Interaction of fentanyl with various cyclodextrins in aqueous solutions

Ogawa, Naoko; Furuishi, Takayuki; Nagase, Hiromasa; Endō, Takeshi; Takahashi, Chisato; Yamamoto, Hiromitsu; Kawashima, Yasunaru; Loftsson, Þorsteinn; Kobayashi, Masaru; Ueda, Hitoshi

doi:10.1111/jphp.12437

Cited by 8 publications

(5 citation statements)

References 33 publications

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“…The chemical stability of nepafenac was determined in aqueous solution containing 1% w / v γCD following heating by sonication [47,48,49,50]. The solution was shaken for 24 h until the drug was completely dissolved and then passed through a 0.45 µm membrane filter.…”

Section: Methodsmentioning

confidence: 99%

Nepafenac-Loaded Cyclodextrin/Polymer Nanoaggregates: A New Approach to Eye Drop Formulation

2019

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The topical administration route is commonly used for targeting therapeutics to the eye; however, improving the bioavailability of drugs applied directly to the eye remains a challenge. Different strategies have been studied to address this challenge. One of them is the use of aggregates that are formed easily by self-assembly of cyclodextrin (CD)/drug complexes in aqueous solution. The aim of this study was to design a new eye drop formulation based on aggregates formed between CD/drug complexes. For this purpose, the physicochemical properties of the aggregates associated with six CDs and selected water-soluble polymers were analysed. Complex formation was studied using differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR) and 1H nuclear magnetic resonance spectroscopy (1H-NMR). Results showed that HPβCD performed best in terms of solubilization, while γCD performed best in terms of enhancing nanoaggregate formation. Formation of inclusion complexes was confirmed by DSC, FT-IR and 1H-NMR studies. A mixture of 15% (w/v) γCD and 8% (w/v) HPβCD was selected for formulation studies. It was concluded that formulations with aggregate sizes less than 1 µm and viscosity around 10–19 centipoises can be easily prepared using a mixture of CDs. Formulations containing polymeric drug/CD nanoaggregates represent an interesting strategy for enhanced topical delivery of nepafenac.

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Section: Methodsmentioning

confidence: 99%

Nepafenac-Loaded Cyclodextrin/Polymer Nanoaggregates: A New Approach to Eye Drop Formulation

2019

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“…For instance, Valdez et al presented optimized syntheses of fentanyl and analogues [5] and Jevtić et al described a route for new derivatives via orthogonally protected (in positions 1 and 3) 3-amino-4-anilidopiperidines [6]. Issues of formulation and drug delivery prompted several groups to study fentanyl interactions with cyclodextrins in aqueous solutions [7] or solid state interactions of fentanyl citrate polymorphs and solvates [8]. In a very interesting contribution, Bick et al described design and synthesis of proteins binding fentanyl for purposes of creating environmental sensors [9].…”

Section: Introductionmentioning

confidence: 99%

Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis

et al. 2019

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Interactions of 21 fentanyl derivatives with μ-opioid receptor (μOR) were studied using experimental and theoretical methods. Their binding to μOR was assessed with radioligand competitive binding assay. A uniform set of binding affinity data contains values for two novel and one previously uncharacterized derivative. The data confirms trends known so far and thanks to their uniformity, they facilitate further comparisons. In order to provide structural hypotheses explaining the experimental affinities, the complexes of the studied derivatives with μOR were modeled and subject to molecular dynamics simulations. Five common General Features (GFs) of fentanyls’ binding modes stemmed from these simulations. They include: GF1) the ionic interaction between D147 and the ligands’ piperidine NH+ moiety; GF2) the N-chain orientation towards the μOR interior; GF3) the other pole of ligands is directed towards the receptor outlet; GF4) the aromatic anilide ring penetrates the subpocket formed by TM3, TM4, ECL1 and ECL2; GF5) the 4-axial substituent (if present) is directed towards W318. Except for the ionic interaction with D147, the majority of fentanyl-μOR contacts is hydrophobic. Interestingly, it was possible to find nonlinear relationships between the binding affinity and the volume of the N-chain and/or anilide’s aromatic ring. This kind of relationships is consistent with the apolar character of interactions involved in ligand–receptor binding. The affinity reaches the optimum for medium size while it decreases for both large and small substituents. Additionally, a linear correlation between the volumes and the average dihedral angles of W293 and W133 was revealed by the molecular dynamics study. This seems particularly important, as the W293 residue is involved in the activation processes. Further, the Y326 (OH) and D147 (Cγ) distance found in the simulations also depends on the ligands’ size. In contrast, neither RMSF measures nor D114/Y336 hydrations show significant structure-based correlations. They also do not differentiate studied fentanyl derivatives. Eventually, none of 14 popular scoring functions yielded a significant correlation between the predicted and observed affinity data (R < 0.30, n = 28).

