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Design of Biodegradable Nanoparticles for Oral Delivery of Doxorubicin: In vivo Pharmacokinetics and Toxicity Studies in Rats

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Abstract

Purpose

Doxorubicin, a potent anticancer drug associated with cardiotoxicity and low oral bioavailability, was loaded into nanoparticles with a view to improve its performance.

Methods

Doxorubicin loaded PLGA nanoparticles were prepared by a double emulsion method. The pH dependent stability of nanoparticles in simulated fluids was evaluated. DSC and XRD studies were carried out in order to ascertain the nature of doxorubicin in formulations in conjunction with accelerated stability studies. The in vitro release was investigated in phosphate buffer. The pharmacokinetic and toxicity studies were conducted in rats.

Results

Nanoparticles had an average size of 185 nm, with 49% entrapment at 10% w/w of polymer. The particles displayed good pH dependent stability in the pH range 1.1–7.4. DSC and XRD studies revealed the amorphous nature of doxorubicin in nanoparticles and the accelerated stability studies revealed the integrity of formulations. Initial biphasic release (20%) followed by a sustained release (80%) for 24 days was observed under in vitro conditions. The doxorubicin loaded nanoparticles demonstrated superior performance in vivo as evident by enhanced bioavailability and lower toxicity.

Conclusions

Together, the data indicates the potential of doxorubicin loaded nanoparticles for oral chemotherapy. Further, these formulations could be explored for new indications like leishmaniasis.

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Abbreviations

AUC:

Area under the curve

BA:

Bioavailability

Dox:

Doxorubicin

EE:

Entrapment Efficiency

IAEC:

Institutional Animal Ethics Committee

i.v.:

intravenous

mV:

milli volts

nm:

Nanometers

NPs:

Nanoparticles

PDI:

Polydispersity Index

SGF:

Simulated gastric fluid

SIF:

Simulated intestinal fluid

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ACKNOWLEDGEMENTS

DK is grateful to NIPER for providing MS fellowships. Director, NIPER is acknowledged for extending the facility to conduct the work reported in here. Mr. Chandu, Research Scholar, Department of Pharmacology and Toxicology is acknowledged for the help with animal experiments.

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Authors and Affiliations

  1. Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S. A. S. Nagar, 160 062, Punjab, India

    D. R. Kalaria & V. Beniwal

  2. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow, G4 0NR, UK

    G. Sharma & M. N. V. Ravi Kumar

Authors
  1. D. R. Kalaria
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  2. G. Sharma
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  3. V. Beniwal
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  4. M. N. V. Ravi Kumar
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Correspondence to M. N. V. Ravi Kumar.

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Kalaria, D.R., Sharma, G., Beniwal, V. et al. Design of Biodegradable Nanoparticles for Oral Delivery of Doxorubicin: In vivo Pharmacokinetics and Toxicity Studies in Rats. Pharm Res 26, 492–501 (2009). https://doi.org/10.1007/s11095-008-9763-4

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  • DOI: https://doi.org/10.1007/s11095-008-9763-4

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