL/6 mice. The optimized SD showed good accelerated stability, high yield, drug content, and content uniformity for bioactive marker piperine (PIP). The X-ray diffraction (XRD), differential scanning calorimetry (DSC), polarized light microscopy (PLM), and selected area electron diffraction (SAED) analysis revealed its amorphous nature. The attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and high-performance thin layer chromatography (HPTLC) revealed the compatibility of excipients with the PLFEE. The contact angle measurement and in vitro dissolution study revealed excellent wetting of SD and improved dissolution profile as compared to the plain PLFEE. The in vivo oral bioavailability of SD reflected a significant (p < 0.05) improvement in bioavailability (Frel = 188.765%) as compared to plain extract. The in vivo tumor regression study revealed the improved therapeutic activity of SD as compared to plain PLFEE. Further, the SD also improved the anticancer activity of dacarbazine (DTIC) as an adjuvant therapy. The overall result revealed the potential of developed SD for melanoma therapy either alone or as an adjuvant therapy with DTIC.

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All the data are encompassed in this manuscript. The scientific data in terms of graphs and figures were generated using MS office package, a 21-day free trial version of Origin Pro 2021 (Microcal Software, Inc., Northampton, USA), GraphPad Prism 5.0 (GraphPad Software Inc., San Diego, CA, USA), and ImageJ software (National Institutes of Health, Bethesda, MD).

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Acknowledgements

The authors are very much thankful to the infrastructural and instrumental facilities provided by the Central Instrument Facility, IIT (BHU); Department of Pharmaceutical Engineering & Technology, IIT (BHU); Department of Physics, IIT (BHU); and Centre for Genetics Disorders, BHU Varanasi, India. The sophisticated analytical instrument facility (SAIF), Indian Institute of Technology (IIT), Mumbai, India, and Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India, were also highly acknowledged for GCHS analysis and DNA-based molecular characterization, respectively.

Funding

The financial support for this research was provided as a scholarship to Debadatta Mohapatra by the Ministry of Human Resource Development (MHRD), Government of India. The authors declare that this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Phytomedicine Research Laboratory, Department of Pharmaceutical Engineering & Technology, IIT (BHU), Uttar Pradesh, Varanasi, 221005, India

    Debadatta Mohapatra, Singh Shreya & Alakh N Sahu

  2. Nanomedicine Research Laboratory, Department of Pharmaceutical Engineering & Technology, IIT (BHU), Uttar Pradesh, Varanasi, 221005, India

    Dulla Naveen Kumar & Ashish Kumar Agrawal

  3. Centre for Genetics Disorders, Institute of Science (BHU), Uttar Pradesh, Varanasi, 221005, India

    Vivek Pandey & Pawan K. Dubey

Authors
  1. Debadatta Mohapatra
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  2. Dulla Naveen Kumar
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  3. Singh Shreya
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  5. Pawan K. Dubey
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  7. Alakh N Sahu
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Contributions

Debadatta Mohapatra performed most of the experimental works, collected, processed, analyzed, validated, interpreted data, and wrote the original manuscript. Dulla Naveen Kumar, Singh Shreya, and Vivek Pandey participated in the experiment, reviewed, edited, and scientifically revised the manuscript. Alakh N Sahu, Ashish Kumar Agrawal, and Pawan K. Dubey contributed to conceptualization, project administration, supervision, experiment designing, evaluating, drawing conclusions from data, providing expert assistance, reviewing, and editing the manuscript.

Corresponding author

Correspondence to Alakh N Sahu.

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Ethical approval

The experiments on animals were carried out following an approved protocol from Institutional Animal Ethics Committee (IAEC Approval Number: IIT(BHU)/IAEC/2022/001 and IIT(BHU)/IAEC/2023/056).

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Mohapatra, D., Kumar, D.N., Shreya, S. et al. Quality by design–based development and optimization of fourth-generation ternary solid dispersion of standardized Piper longum extract for melanoma therapy. Drug Deliv. and Transl. Res. 13, 3094–3131 (2023). https://doi.org/10.1007/s13346-023-01375-y

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