Diclofenac prodrugs for intra-articular depot injectables: In vitro hydrolysis and species variation

Research output: Contribution to journalJournal articlepeer-review

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Diclofenac prodrugs for intra-articular depot injectables : In vitro hydrolysis and species variation. / Storgaard, Ida Hagen; Kristensen, Jesper; Larsen, Claus; Mertz, Nina; Østergaard, Jesper; Larsen, Susan Weng.

In: Journal of Pharmaceutical Sciences, Vol. 109, No. 4, 2020, p. P1529-1536.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Storgaard, IH, Kristensen, J, Larsen, C, Mertz, N, Østergaard, J & Larsen, SW 2020, 'Diclofenac prodrugs for intra-articular depot injectables: In vitro hydrolysis and species variation', Journal of Pharmaceutical Sciences, vol. 109, no. 4, pp. P1529-1536. https://doi.org/10.1016/j.xphs.2020.01.003

APA

Storgaard, I. H., Kristensen, J., Larsen, C., Mertz, N., Østergaard, J., & Larsen, S. W. (2020). Diclofenac prodrugs for intra-articular depot injectables: In vitro hydrolysis and species variation. Journal of Pharmaceutical Sciences, 109(4), P1529-1536. https://doi.org/10.1016/j.xphs.2020.01.003

Vancouver

Storgaard IH, Kristensen J, Larsen C, Mertz N, Østergaard J, Larsen SW. Diclofenac prodrugs for intra-articular depot injectables: In vitro hydrolysis and species variation. Journal of Pharmaceutical Sciences. 2020;109(4):P1529-1536. https://doi.org/10.1016/j.xphs.2020.01.003

Author

Storgaard, Ida Hagen ; Kristensen, Jesper ; Larsen, Claus ; Mertz, Nina ; Østergaard, Jesper ; Larsen, Susan Weng. / Diclofenac prodrugs for intra-articular depot injectables : In vitro hydrolysis and species variation. In: Journal of Pharmaceutical Sciences. 2020 ; Vol. 109, No. 4. pp. P1529-1536.

Bibtex

@article{b0764ca89df845358e3647e6bc932663,
title = "Diclofenac prodrugs for intra-articular depot injectables: In vitro hydrolysis and species variation",
abstract = "Intra-articular depot injectables based on in situ suspension formation of ester prodrugs of non-steroidal anti-inflammatory drugs (NSAIDs) are promising for management of joint pain. As candidates for this delivery approach, five diclofenac ester prodrugs comprising different imidazole-containing promoieties were synthesized and their physicochemical properties characterized. In vitro hydrolysis rates were investigated in buffer solutions, in 40% (v/v) human, equine, canine, and rat plasma, and in 80% (v/v) human and equine synovial fluid. Bioconversion of the prodrugs to diclofenac was found to be enzyme-mediated and follow pseudo-first-order kinetics. Large variations in hydrolysis rates were observed between species and between prodrugs, with prodrug half-lives in plasma from canine, rat, horse and human of 3.44 - 141 min, 2.51 - 14 min, 0.58 - 1.31 min, and 0.23 - 1.70 min, respectively. Half-lives in human and equine synovial fluid were 1.6 to 28-fold larger than in plasma. The results highlight the significance of species as well as tissue variation in prodrug design and suggest that the horse may constitute a suitable model for testing the intra-articular depot approach. Two prodrug candidates appeared promising for future in vivo studies based on their rapid in vitro enzyme-mediated bioconversion to diclofenac and physiochemical characteristics.",
author = "Storgaard, {Ida Hagen} and Jesper Kristensen and Claus Larsen and Nina Mertz and Jesper {\O}stergaard and Larsen, {Susan Weng}",
note = "Copyright {\textcopyright} 2020. Published by Elsevier Inc.",
year = "2020",
doi = "10.1016/j.xphs.2020.01.003",
language = "English",
volume = "109",
pages = "P1529--1536",
journal = "Journal of Pharmaceutical Sciences",
issn = "0022-3549",
publisher = "Elsevier",
number = "4",

}

RIS

TY - JOUR

T1 - Diclofenac prodrugs for intra-articular depot injectables

T2 - In vitro hydrolysis and species variation

AU - Storgaard, Ida Hagen

AU - Kristensen, Jesper

AU - Larsen, Claus

AU - Mertz, Nina

AU - Østergaard, Jesper

AU - Larsen, Susan Weng

N1 - Copyright © 2020. Published by Elsevier Inc.

PY - 2020

Y1 - 2020

N2 - Intra-articular depot injectables based on in situ suspension formation of ester prodrugs of non-steroidal anti-inflammatory drugs (NSAIDs) are promising for management of joint pain. As candidates for this delivery approach, five diclofenac ester prodrugs comprising different imidazole-containing promoieties were synthesized and their physicochemical properties characterized. In vitro hydrolysis rates were investigated in buffer solutions, in 40% (v/v) human, equine, canine, and rat plasma, and in 80% (v/v) human and equine synovial fluid. Bioconversion of the prodrugs to diclofenac was found to be enzyme-mediated and follow pseudo-first-order kinetics. Large variations in hydrolysis rates were observed between species and between prodrugs, with prodrug half-lives in plasma from canine, rat, horse and human of 3.44 - 141 min, 2.51 - 14 min, 0.58 - 1.31 min, and 0.23 - 1.70 min, respectively. Half-lives in human and equine synovial fluid were 1.6 to 28-fold larger than in plasma. The results highlight the significance of species as well as tissue variation in prodrug design and suggest that the horse may constitute a suitable model for testing the intra-articular depot approach. Two prodrug candidates appeared promising for future in vivo studies based on their rapid in vitro enzyme-mediated bioconversion to diclofenac and physiochemical characteristics.

AB - Intra-articular depot injectables based on in situ suspension formation of ester prodrugs of non-steroidal anti-inflammatory drugs (NSAIDs) are promising for management of joint pain. As candidates for this delivery approach, five diclofenac ester prodrugs comprising different imidazole-containing promoieties were synthesized and their physicochemical properties characterized. In vitro hydrolysis rates were investigated in buffer solutions, in 40% (v/v) human, equine, canine, and rat plasma, and in 80% (v/v) human and equine synovial fluid. Bioconversion of the prodrugs to diclofenac was found to be enzyme-mediated and follow pseudo-first-order kinetics. Large variations in hydrolysis rates were observed between species and between prodrugs, with prodrug half-lives in plasma from canine, rat, horse and human of 3.44 - 141 min, 2.51 - 14 min, 0.58 - 1.31 min, and 0.23 - 1.70 min, respectively. Half-lives in human and equine synovial fluid were 1.6 to 28-fold larger than in plasma. The results highlight the significance of species as well as tissue variation in prodrug design and suggest that the horse may constitute a suitable model for testing the intra-articular depot approach. Two prodrug candidates appeared promising for future in vivo studies based on their rapid in vitro enzyme-mediated bioconversion to diclofenac and physiochemical characteristics.

U2 - 10.1016/j.xphs.2020.01.003

DO - 10.1016/j.xphs.2020.01.003

M3 - Journal article

C2 - 31927039

VL - 109

SP - P1529-1536

JO - Journal of Pharmaceutical Sciences

JF - Journal of Pharmaceutical Sciences

SN - 0022-3549

IS - 4

ER -

ID: 234642775