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“…Conversely, for the HP-β-CD system, the solubility of RBG increased nonlinearly and deviated from the straight line in the negative direction as the HP-β-CD concentration was increased, indicating the formulation of a soluble inclusion complex. According to the Higuchi and Connors classification [ 33 ], the diagrams obtained could be classified as B S -type and A N -type for β-CD and HP-β-CD [ 34 ], respectively. Additionally, the stability constants (Kc) estimated from the slope of the phase solubility plots of the RBG/β-CD and RBG/HP-β-CD systems ( Figures S2 and S3 ) were found to be 9581 ± 360 M −1 and 10,765 ± 492 M −1 , respectively.…”

Section: Resultsmentioning

confidence: 99%

Enhancement of Dissolving Capacity and Reducing Gastric Mucosa Irritation by Complex Formation of Resibufogenin with β-Cyclodextrin or 2-Hydroxypropyl-β-cyclodextrin

et al. 2022

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Resibufogenin (RBG) is a natural medicinal ingredient with promising cardiac protection and antitumor activity. However, poor solubility and severe gastric mucosa irritation restrict its application in the pharmaceutical field. In this study, the inclusion complex of RBG with β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) was prepared using the co-evaporation method, and the molar ratio of RBG to CD was determined to be approximately 1:2 by continuous variation plot for both CDs. The formation of inclusion complexes between RBG and each CD (RBG/β-CD and RBG/HP-β-CD) was evaluated by phase solubility study, Fourier transform infrared spectroscopy, and thin-layer chromatography. Powder X-ray diffraction and differential scanning calorimetry confirmed drug amorphization and encapsulation in the molecular cage for both CDs. Moreover, the inclusion complexes’ morphologies were observed using scanning electron microscopy. The dissolution rate of the inclusion complexes was markedly improved compared to that of RBG, and the complexes retained their antitumor activity, as shown in the in vitro cytotoxicity assay on a human lung adenocarcinoma cancer (A549) cell line. Moreover, less gastric mucosal irritation was observed for the inclusion complex. Thus, the inclusion complex should be considered a promising strategy for the delivery of poorly water-soluble anticancer agents, such as RBG.

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Interaction of fentanyl with various cyclodextrins in aqueous solutions

Abstract: This study revealed that hydrophilic β-CD derivatives, such as G1-β-CD, could be useful pharmaceutical additives for oral mucosal formulations because of the improved fentanyl base solubility via inclusion complexation.

Cited by 8 publications

References 33 publications

Nepafenac-Loaded Cyclodextrin/Polymer Nanoaggregates: A New Approach to Eye Drop Formulation

Nepafenac-Loaded Cyclodextrin/Polymer Nanoaggregates: A New Approach to Eye Drop Formulation

Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis

Enhancement of Dissolving Capacity and Reducing Gastric Mucosa Irritation by Complex Formation of Resibufogenin with β-Cyclodextrin or 2-Hydroxypropyl-β-cyclodextrin

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