Long-Acting Diclofenac Ester Prodrugs for Joint Injection: Kinetics, Mechanism of Degradation, and In Vitro Release From Prodrug Suspension

Research output: Contribution to journalJournal articlepeer-review

Standard

Long-Acting Diclofenac Ester Prodrugs for Joint Injection : Kinetics, Mechanism of Degradation, and In Vitro Release From Prodrug Suspension. / Mertz, Nina; Larsen, Susan Weng; Kristensen, Jesper; Østergaard, Jesper; Larsen, Claus.

In: Journal of Pharmaceutical Sciences, Vol. 105, No. 10, 27.07.2016, p. 3079–3087.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Mertz, N, Larsen, SW, Kristensen, J, Østergaard, J & Larsen, C 2016, 'Long-Acting Diclofenac Ester Prodrugs for Joint Injection: Kinetics, Mechanism of Degradation, and In Vitro Release From Prodrug Suspension', Journal of Pharmaceutical Sciences, vol. 105, no. 10, pp. 3079–3087. https://doi.org/10.1016/j.xphs.2016.06.013

APA

Mertz, N., Larsen, S. W., Kristensen, J., Østergaard, J., & Larsen, C. (2016). Long-Acting Diclofenac Ester Prodrugs for Joint Injection: Kinetics, Mechanism of Degradation, and In Vitro Release From Prodrug Suspension. Journal of Pharmaceutical Sciences, 105(10), 3079–3087. https://doi.org/10.1016/j.xphs.2016.06.013

Vancouver

Mertz N, Larsen SW, Kristensen J, Østergaard J, Larsen C. Long-Acting Diclofenac Ester Prodrugs for Joint Injection: Kinetics, Mechanism of Degradation, and In Vitro Release From Prodrug Suspension. Journal of Pharmaceutical Sciences. 2016 Jul 27;105(10):3079–3087. https://doi.org/10.1016/j.xphs.2016.06.013

Author

Mertz, Nina ; Larsen, Susan Weng ; Kristensen, Jesper ; Østergaard, Jesper ; Larsen, Claus. / Long-Acting Diclofenac Ester Prodrugs for Joint Injection : Kinetics, Mechanism of Degradation, and In Vitro Release From Prodrug Suspension. In: Journal of Pharmaceutical Sciences. 2016 ; Vol. 105, No. 10. pp. 3079–3087.

Bibtex

@article{afb7fedfd9fc4e87a4012557350aea62,
title = "Long-Acting Diclofenac Ester Prodrugs for Joint Injection: Kinetics, Mechanism of Degradation, and In Vitro Release From Prodrug Suspension",
abstract = "A prodrug approach for local and sustained diclofenac action after injection into joints based on ester prodrugs having a pH-dependent solubility is presented. Inherent ester prodrug properties influencing the duration of action include their pH-dependent solubility and charge state, as well as susceptibility to undergo esterase facilitated hydrolysis. In this study, physicochemical properties and pH rate profiles of 3 diclofenac ester prodrugs differing with respect to the spacer carbon chain length between the drug and the imidazole-based promoiety were determined and a rate equation for prodrug degradation in aqueous solution in the pH range 1-10 was derived. In the pH range 6-10, the prodrugs were subject to parallel degradation to yield diclofenac and an indolinone derivative. The prodrug degradation was found to be about 6-fold faster in 80% (vol/vol) human plasma as compared to 80% (vol/vol) human synovial fluid with 2-(1-methyl-1H-imidazol-2-yl)ethyl 2-(2-(2,6 dichlorophenyl)amino)phenylacetate being the poorest substrate toward enzymatic cleavage. The conversion and release of parent diclofenac from prodrug suspensions in vitro were studied using the rotating dialysis model. The results suggest that it is possible to alter and control dissolution and reconversion behavior of the diclofenac prodrugs, thus making the prodrug approach feasible for local and sustained diclofenac action after joint injection.",
author = "Nina Mertz and Larsen, {Susan Weng} and Jesper Kristensen and Jesper {\O}stergaard and Claus Larsen",
note = "Copyright {\textcopyright} 2016 American Pharmacists Association{\textregistered}. Published by Elsevier Inc. All rights reserved.",
year = "2016",
month = jul,
day = "27",
doi = "10.1016/j.xphs.2016.06.013",
language = "English",
volume = "105",
pages = "3079–3087",
journal = "Journal of Pharmaceutical Sciences",
issn = "0022-3549",
publisher = "Elsevier",
number = "10",

