Increased Absorption Rate of Diclofenac from Fast Acting Formulations Containing Its Potassium Salt

Abstract

Diclofenac (CAS 15307-86-5) is a non-steroidal anti-inflammatory drug largely used, mainly to relief pain of various origin. Diclofenac is present on the market as free acid, as sodium salt (CAS 15307-79-6) and as potassium salt (CAS 15307-81-0). The last salification form has shown a prompter absorption rate and a faster onset of analgesic activity than the acid form and sodium salt. This paper extensively reviews three trials carried out on healthy volunteers, where potassium salt of diclofenac present in three fast-acting formulations, namely sachets (Trial 1), tablets (Trial 2) and oral drops (Trial 3), were compared to reference tablet formulations from the market. A very fast absorption rate was encountered with the three test formulations, with the peak reached in one case 5 min and in most cases within 10-15 min after dosing. The quick absorption rate of test formulations was attributed to the special combination of the salt of diclofenac with a dynamic buffering agent, namely bicarbonate, present in the test formulations and covered by an international patent. The prompt absorption of diclofenac from the new fast-acting formulations was accompanied by the presence of only one peak, whereas the reference formulations produced in most cases two peaks, as widely described in literature. This finding suggested the hypothesis that the absorption of test formulations should occur in a shorter tract of the gut. The faster absorption of diclofenac from the three fast-acting formulations is expected to produce a faster onset of analgesic action, which highlights these new formulations as particularly indicated to relief pain of any origin.

Single-dose pharmacokinetic study of rapidly dispersing diclofenac potassium formulations in healthy volunteers

“…Given the similar rates of absorption among the preparations, all three formulations achieved the desired study outcome of bioequivalence. The DPSGC preparations are rapidly absorbed with a mean t max of approximately 0.5 hours, a timeframe that is shorter than or similar to those that have been reported for other diclofenac potassium formulations 15,16,18,[26][27][28] . These PK data also confirm C max and t max values introduced in a previously published clinical efficacy study in patients undergoing third molar extraction 9 .…”

“…Whereas results from previously published diclofenac trials illustrate the overall value of diclofenac as an analgesic, numerous pharmacokinetic (PK) studies show significant interindividual variability in diclofenac absorption, often coupled with reductions in maximal plasma concentration (C max ), delays in the time to achieve C max (t max ), and the presence of late and/or secondary plasma peaks [13][14][15][16][17][18] (Table 1). These characteristics of diclofenac may translate into delayed analgesic onset [19][20][21] .…”

A miniaturized in vitro release method for investigating drug-release mechanisms

“…Collection of API release data was possible for both solid and non-solid formulations, as well as for charged and uncharged APIs. Both the miniaturized-method and the historical release data were used to estimate the release mechanisms and to predict the plasma concentration-time profiles in a biopharmaceutical GI absorption model (Al Ameri et al, 2012;Elqidra et al, 2004;Friedman et al, 2000;Gohel et al, 2009;Kovacevic et al, 2008;Löbenberg et al, 2005;Nan et al, 2012;Nishihata, 1987;Parsaee et al, 2002;Reiner et al, 2001;Sandberg et al, 1988;Sjögren et al, 2013;Yuksel et al, 2000;Zhang et al, 2011;Zhou et al, 1998). The indicated release mechanisms for the APIs varied according to the source of the data.…”

“…The simulations of the plasma profiles obtained with GI-Sim were based on the miniaturized-method (mDISS TM ) or historical in vitro release profiles (Al Ameri et al, 2012;Elqidra et al, 2004;Friedman et al, 2000;Gohel et al, 2009;Kovacevic et al, 2008;Löbenberg et al, 2005;Nan et al, 2012;Nishihata, 1987;Parsaee et al, 2002;Reiner et al, 2001;Sandberg et al, 1988;Yuksel et al, 2000;Zhang et al, 2011;Zhou et al, 1998). The plasma-time concentration profiles and the AUCs, maximum concentrations (C max ) and times to C max (t max ) from the experimental and simulated data are shown in Fig.…”

“…(F) observed data from Zhou et al (1998), red line data from Yuksel et al (2000), and blue line data from the miniaturized method. (G) observed data from Reiner et al (2001), red line data from Al Ameri et al (2012), green line data from Nishihata et al (1987), and blue line data from the miniaturized method. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)…”