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Pharmaceutical Research

, Volume 34, Issue 7, pp 1505–1516 | Cite as

Improved Stability and Enhanced Oral Bioavailability of Atorvastatin Loaded Stearic Acid Modified Gelatin Nanoparticles

  • Deepanshu Shilpi
  • Varun Kushwah
  • Ashish Kumar Agrawal
  • Sanyog JainEmail author
Research Paper

Abstract

Purpose

The present study evaluates the effects of stearic acid conjugation with gelatin and, its pharmaceutical potential to formulate novel atorvastatin (AT) loaded nanoparticles.

Method

AT loaded stearic acid modified gelatin nanoparticles (AT-MG NPs) were prepared via two-step desolvation method with extensive optimization of different process variables. Further, the developed nanoparticles where evaluated against in vitro Caco-2 cell model and in vivo bioavailability.

Results

Extensive optimization of nanoformulation resulted into the formation of AT-MG NPs with particle size 247.7 ± 10.9 nm, PDI 0.219 ± 0.07, and entrapment efficiency 58.7 ± 5.3%. Freeze dried nanoparticles were found to have spherical shape as determined by SEM and demonstrated excellent stability in simulated gastrointestinal conditions and during storage. Developed nanoparticles exhibited sustained release up to 24 h and remarkably higher Caco-2 cell uptake. Mechanistic studies further revealed the clathrin and caveolae mediated endocytosis as principle mechanism. In line with Caco-2 cell uptake observations, AT-MG NPs showed ∼4.84-fold increase in the AUC0-∞ values of AT in comparison with free AT following oral administration.

Conclusion

Overall, the stearic acid conjugated gelatin NPs demonstrates a promising potential in improving the drug payload of BCS class II drugs and enhancing oral bioavailability.

Key words

atorvastatin Caco-2 gelatin nanoparticles oral delivery stearic acid 

Abbreviations

AT

Atorvastatin calcium

AUC

Area Under the Curve

C-6

Coumarin-6

CLSM

Confocal Laser-Scanning Microscope

Cmax

Maximum Concentration Observed

CPZ

Chlorpromazine

DIC

Differential Interference Contrast

DMEM

Dulbecco’s modified Eagle’s culture medium

EDC

N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride

eNOS

Nitric Oxide Synthase

FBS

Fetal Bovine Serum

GIT

Gastrointestinal Tract

GEN

Genistein

HDL

High Density Lipoprotein

HMG-CoA

3-hydroxy-3-methylglutaryl coenzyme A

LDL

Low Density Lipoprotein

MG

Modified Gelatin

MG-NPs

Modified Gelatin Nanoparticles

MWCO

Molecular Weight Cut-Off

NHS

N-Hydroxysuccinimide

NG

Native Gelatin

PAA

Poly Acrylic Acid

PDI

Polydispersity Index

SA

Stearic Acid

SEM

Scanning Electron Microscopy

SGF

Simulated Gastrointestinal Fluids

SIF

Simulated Intestinal Fluid

SLS

Sodium Lauryl Sulfate

Notes

Acknowledgments and Disclosures

The authors report no financial interest that might pose a potential, perceived, or real conflict of interest. The authors are thankful to the Director, NIPER for providing the necessary infrastructure and facilities. Varun Kushwah and Ashish Kumar Agrawal are grateful to Council of Scientific and Industrial Research (CSIR), GOI, New Delhi, for providing research fellowships.

Supplementary material

11095_2017_2173_MOESM1_ESM.docx (420 kb)
ESM 1 (DOCX 419 kb)

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Deepanshu Shilpi
    • 1
  • Varun Kushwah
    • 1
  • Ashish Kumar Agrawal
    • 1
    • 2
  • Sanyog Jain
    • 1
    Email author
  1. 1.Centre for Pharmaceutical Nanotechnology, Department of PharmaceuticsNational Institute of Pharmaceutical Education and Research,SAS NagarIndia
  2. 2.James Graham Brown Cancer CenterUniversity of LouisvilleLouisvilleUSA

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