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QbD-driven development of phospholipid-embedded lipidic nanocarriers of raloxifene: extensive in vitro and in vivo evaluation studies

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Abstract

Raloxifene (RLX) is popularly indicated in treatment of osteoporosis and prevention of breast cancer. Owing to its poor aqueous solubility, high pre-systemic metabolism, intestinal glucuronidation, and P-glycoprotein (P-gp) efflux, however, it demonstrates low (< 2%) and inconsistent oral bioavailability. The current work, Quality by Design (QbD)-driven development of phospholipid-embedded nanostructured lipidic carriers (NLCs) of RLX, accordingly, was undertaken to potentiate its lymphatic uptake, augment oral bioavailability, and possibly reduce drug dosage. Factor screening and failure mode effect analysis (FMEA) studies were performed to delineate high-risk factors using solid lipid (glyceryl monostearate), liquid lipid (vitamin E), and surfactant (Tween 80). Response surface optimization studies were performed employing the Box-Behnken design. Mathematical and graphical methods were adopted to embark upon the selection of optimized NLCs with various critical quality attributes (CQAs) of mean particle size as 186 nm, zeta potential of − 23.6 mV, entrapment efficiency of 80.09%, and cumulative drug release at 12 h of 83.87%. The DSC and FTIR studies, conducted on optimized NLCs, indicated successful entrapment of drug into the lipid matrix. In vitro drug release studies demonstrated Fickian diffusion mechanism. In vivo pharmacokinetic studies in rats construed significant improvement in AUC0–72 h (4.48-folds) and in Cmax (5.11-folds), unequivocally indicating markedly superior (p < 0.001) oral bioavailability of RLX-NLCs vis-à-vis marketed tablet formulation. Subsequently, level “A” in vitro/in vivo correlation (IVIVC) was also successfully attempted between the percentages of in vitro drug dissolved and of in vivo drug absorbed at the matching time points. In vitro cytotoxicity and cellular uptake studies also corroborated higher efficacy and successful localization of coumarin-6-loaded NLCs into MG-63 cells through microfluidic channels.

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All the pertinent data generated or analyzed during these studies have been included in this article and its supplementary information files.

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Acknowledgements

The authors enunciate their thankfulness to the Department of Science & Technology, New Delhi, India, for providing requisite fiscal grants for the research work. The generosity of Stat-Ease Inc., USA, is also gratefully acknowledged for gifting premium and annual licenses of Design Expert® software 12.0 version to the corresponding author (B.S.) and his team, as an Award of Distinction for his stellar contribution in QbD-steered research work for systematic development of novel drug delivery systems and for analytical method development and validation of varied drugs.

Funding

Department of Science & Technology, New Delhi, India, for the requisite funding to the first author (A.P.) to perform the present work as a DST-INSPIRE Research Fellow (IF170942) availing the facilities of the University Institute of Pharmaceutical Sciences for the present research work.

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Authors and Affiliations

  1. University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India

    Anjali Pant, Gajanand Sharma, Anil Thakur & Bhupinder Singh

  2. School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, 144411, India

    Sumant Saini

  3. Department of Renal Transplant Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Gurjeet Kaur

  4. Delhi Institute of Pharmaceutical Sciences and Research, Delhi Pharmaceutical Sciences and Research University, New Delhi, 110017, India

    Atul Jain

  5. Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India

    Bhupinder Singh

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  1. Anjali Pant
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  2. Gajanand Sharma
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  3. Sumant Saini
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  4. Gurjeet Kaur
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  5. Atul Jain
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  6. Anil Thakur
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  7. Bhupinder Singh
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Contributions

Anjali Pant: data curation, formal analysis, funding acquisition, investigation, methodology, validation, writing—original draft. Gajanand Sharma: methodology and validation. Sumant Saini: software, validation, original draft review. Gurjeet Kaur: cell line studies and validation. Atul Jain: validation and editing. Anil Thakur: In vivo experimental studies. Bhupinder Singh: conceptualization, visualization, project administration, resources, software, supervision, writing—review and editing.

Corresponding author

Correspondence to Bhupinder Singh.

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Ethics approval and consent to participate

The In vivo studies were carried out in female Wistar rats (220–280 g), after obtaining the requisite permission from the Institutional Animal Ethics Committee (IAEC) of the Panjab University, Chandigarh, India, vide their letter no. PU/45/99/CPCSEA/IAEC/2021/463. All institutional and national guidelines for the care and use of laboratory animals were followed.

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Pant, A., Sharma, G., Saini, S. et al. QbD-driven development of phospholipid-embedded lipidic nanocarriers of raloxifene: extensive in vitro and in vivo evaluation studies. Drug Deliv. and Transl. Res. 14, 730–756 (2024). https://doi.org/10.1007/s13346-023-01427-3

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