Potential interaction between zinc ions and a cyclodextrin-based diclofenac formulation

Abstract

Complexes of diclofenac sodium (DF-Na) with hydroxypropyl betacyclodextrin (HPβCD) were prepared by co-evaporation in a 1:1 ratio and characterized in light of previously reported data. Phase solubility diagrams were obtained for DF-Na with HPβCD in the presence and absence of zinc ions. Dissolution profiles were obtained for DF-Na and its HPβCD complex at acidic (pH 1.2) as well as in phosphate buffer (pH 6.8), in the presence and absence of zinc. HPβCD, as expected, was shown to improve the dissolution of DF-Na in acidic medium but not in phosphate buffer (pH 6.8). The presence of zinc ions decreased the in vitro dissolution of DF-HPβCD complex in acidic medium (pH 1.2) but not in phosphate buffer (pH 6.8). It was confirmed that the precipitate that was formed by zinc ions in the presence of HPβCD and DF-Na contained no cyclodextrin and most likely it was a mixture of the complexes: DF-Zn and DF-Zn with some molecules of water. In vivo experiments on rats have shown that HPβCD has no statistically significant effect on absorption or bioavailability of DF-Na in spite of the observed improvement of its in vitro dissolution by HPβCD. Moreover, zinc ions were shown to decrease the absorption rate of DF-Na in rats model but did neither significantly alter the absorption nor bioavailability of DF-HPβCD complex. The zinc induced precipitates of DF were shown to have significantly different crystalline properties when HPβCD was present. Therefore, the pharmaceutical details of a DF-Na preparation should be considered when designing the formulation and predicting possible interaction between DF-Na (or other potential NSAIDs) and zinc metal.

Rational Design of Rapidly Separating Dissolving Microneedles for Precise Drug Delivery by Balancing the Mechanical Performance and Disintegration Rate

“…The addition of HP‐β‐CD to the drug solution gave significant shift to the system protons and H7 appeared, indicating that NH situated inside the hydrophobic cavity. Similarly, significant shifts were observed in H3, H4, and H5 of drug molecule, demonstrating that the “A” part of drug was included in the CD cavity and verified the reality of inclusion process . Based on the results, the scheme (Figure S3A, Supporting Information) could be presumed for the inclusion process occurring in the solution phase.…”

“…HP‐β‐CD was used to increase the drug loading and decrease the drug irritation when directly contact with the tissue . To evaluate the interaction between DS and HP‐β‐CD molecules, 1 H NMR spectra were recorded using a 500 MHz Bruker NMR spectrometer (Ascend TM 500, German) by monitoring the change in the peak positions . ≈10 mg of samples for 1 NMR were dissolved in 1 mL of deuterated water (D 2 O).…”

Inclusion Complexes of Non-Steroidal Anti-Inflammatory Drugs with Cyclodextrins: A Systematic Review

“…Following this principle, several studies included in the present review used cyclodextrins (especially β-CD and HP-β-CD) to improve the water solubility and increase the bioavailability of NSAIDs such as aceclofenac [29], meloxicam [80], flurbiprofen [54], diclofenac [37], and lornoxicam. It is worth mentioning that increased solubility was associated with improved bioavailability [37,54] and anti-inflammatory activity [70]. In general, NSAIDs are acidic lipophilic compounds characterized by the presence of an aromatic ring bearing an acidic moiety and can differ in their lipophilicities based on their aryl structure and substituents.…”

“…Hamdan et al, 2016 [37] Diclofenac/HP-β-CD Evaluated effects of the preparation on drug absorption, bioavailability, and dissolution (in vivo and in vitro).…”

Recent advances in solid dispersions and the formulation of poorly absorbed drugs

“…Hamdan et al 9 assessed the in vivo bioavailability of diclofenac sodium from its cyclodextrin complexes and the importance of zinc in this system. Liu et al 10 presented their efforts to enhance the bioavailability of a drug that undergoes metabolism in the colon and rectum, Oxymatrine, by formulating alginate-chitosan floating beads prepared by the ionotropic gelation method to increase gastroretention.…”