Piroxicam/Cyclodextrin: 35 years on the market

On the occasion of the 25th anniversiary of cyclodextrin/piroxicam complex’ launching on the market a review of C. Scarpignato in 2013 gave an overview on this nonsteroidal anti-inflammatory drug (NSAID) covering the details on the development, pharmacokinetic properties and efficacy of the cyclodextrin formulation [1].
Complexation of piroxicam, with βCD potentially leads to a more rapid onset of action after oral dministration and improved GI tolerability because of minimization of the drug gastric effects. In the early studies the 2:1 stoichiometry has been proved by X-ray diffractometry and molecular dynamics calculations (Fig. 1) [2]. Based on these results the molar ratio of 2.5:1 has been applied in the commercial products produced and marketed by Chiesi [3]. To improve the patients compliance and reduce the GI irritation, effervescent tablets and sachet formulations were worked out and marketed under various trade names such as Brexin®, Cycladol®, and Flamexin®. As it became generic further trade names, such as Brexidol, Brexicam, Briax, Cyclodex, Cicladol , Dexpir, Flamexin, Medicam and Pyrodex can be found [4]. Suppository and pediatric formulations (Brexin, Flogene, respectively) are malso available. Recently further formulations of the complex were developed such as orally disintegrating tablet [5], fast dissolving electrospun nanofiber [6] and a nanosponge formuklation [7].
The analgesic and anti-inflammatory efficiency of the complex was at least as high as that of the pure drug in rats [8]. Pronounced and marked gastric ulceration with complete loss of the mucosa, extensive deposition of fibrin and dense neutrophilic infiltrate were observed in rats treated with Piroxicam alone while no damaged tissues were found in rats treated with the complex [9].
Randomized crossover single- and multiple-dose studies of Piroxicam/βCD in healthy volunteers have confirmed the expected more rapid absorption of this formulation, compared with uncomplexed piroxicam without significantly changing the other pharmacokinetic parameters [10].
The fast onset and enhanced duration of action were proved in patients with dysmenorrhea [11], postoperative [12] and dental pain [13], headache [14], back pain [15], degenerative or inflammatory knee diseases [16], etc. The efficiency in pain relief was usually similar to that of the free Piroxicam but better tolerated in the upper GI tract.
A detailed analysis of nearly 100 published and unpublished studies of Piroxicam/βCD documenting the incidence of minor and major GI adverse events in a total of 29,190 patients showed that the incidence of minor GI events was lower for the complex (0.07-1.37%) than for Piroxicam alone (0-6.4%) or placebo (0.11-3.21%) or the other reference agents (0.1- 3.45%), while hardly any major events were recorded during chronic treatment with the complex [1].
Ten years ago Scarpignato concluded that “after 25 years of use in Europe and South America, also Piroxicam/βCD – like piroxicam – has stood the test of time and, on the grounds of its efficacy and safety, should be considered as a useful addition to our therapeutic armamentarium” [1].

References

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