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Folate Conjugated Double Liposomes Bearing Prednisolone and Methotrexate for Targeting Rheumatoid Arthritis

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Abstract

Purpose

This investigation was aimed to explore the targeting potential of folate conjugated double liposomes (fDLs) bearing combination of synergistic drugs (Prednisolone and Methotrexate) for effective management of the rheumatoid arthritis (RA).

Methods

To overcome the drawbacks of monotherapy, a combination of prednisolone (PRD) (an anti-inflammatory agent) and methotrexate (MTX) (a disease modifying anti-rheumatoid agent, DMARDs) was chosen for dual targeting approach. fDLs were prepared in two steps i.e. development of inner liposomes (ILs) using thin film casting method followed by encapsulation of ILs within folate conjugated outer liposomes (double liposomes; fDLs). Developed liposomes were characterized for various physicochemical parameters and in vivo performance.

Results

fDLs were prepared using FA-PEG-4000-NH-DSPE conjugate. These double liposomes were having 429.3 ± 3.6 nm in size with 0.109 PDI, 8.01 ± 0.3 mV zeta potential (ζ) and 66.7 ± 3.9% and 45.3 ± 1.7% entrapments of PRD and MTX, respectively. After 24 h, the concentrations of PRD in blood were observed to be 8.66 ± 3.11 (ILs) and 15.13 ± 0.81% (DLs) while concentration of MTX were found to be 10.89 ± 0.69 and 2.34 ± 3.15% when given as ILs and fDLs, respectively. The concentration of both drugs in inflamed joint was observed to be higher than that in the non-inflamed joints.

Conclusions

The folate conjugated double liposomes possess superior targeting efficiency than conjugated and unconjugated single liposomes.

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Abbreviations

CIA:

Collagen-induced arthritis

CHOL:

Cholesterol

DCC:

Dicyclohexylcarbodiimide

DMARDs:

Disease Modifying Anti-Rheumatoid Drugs

DMSO:

Dimethyl sulfoxide

DSPC:

1, 2-Distearoyl-sn-glycero-3-phosphocholine

DSPE:

1, 2-Distearoyl-sn-glycero-3-phosphoethanolamine

ER:

Erythrosine

FA:

Folic acid

fDLs:

Folate Conjugated Double Liposomes

FR:

Folate Receptor

hr./h:

Hour/Hours

HVD:

Half-value duration

ILs:

Inner Liposomes

MRT:

Mean Residence Time

MTX:

Methotrexate

NHS :

N-Hydroxysuccinimide

PBS:

Phosphate buffered saline

PRD:

Prednisolone

RA:

Rheumatoid Arthritis

RBF:

Round Bottom Flask

SA :

Stearylamine

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Acknowledgments and Disclosures

We are highly thankful for financial support obtained from AICTE Fellowship to Mr. Amit Verma. Authors report no potential conflict of interest.

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Authors and Affiliations

  1. Pharmaceutics Research Projects Laboratory, School of Engineering and Technology, Department of Pharmaceutical Sciences, Dr. H. S. Gour Central University, M.P, Sagar, 470 003, India

    Amit Verma, Ankita Tiwari, Shivani Saraf, Pritish K. Panda, G. P. Agrawal & Sanjay K. Jain

  2. Institute of Pharmaceutical Research, GLA University, NH-2, Mathura-Delhi Road, Mathura, U.P., 281 406, India

    Ankit Jain

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  1. Amit Verma
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Correspondence to Sanjay K. Jain.

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Verma, A., Jain, A., Tiwari, A. et al. Folate Conjugated Double Liposomes Bearing Prednisolone and Methotrexate for Targeting Rheumatoid Arthritis. Pharm Res 36, 123 (2019). https://doi.org/10.1007/s11095-019-2653-0

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