Piroxicam-β-cyclodextrin: a GI safer piroxicam

Abstract

Although NSAIDs are very effective drugs, their use is associated with a broad spectrum of adverse reactions in the liver, kidney, cardiovascular (CV) system, skin and gut. Gastrointestinal (GI) side effects are the most common and constitute a wide clinical spectrum ranging from dyspepsia, heartburn and abdominal discomfort to more serious events such as peptic ulcer with life-threatening complications of bleeding and perforation. The appreciation that CV risk is also increased further complicates the choices of physicians prescribing anti-inflammatory therapy. Despite prevention strategies should be implemented in patients at risk, gastroprotection is often underused and adherence to treatment is generally poor. A more appealing approach would be therefore to develop drugs that are devoid of or have reduced GI toxicity. Gastro- duodenal mucosa possesses many defensive mechanisms and NSAIDs have a deleterious effect on most of them. This results in a mucosa less able to cope with even a reduced acid load. NSAIDs cause gastro-duodenal damage, by two main mechanisms: a physiochemical disruption of the gastric mucosal barrier and systemic inhibition of gastric mucosal protection, through inhibition of cyclooxygenase (COX, PG endoperoxide G/H synthase) activity of the GI mucosa. However, against a background of COX inhibition by anti-inflammatory doses of NSAIDs, their physicochemical properties, in particular their acidity, underlie the topical effect leading to short-term damage. It has been shown that esterification of acidic NSAIDs suppresses their gastrotoxicity without adversely affecting anti-inflammatory activity. Another way to develop NSAIDs with better GI tolerability is to complex these molecules with cyclodextrins (CDs), giving rise to so-called "inclusion complexes" that can have physical, chemical and biological properties very different from either those of the drug or the cyclodextrin. Complexation of NSAIDs with β-cyclodextrin potentially leads to a more rapid onset of action after oral administration and improved GI tolerability because of minimization of the drug gastric effects. One such drug, piroxicam-β-cyclodextrin (PBC), has been used in Europe for 25 years. Preclinical and clinical pharmacology of PBC do show that the β-cyclodextrin inclusion complex of piroxicam is better tolerated from the upper GI tract than free piroxicam, while retaining all the analgesic and anti-inflammatory properties of the parent compound. In addition, the drug is endowed with a quick absorption rate, which translates into a faster onset of analgesic activity, an effect confirmed in several clinical studies. An analysis of the available trials show that PBC has a GI safety profile, which is better than that displayed by uncomplexed piroxicam. Being an inclusion complex of piroxicam, whose CV safety has been pointed out by several observational studies, PBC should be viewed as a CV safe anti-inflmmatory compound and a GI safer alternative to piroxicam. As a consequence, it should be considered as a useful addition to our therapeutic armamentarium.

Fig. (1)

Main mechanisms underlying the upper GI toxicity of NSAIDs. The mucosal lesion (either erosion or ulcer) results from the combination of both topical (prostaglandin-independent) and systemic (prostaglandin-dependent) effects. COX inhibition by NSAIDs will give rise to diversion of arachidonate through the lipoxygenase (LO) pathway leading to enhanced leukotriene (LT) synthesis. These mediators cause vasoconstriction and release oxygen free radicals, which add to damage due to the impairment of mucosal defense.

Fig. (2)

Relative selectivity of agents as inhibitors of human COX-1 and COX-2 dis- played as the ratio of IC₈₀ concentrations. Inhibitor curves for compounds against COX-1 and COX-2 were constructed in a human modified whole blood assay and used to calculate IC₈₀ concentrations. The IC₈₀ ratios are expressed logarithmically so that 0 represents the line of unity, i.e., compounds on this line are equiactive against COX-1 and COX-2. Compounds appearing above the line are COX- 1-selective, those below the line COX-2- selective (from Warner & Mitchell [64]).

Fig. (3)

On the top: Structural formula of β-cyclodextrin together with its 3D structure, showing the lipophilic inner cavity and the hydrophilic outer surface. On the botton: Structural formula of free piroxicam and piroxicam-β-cyclodextrin.

Fig. (4)

Crystallographic investigations on piroxicam-β-cyclodextrin. On the left side: the SCHAKAL drawing showing the host-guest interaction between piroxicam and β-cyclodextrin (from Chiesi-Villa et al., [83]). On the right side: the MAESTRO drawing showing the same host-guest interaction (courtesy of Dr. Andrea Rizzi, Computational Chemistry, Chiesi Farmaceutici S.p.A, Parma Italy). Both drawings have been generated with proprietary software packages (available at the following URL addresses: http://www.krist.unifreiburg.de/ki/Mitarbeiter/Keller/schakal.html and http://www.schrodinger.com)

Fig. (5)

Dissolution and absorption of piroxicam from piroxicam-β-cyclodextrin. k_d = dissolution constant k_c = equilibrium constant for the formation of the inclusion complex k_a = absorption rate constant.

Fig. (6)

Mean piroxicam plasma levels after oral administration of PBC or free piroxicam in healthy volunteers. One PBC tablet (20 mg) or piroxicam tablet (20 mg) were given with 200 ml of water in a crossover fashion. Subjects were fasted but received a standard breakfast 2 h after drug administration (from Acerbi et al., [96]).

Fig. (7)

Summary findings regarding the relative efficacy and safety of piroxicam against other non selective NSAIDs. X (Global Safety) and Y (Global Efficacy) axes (logarithmic scales), displayed in red represent piroxicam, considered as the reference drug. Compared to naproxen and ibuprofen, the drug was found to display better safety and efficacy whereas, compared to diclofenac, piroxicam displayed a better safety and a (slightly) lower efficacy (from Richy et al. [44]).