Effect of chemical structure on complexation efficiency of aromatic drugs with cyclodextrins: The example of dibenzazepine derivatives

Hemine, Koleta; Skwierawska, Anna; Kleist, Cyprian; Olewniczak, Michal; Szwarc-Karabyka, Katarzyna; Wyrzykowski, Dariusz; Mieszkowska, Anna; Chojnacki, Jarosław; Nierzwicki, Łukasz

doi:10.1016/j.carbpol.2020.116957

Cited by 5 publications

(4 citation statements)

References 54 publications

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“…Complexation of MTX with CD molecules enhances the bioavailability of MTX by increasing the drug solubility, dissolution, and/or permeability, presenting it in a more soluble form at the absorption site, leading to its higher systemic absorption. Evidently, structural and functional changes to CDs will fine-tune the degree of complexation and, as a result, drug solubilization tendency and bioavailability benefits, suggesting that judicious CDs selection is crucial [ 48 ]. In terms of clinical implications, improved solubility and increased bioavailability achieved through the “host-guest” interaction of IC can enhance the systemic absorption of lipophilic molecules that inherently shows slow or erratic absorption profiles.…”

Section: Resultsmentioning

confidence: 99%

Alternative Methotrexate Oral Formulation: Enhanced Aqueous Solubility, Bioavailability, Photostability, and Permeability

et al. 2022

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The poor aqueous solubility and/or permeability and thereby limited bioavailability largely restricts the pharmaco-therapeutic implications of potent anticancer drugs such as methotrexate (MTX). Furthermore, MTX’s inherently unstable nature makes it difficult to develop a viable oral formulation. In this study we developed the spray-dried amorphous inclusion complexes of MTX with native β-cyclodextrin (β-CD) and its derivatives, namely HP-β-CD, M-β-CD, and DM-β-CD to enhance the aqueous solubility, photostability, permeability, and oral bioavailability of MTX in rats. Our findings show that the 1:1 stoichiometry ratio of MTX and CDs improves the aqueous solubility, stability, and pharmacokinetic profiles of the drug, the better results being obtained particularly with DM-β-CD as a host, which has a higher complexation ability with the drug compared to other β-CDs. Specifically, the pharmacokinetic analysis demonstrated 2.20- and 3.29-fold increments in AUC and Cmax, respectively, in comparison to free MTX. Even though the absorptive permeability of MTX and MTX/DM-β-CD inclusion complexes was similar, the efflux of the absorbed MTX from ICs was significantly lower compared to the free MTX (4.6- vs. 8.0-fold). Furthermore, the physicochemical characterization employing SEM, DSC, and PXRD confirmed the transformation of crystalline MTX to its amorphous state. In solution, 1H NMR studies revealed that MTX embedded into the DM-β-CD cavity resulting in both H-3 and H-5 chemical shifts implied the presence of intermolecular interaction between the drug and CD moiety. It was, therefore, evident that an MTX IC could be a successful oral formulation technique, preventing MTX degradation and enhancing its pharmacologically relevant properties.

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Section: Resultsmentioning

confidence: 99%

Alternative Methotrexate Oral Formulation: Enhanced Aqueous Solubility, Bioavailability, Photostability, and Permeability

et al. 2022

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“…Chemicals were obtained from Merck KGaA (Darmstadt, Germany): Opipramol (IS-opi), methanol (gradient grade for liquid chromatography), HEPES, alamethicin, NADPH and UDPGA. IS-noh was synthesized according to the method described in Ref (Hemine et al 2020). Ammonium formate was from Fisher Scientific (Loughborough, UK).…”

Section: Methodsmentioning

confidence: 99%

“…Opipramol was chosen for study because the metabolism of IS-opi with UGTs has not yet been described in detail. Compound IS-noh is an analog of opipramol synthesized in the Gdansk University of Technology (Hemine et al 2020). The metabolic pathway of IS-noh has not been known yet.…”

