Diclofenac-β-cyclodextrin for colonic drug targeting: In vivo performance in rats

Abstract

The aim of this in vivo study was to assess the ability of the prodrug conjugate diclofenac-β-cyclodextrin to release diclofenac in the colon following oral administration, using sulfapyridine (a metabolite of sulfasalazine) as a marker of colonic absorption. Two groups of rats were used; the test rats received a suspension containing the two prodrugs, diclofenac-β-cyclodextrin and sulfasalazine, while the control rats received a suspension containing the corresponding free drugs, sodium diclofenac and sulfapyridine. The rats were fasted overnight with free access to water before and throughout the first 12h of the study. Blood was collected from the tail vein at pre-determined time points and the plasma analyzed for the concentrations of diclofenac and sulfapyridine. Following the oral administration of the two prodrugs, a more extended absorption profile was observed and Cmax was achieved 10h post-dose, in contrast to rapid absorption of the free drugs (tmax of diclofenac being 1.3h, and that of sulfapyridine being 2.1h). In addition to a later tmax, conjugation of diclofenac to β-cyclodextrin also resulted in a reduced Cmax and a reduced AUC. The same tmax for diclofenac-β-cyclodextrin as for sulfasalazine confirms the colonic metabolism of diclofenac-β-cyclodextrin. This study shows the potential of this new cyclodextrin-based prodrug to target and release diclofenac specifically in the colon following oral administration.

Development and validation of a new HPLC analytical method for the determination of diclofenac in tablets

“…Various analytical techniques have been reported for the quantification of diclofenac sodium (DS) in different matrices. High-pressure liquid chromatography detection (HPLC) is the most common used method for the determination of DS in biological sample or dosage forms (Bhattacharya et al, 2013, Klimeš et al, 2001, Yan et al, 2014, Vieira et al, 2016, Mahdi et al, 2016, Cordery et al, 2017, Khan et al, 2016, Pireddu et al, 2015, Aldwaikat and Alarjah, 2015, Hegazy et al, 2015, Kasperek, 2008, Basusarkar, 2011, Nivsarkar et al, 2015, Korodi et al, 2012, Chaudhary et al, 2011, Kubala et al, 1993, Mulgund et al, 2009, Gaudiano et al, 2003).…”

Synergistic Effect of Acetazolamide-(2-hydroxy)propyl β-Cyclodextrin in Timolol Liposomes for Decreasing and Prolonging Intraocular Pressure Levels

“…This enhancer effect of TM in the lipid bilayer was exhibited in the in vitro release profiles, showing the same relationship as the permeation behavior. Therefore, it can be concluded from the study that the optimized formulation could act as an enhancer of permeation for Acz and TM because of the presence of a lipophilic structure, cationic charge, and HPβCD, according to other authors [96].…”

Cyclodextrin complexes: Perspective from drug delivery and formulation

“…Promising results were shown after clinical trials of KLEPTOSE CRYSMEB and 2‐HP‐β‐CD‐based therapy as cholesterol‐chelating agent in atherosclerosis and Niemann‐Pick type C disease (Coisne et al, ). β‐CD‐based inclusion complexes for targeted drug delivery system incorporating aspirin (Ma et al, ) and diclofenac (Vieira et al, ) have been demonstrated. Advantages of modified β‐CDs as brain delivery vectors for RNAi‐based therapies in Huntington's disease were investigated (Godinho, Ogier, Darcy, O'Driscoll, & Cryan, ).…”

“…Promising results were Clonazepam Me-β-CD Liposomal and microemulsion formulations contain drug-CD complex showed greater solubility and permeation Mura, Bragagni, Mennini, Cirri, and Maestrelli (2014) Curcumin HP-β-CD Increases solubility, transdermal permeation of curcumin, and demonstrated better anti-inflammatory effect Ghanghoria, Kesharwani, Agashe, and Jain (2013) Diclofenac sodium HP-β-CD HP-β-CD grafted polyethyleneimine has proved as a potent skin penetration enhancer with no toxicity or skin irritation Yan et al (2014) Epalrestat ME-β-CD Enhanced dissolution and skin permeation through hairless mouse skin Furuishi et al (2017) Flurbiprofen HP-β-CD Polymeric nanospheres with drug-CD complex showed greater retention of drug in skin as well as stronger anti-inflammatory effect Vega et al (2013) Isotretinoin HP-β-CD Elastic liposomes significantly increased the skin deposition, prolonged drug release and reduce skin irritation Kaur, Puri, and Jain (2010) Itraconazole HP-β-CD Deformable liposomes contain drug-CD complex showed greater cutaneous drug deposition Alomrani, Shazly, Amara, and Badran (2014) Levodopa β-CD Stability of levodopa was enhanced when complexed with β-CD in transdermal patches Obaidat, Al-Shar'i, Tashtoush, and Athamneh (2016) Lornoxicam HP-β-CD Incorporation of CD and propylene glycol in gel improved the skin permeation Al-Suwayeh, Taha, Al-Qahtani, Ahmed, and Badran (2014) Propofol SBE-β-CD Complexation significantly improved the passive and iontophoretic transdermal flux Juluri, Peddikotla, Repka, and Murthy (2013) Terbinafine HP-β-CD Demonstrated the potential of CD as a transungual permeation enhancer Chouhan and Saini (2014) shown after clinical trials of KLEPTOSE CRYSMEB and 2-HP-β-CDbased therapy as cholesterol-chelating agent in atherosclerosis and Niemann-Pick type C disease (Coisne et al, 2016). β-CD-based inclusion complexes for targeted drug delivery system incorporating aspirin (Ma et al, 2015) and diclofenac (Vieira et al, 2016) have been demonstrated. Advantages of modified β-CDs as brain delivery vectors for…”