Effect of formulation parameters on pharmacokinetics, pharmacodynamics, and safety of diclofenac nanomedicine
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ORIGINAL ARTICLE
Effect of formulation parameters on pharmacokinetics, pharmacodynamics, and safety of diclofenac nanomedicine Dhanya Narayanan 1 & Gopikrishna J. Pillai 1 & Shantikumar V. Nair 1 & Deepthy Menon 1
# Controlled Release Society 2018
Abstract This study reports the development of a nanoformulation of diclofenac sodium, a potent non-steroidal anti-inflammatory drug, at its clinical dose, utilizing a FDA approved polymer, hydroxyethyl starch. The study specifically focused on the control of pharmacokinetics, pharmacodynamics, and biodistribution by particle surface functionalization and alteration of excipient levels in the final formulation. Stable diclofenac sodium–loaded hydroxyethyl starch nanoparticles (nanodiclo) of size 170 ± 5 nm and entrapment efficiency 72 ± 3% were prepared. Free diclofenac, nanodiclo, nanodiclo surface functionalized by PEGylation, nanodiclo with excipients removed, and finally PEGylated nanodiclo with excipients removed were all tested comparatively at two different doses. The results showed substantial impact of both excipients and PEGylation on the pharmacokinetics and pharmacodynamics in vivo. Further, the results proved that excipient removed PEGylated nanodiclo at lower dose achieved clinical therapeutic levels in blood for up to 120 h, with minimal accumulation in critical organs, and much better efficacy than other controls. Keywords Diclofenac sodium . Excipients . Hydroxyethyl starch nanoparticles . Pharmacokinetics . Pharmacodynamics
Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) [1] are widely used as a standard of care as an analgesic and an anti-inflammatory agent in both acute and chronic inflammation cases. Diclofenac sodium (DS) is the most commonly prescribed NSAID worldwide [2], with its name on 74 national essential medical lists (EMLs). The problem with NSAIDs in general is the high clinical dose required (75 mg BID for DS), at which gastro-intestinal [3–5], cardiovascular [6], renal [7] and hepatic toxicities [8] have been observed, depending on the duration and extent of use. When consumed orally, Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13346-018-00614-x) contains supplementary material, which is available to authorized users. * Shantikumar V. Nair [email protected] * Deepthy Menon [email protected] 1
Centre for Nanosciences & Molecular Medicine, Amrita Institute of Medical Sciences & Research Centre, Amrita Viswavidyapeetham, Kochi, Kerala 682041, India
bioavailability is poor, while for parenteral administration, the drug has a short half-life (1.5–2 h), high protein binding, and rapid clearance, all of which diminish the potentially positive effects of the drug. Thus, there is an unmet clinical need for developing alternate drug delivery strategies for DS. Herein, a nanomedicine formulation of DS, wherein the drug is encapsulated in a carrier material of nanoscale dimensions, would be advantageous. Nanoencapsulation of a drug can protect it from degradation
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