Section: Introductionmentioning

confidence: 99%

Detoxification of the tricyclic antidepressant opipramol and its analog – IS-noh by UGT enzymes before and after activation by phase I enzymes in rat liver microsomes

et al. 2021

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The present studies were carried out to evaluate the simultaneous one-pot metabolism of opipramol (IS-opi) and analog (IS-noh) by phase I and phase II enzymes present in rat liver microsomes (RLM) as an alternative to separate testing with recombinant enzymes. This approach allows for more time-saving and cost-effective screening of the metabolism of newly discovered drugs. We also considered that the lack of results for phase II, including UGT, often creates problems in correct selection of valuable compounds. Moreover, microsomes data set is richer in the contest and provides medical scientist to determine also the susceptibility of drugs to undergo phase I and then phase II. In the present work, we have shown that IS-noh was metabolized in vitro by phase I enzymes to the oxidation product, which was next transformed with UGTs to glucuronide. The results showed also that the previously known oxidation product of opipramol was changed to previously no reported glucuronidation product by UDP-glucuronosyltransferases. In addition, unlike IS-noh, opipramol did not prove to be the substrate for UGTs. Therefore, tricyclic antidepressants depending on the structure can trigger a different response after contact with UGT enzymes. Some will metabolize directly with UGTs, others only after activation by phase I enzymes.

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“…31,32 In the host-guest system, β-cyclodextrins (β-CD) have been chosen as host molecules because of their biocompatibility, which possesses hydrophilic outers and hydrophobic cavities. 33,34 The cavities can form host-guest inclusions with CHX molecules (CHX⊂CD) through dipole-dipole and hydrophobic interactions. [35][36][37] After the inclusions are released from MSN, CHX will slowly dissociate from the hostguest complex to achieve the long-lasting antibacterial activity.…”

Section: Introductionmentioning

confidence: 99%

Hybrid Hydrogel Loaded with Chlorhexidine⊂β-CD-MSN Composites as Wound Dressing

Jiang¹,

Shi²,

Wang³

et al. 2023

IJN

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Background Much attention has been paid to sustained drug release and anti-infection in wound management. Hydrogels, which are biocompatible materials, are promising tools for controlled drug release and infective protection during wound healing. However, hydrogels also demonstrate limitations in the highly efficient treatment of wounds because of the diffusion rate. In this work, we explored pH-sensitive hydrogels that enable ultra-long-acting drug release and sustained antibacterial properties. Methods We constructed a hybrid gelatin methacrylate (GelMA) system with sustainable antibacterial properties combining hyaluronic acid (HA)-coated mesoporous silica nanoparticles (MSN), which loaded host-guest complexes of chlorhexidine (CHX) with β-cyclodextrins (β-CD) (CHX⊂CD-MSN@HA@GelMA). The release mechanism of CHX was explored using UV-vis spectra after intermittent diffusion of CHX. The hybrid hydrogels were characterized, and the drug content in terms of the release profile, bacterial inhibition, and in vivo experiments were investigated. Results Except for dual protection from both hydrogels, MSN in the HA improved the drug loading efficiency to promote the local drug concentration. It showed that complicated CHX-loaded MSN releases CHX more gradually and over a longer duration than CHX-loaded MSNs. This demonstrated a 12-day CHX release time and antibacterial activity, primarily attributable to the capacity of β-CD to form an inclusion complex with CHX. Meanwhile, in vivo experiments revealed that the hydrogels safely promote skin wound healing and enhance therapeutic efficacy. Conclusion We constructed pH-sensitive CHX⊂CD-MSN@HA@GelMA hydrogels that enable ultra-long-acting drug release and sustained antibacterial properties. The combination of β-CD and MSN would be better suited to release a reduced rate of active molecules over time (slow delivery), making them great candidates for wound dressing anti-infection materials.

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Effect of chemical structure on complexation efficiency of aromatic drugs with cyclodextrins: The example of dibenzazepine derivatives

Cited by 5 publications

References 54 publications

Alternative Methotrexate Oral Formulation: Enhanced Aqueous Solubility, Bioavailability, Photostability, and Permeability

Alternative Methotrexate Oral Formulation: Enhanced Aqueous Solubility, Bioavailability, Photostability, and Permeability

Detoxification of the tricyclic antidepressant opipramol and its analog – IS-noh by UGT enzymes before and after activation by phase I enzymes in rat liver microsomes

Hybrid Hydrogel Loaded with Chlorhexidine⊂β-CD-MSN Composites as Wound Dressing

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