Cucurbit[7]uril-based host-guest complexes for improving bioavailability and reducing side effects of piroxicam

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems
• Medicinal Chemistry

Background:

• Piroxicam (PX), a nonsteroidal anti-inflammatory drug (NSAID), frequently causes gastrointestinal (GI) injuries due to its limited solubility.
• Existing formulations using β-cyclodextrin (β-CD) show moderate improvements in solubility and dissolution but still result in common adverse reactions.
• The low binding affinity between PX and β-CD limits the extent of solubility enhancement.

Purpose of the Study:

• To investigate the potential of Cucurbit[7]uril (CB[7]) as a superior host molecule for piroxicam (PX) formulation.
• To evaluate the impact of CB[7] complexation on PX's solubility, dissolution rate, oral bioavailability, and anti-inflammatory efficacy.
• To assess the gastrointestinal safety profile of PX formulated with CB[7] compared to PX alone and PX with β-CD.

Main Methods:

• Complexation of PX with CB[7] in a simulated gastric environment and determination of binding constants.
• In vitro assessment of dissolution rates for PX, PX@CD, and PX@CB[7] formulations.
• In vivo evaluation of oral bioavailability, maximum concentration (Cmax), anti-inflammatory effects in mouse and rat models, and gastric mucosal adhesion.
• Subacute toxicity studies to assess the oral biocompatibility of CB[7].

Main Results:

• CB[7] forms PX inclusion complexes (PX@CB[7]) with a binding constant approximately 70 times higher than that of β-CD with PX.
• PX@CB[7] exhibited rapid dissolution rates in gastric conditions.
• PX@CB[7] demonstrated significantly enhanced oral bioavailability and Cmax, leading to improved anti-inflammatory activity in animal models.
• PX@CB[7] (1:2.5) showed minimal gastric mucosal adhesion and the mildest GI side effects compared to PX and PX@CD formulations.
• CB[7] exhibited good oral biocompatibility in toxicity studies.

Conclusions:

• CB[7] is a highly effective host molecule for piroxicam, significantly improving its solubility, bioavailability, and therapeutic efficacy.
• PX@CB[7] formulations offer a promising strategy to mitigate NSAID-induced gastrointestinal toxicity.
• CB[7] presents a favorable safety profile, indicating its potential as a valuable excipient for developing safer and more effective oral drug formulations.