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Raloxifene-loaded SLNs with enhanced biopharmaceutical potential: QbD-steered development, in vitro evaluation, in vivo pharmacokinetics, and IVIVC

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Abstract

Raloxifene hydrochloride, a second-generation selective estrogen receptor modulator, has been approved for the management of breast cancer. However, it is known to exhibit poor (~ 2%) and inconsistent oral bioavailability in humans, primarily ascribable to its low aqueous solubility, extensive first-pass metabolism, P-gp efflux, and presystemic glucuronide conjugation. The present research work entails the systematic development and evaluation of SLNs of RLX for its enhanced biopharmaceutical performance against breast cancer. Factor screening studies were conducted using Taguchi design, followed by optimization studies employing Box-Behnken design. Preparation of SLNs was carried out using glyceryl monostearate and Compritol® 888 ATO (i.e., lipid), Phospholipid S-100 (i.e., co-surfactant), and TPGS-1000 (i.e., surfactant) employing solvent diffusion method. The optimized formulation was evaluated for zeta potential, average particle size, field emission scanning electron microscope, transmission electron microscopy, and in vitro release study. Further, MCF-7 cells (cell cytotoxicity assay, apoptosis assay, and reactive oxygen species assay) and Caco-2 cells (cell uptake studies and P-gp efflux assay) were employed to evaluate the in vitro anticancer potential of the developed optimized formulation. In vivo pharmacokinetic studies were conducted in Sprague–Dawley rats to evaluate the therapeutic profile of the developed formulation. The optimized SLN formulations exhibited a mean particle size of 109.7 nm, PDI 0.289 with a zeta potential of − 13.7 mV. In vitro drug dissolution studies showed Fickian release, with release exponent of 0.137. Cell cytotoxicity assay, apoptosis assay, and cellular uptake indicated 6.40-, 5.40-, and 3.18-fold improvement in the efficacy of RLX-SLNs vis-à-vis pure RLX. Besides, the pharmacokinetic studies indicated quite significantly improved biopharmaceutical performance of RLX-SLNs vis-à-vis pure drug, with 4.06-fold improvement in Cmax, 4.40-fold in AUC(0-72 h), 4.56-fold in AUC(0-∞), 1.53-fold in Ka, 2.12-fold in t1/2, and 1.22-fold in Tmax. Further, for RLX-SLNs and pure drug, high degree of level A linear correlation was established between fractions of drug dissolved (in vitro) and of drug absorbed (in vivo) at the corresponding time-points. Stability studies indicated the robustness of RLX-SLNs when stored at for 3 months. Results obtained from the different studies construe promising the anticancer potential of the developed RLX-SLNs, thereby ratifying the lipidic nanocarriers as an efficient drug delivery strategy for improving the biopharmaceutical attributes of RLX.

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Acknowledgements

The authors appreciate the generosity of M/s Stat-Ease Inc., Minneapolis, USA, for providing Design Expert software 11.0 version to the corresponding author (B.S.) ex-gratis as a mark of recognition for his exemplary contribution in the QbD-oriented drug delivery research work.

Funding

National UGC Centre of Excellence in NanoBioMedical Applications, Panjab University, liberal grants and facilities for the present research work.

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  1. Atul Jain and Teenu Sharma contributed equally to this work.

Authors and Affiliations

  1. National UGC Centre of Excellence in Application of Nanomaterials Nanoparticles and Nanocomposites (Biomedical Sciences), Panjab University, Chandigarh, India, 160014

    Atul Jain, Rajendra Kumar & Bhupinder Singh

  2. University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh, India, 160014

    Teenu Sharma, O. P. Katare & Bhupinder Singh

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  1. Atul Jain
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Contributions

Atul Jain: data curation; formal analysis; funding acquisition; investigation; methodology; validation; writing—original draft. Teenu Sharma: validation, methodology, editing. Rajnedra Kumar: cell lines studies. OP Katare: supervision. Bhupinder Singh: conceptualization; visualization; project administration; resources; software; supervision; writing—review and editing.

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Correspondence to Bhupinder Singh.

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The in vivo studies were carried out in female Sprague–Dawley rats (180–220 g), after obtaining the requisite permission from institutional animal ethics committee (IAEC) of the Panjab University, Chandigarh, India, vide their letter no PU/IAEC/S/15/31. All institutional and national guidelines for the care and use of laboratory animals were followed.

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Jain, A., Sharma, T., Kumar, R. et al. Raloxifene-loaded SLNs with enhanced biopharmaceutical potential: QbD-steered development, in vitro evaluation, in vivo pharmacokinetics, and IVIVC. Drug Deliv. and Transl. Res. 12, 1136–1160 (2022). https://doi.org/10.1007/s13346-021-00990-x

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