}

RIS

TY - JOUR

T1 - Long-Acting Diclofenac Ester Prodrugs for Joint Injection

T2 - Kinetics, Mechanism of Degradation, and In Vitro Release From Prodrug Suspension

AU - Mertz, Nina

AU - Larsen, Susan Weng

AU - Kristensen, Jesper

AU - Østergaard, Jesper

AU - Larsen, Claus

N1 - Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

PY - 2016/7/27

Y1 - 2016/7/27

N2 - A prodrug approach for local and sustained diclofenac action after injection into joints based on ester prodrugs having a pH-dependent solubility is presented. Inherent ester prodrug properties influencing the duration of action include their pH-dependent solubility and charge state, as well as susceptibility to undergo esterase facilitated hydrolysis. In this study, physicochemical properties and pH rate profiles of 3 diclofenac ester prodrugs differing with respect to the spacer carbon chain length between the drug and the imidazole-based promoiety were determined and a rate equation for prodrug degradation in aqueous solution in the pH range 1-10 was derived. In the pH range 6-10, the prodrugs were subject to parallel degradation to yield diclofenac and an indolinone derivative. The prodrug degradation was found to be about 6-fold faster in 80% (vol/vol) human plasma as compared to 80% (vol/vol) human synovial fluid with 2-(1-methyl-1H-imidazol-2-yl)ethyl 2-(2-(2,6 dichlorophenyl)amino)phenylacetate being the poorest substrate toward enzymatic cleavage. The conversion and release of parent diclofenac from prodrug suspensions in vitro were studied using the rotating dialysis model. The results suggest that it is possible to alter and control dissolution and reconversion behavior of the diclofenac prodrugs, thus making the prodrug approach feasible for local and sustained diclofenac action after joint injection.

AB - A prodrug approach for local and sustained diclofenac action after injection into joints based on ester prodrugs having a pH-dependent solubility is presented. Inherent ester prodrug properties influencing the duration of action include their pH-dependent solubility and charge state, as well as susceptibility to undergo esterase facilitated hydrolysis. In this study, physicochemical properties and pH rate profiles of 3 diclofenac ester prodrugs differing with respect to the spacer carbon chain length between the drug and the imidazole-based promoiety were determined and a rate equation for prodrug degradation in aqueous solution in the pH range 1-10 was derived. In the pH range 6-10, the prodrugs were subject to parallel degradation to yield diclofenac and an indolinone derivative. The prodrug degradation was found to be about 6-fold faster in 80% (vol/vol) human plasma as compared to 80% (vol/vol) human synovial fluid with 2-(1-methyl-1H-imidazol-2-yl)ethyl 2-(2-(2,6 dichlorophenyl)amino)phenylacetate being the poorest substrate toward enzymatic cleavage. The conversion and release of parent diclofenac from prodrug suspensions in vitro were studied using the rotating dialysis model. The results suggest that it is possible to alter and control dissolution and reconversion behavior of the diclofenac prodrugs, thus making the prodrug approach feasible for local and sustained diclofenac action after joint injection.

U2 - 10.1016/j.xphs.2016.06.013

DO - 10.1016/j.xphs.2016.06.013

M3 - Journal article

C2 - 27475785

VL - 105

SP - 3079

EP - 3087

JO - Journal of Pharmaceutical Sciences

JF - Journal of Pharmaceutical Sciences

SN - 0022-3549

IS - 10

ER -

ID: 164786385