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Experimental investigations, cytotoxicity and cellular uptake outcomes of physically modified duloxetine HCl inclusion complexes

  • Rajiv Kumar
  • Amita SarwalEmail author
  • Lalita Dahiya
  • Dikshi Gupta
  • V. R. Sinha
Original Paper
  • 17 Downloads

Abstract

Duloxetine HCl, an antidepressive drug, has poor water solubility and poor oral absorption leading to low bioavailability of the drug. The drug is also found to be acid labile, resulting in degradation in gastric environment. To overcome such drawbacks, inclusion complexation process was explored to improve the solubility and dissolution rate of duloxetine HCl by formulating its complexes with beta-cyclodextrin using different complexation techniques. Equimolar complexes of the drug with β-CD (1:1 molar) were prepared based on phase solubility analysis. Behaviour of complexes was characterized both in solution state and in solid state using DSC, FTIR, SEM, 1H NMR and PXRD techniques. Molecular docking studies were also carried out to investigate mode of inclusion and stability. Also, the cell culture studies, viz. MTT assay and cellular uptake, were investigated. Apparent stability or association constant (Ks) was predicted to be 165.64 M−1. Results of characterization techniques indicate the drug to be completely included in the hydrophobic cavity of β-CD, and hence, the physicochemical properties of the drug differ from parent molecule. Cytotoxicity studies indicated low IC50 value for complexes in comparison with native drug moiety, and cellular uptake of the complex was also found to be improved in case of complexed drug at different time points. Enhanced solubility and improved drug release was observed for physically characterized less crystalline complexes. Cellular uptake is also reported to be appreciably enhanced in complexed form. Thus, the process has logistic approach in reducing the dose of drug and related side effects.

Keywords

Inclusion complexation Dissolution rate Phase solubility analysis Cellular uptake Cytotoxicity Characterization 

Abbreviations

DLX

Duloxetine HCl

β-CD

Beta-cyclodextrin

PM

Physical mixture

KN

Kneading complex

FD

Freeze-dried

SD

Spray-dried

DSC

Differential scanning calorimetry

FTIR

Fourier transform infrared

SEM

Scanning electron microscopy

PXRD

Powder X-ray diffraction

AO

Acridine orange

DMEM

Dulbecco’s modified Eagle’s medium

FBS

Fetal bovine serum

OD

Optical density

AIC

Akaike information criteria

MSC

Model selection criteria

Notes

Acknowledgements

The authors are grateful to Shodhana Laboratories Ltd., Hyderabad, India, for providing gift samples of drug. The author would also like to acknowledge and thank University Grants Commission (UGC), India, for providing fellowship (No. F1-17.1/2014-15/RGNF-2014-15-SC-HAR-68055) to the first author for carrying out the research work at UIPS, Panjab University, Chandigarh, India. The authors are thankful for and acknowledge the support of Department of SAIF/CIL, Panjab University, Chandigarh, for extending their help for characterization purposes.

Compliance with ethical standards

Conflict of interest

The authors confirm that this article content has no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Rajiv Kumar
    • 1
  • Amita Sarwal
    • 1
    Email author
  • Lalita Dahiya
    • 1
  • Dikshi Gupta
    • 2
    • 3
  • V. R. Sinha
    • 1
  1. 1.University Institute of Pharmaceutical SciencesPanjab UniversityChandigarhIndia
  2. 2.Centre for Biomedical EngineeringIndian Institute of TechnologyNew DelhiIndia
  3. 3.Department of Basic and Applied Sciences, School of EngineeringG D Goenka UniversityGurgaonIndia

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