In Vitro Enhanced Skin Permeation and Retention of Imiquimod Loaded in β-Cyclodextrin Nanosponge Hydrogel

Argenziano, Monica; Haimhoffer, Ádám; Bastiancich, Chiara; Jicsinszky, László; Caldera, Fabrizio; Trotta, Francesco; Scutera, Sara; Alotto, Daniela; Fumagalli, Mara; Musso, Tiziana; Castagnoli, Carlotta; Cavalli, Roberta

doi:10.3390/pharmaceutics11030138

Cited by 64 publications

(57 citation statements)

References 36 publications

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“…Argenziano et al 1 investigated IMQ inclusion complexes prepared with (2-hydroxy) propyl β-cyclodextrin (HPβCD) and carboxymethyl β-cyclodextrin (CMβCD). For phase solubility studies, IMQ was suspended in a water solution containing an equimolar amount of HPβCD or CMβCD.…”

Section: Resultsmentioning

confidence: 99%

“…The molar fraction of IMQ (R) corresponding to the maximum of the curve indicates the inclusion complex stoichiometry where R = m / (m + n) and m and n are the stoichiometric coefficients of IMQ and βCD in the complex, respectively. 22 1 H NMR spectra were 64 scans, 1.992 s acquisition time and 1.0 s relaxation delay. The residual water signal was suppressed by pre-saturation during the recycling delay.…”

Section: Determination Of Complex Stoichiometrymentioning

confidence: 99%

“…The spectrum was acquired with 2 transients for each of the 256 increments. 1 H, COSY and 1D-ROESY NMR data were processed with Bruker TopSpin software.…”

Section: Determination Of Complex Stoichiometrymentioning

confidence: 99%

“…It is an immune response modifier and is indicated for topical treatment of external genital and perianal warts, basal cell carcinoma, Bowen's disease and actinic keratosis. [1][2][3][4] IMQ (Figure 1a) is a weakly basic drug (pK a 7.3 at 22 °C) whose solubility is strongly influenced by pH variations. It has a molecular weight of 240.30 Da and high melting point 297-299 °C.…”

Section: Introductionmentioning

confidence: 99%

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Imiquimod/β-Cyclodextrin Inclusion Complex: Experimental and Theoretical Studies

Guedes

Morgon

Martins

et al. 2020

J. Braz. Chem. Soc.

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Imiquimod (IMQ), an immune response modifier, is used for topical treatment of basal cell carcinoma and actinic keratosis. The very poor aqueous solubility of imiquimod gives rise to difficulties in designing aqueous formulations with this drug. One approach that is widely used to enhance drug solubility is complexation with cyclodextrins. The formation of the inclusion complex between IMQ and β-cyclodextrin was investigated in solution and in solid state. IMQ aqueous solubility was improved in the presence of citric acid. The experimental results and molecular modeling indicated the formation of the inclusion complex in aqueous solution of citric acid pH 3.0; however, the low apparent stability constant suggested weak interaction between β-cyclodextrin and IMQ which hampered the use of this approach to improve imiquimod aqueous solubility and the development of an aqueous formulation containing IMQ in the same concentration as in the commercial product.

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Section: Resultsmentioning

confidence: 99%

Section: Determination Of Complex Stoichiometrymentioning

confidence: 99%

“…The spectrum was acquired with 2 transients for each of the 256 increments. 1 H, COSY and 1D-ROESY NMR data were processed with Bruker TopSpin software.…”

Section: Determination Of Complex Stoichiometrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Imiquimod/β-Cyclodextrin Inclusion Complex: Experimental and Theoretical Studies

Guedes

Morgon

Martins

et al. 2020

J. Braz. Chem. Soc.

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“…Previous work has demonstrated the use of modified cyclodextrins and cyclodextrin polymers to deliver poorly soluble drugs [7][8][9]. However, using cyclodextrins (CD) in a different line of work, we sought to provide a sustained delivery of small molecules for longer than their short, diffusion-based half-lives to better match the timeline of fibrosis and wound healing.…”

Section: Introductionmentioning

confidence: 99%

Affinity Effects on the Release of Non-Conventional Antifibrotics from Polymer Depots

2020

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For many chronic fibrotic conditions, there is a need for local, sustained antifibrotic drug delivery. A recent trend in the pharmaceutical industry is the repurposing of approved drugs. This paper investigates drugs that are classically used for anthelmintic activity (pyrvinium pamoate (PYR)), inhibition of adrenal steroidgenesis (metyrapone (MTP)), bactericidal effect (rifampicin (RIF), and treating iron/aluminum toxicity (deferoxamine mesylate (DFOA)), but are also under investigation for their potential positive effect in wound healing. In this role, they have not previously been tested in a localized delivery system suitable for obtaining the release for the weeks-to-months timecourse needed for wound resolution. Herein, two cyclodextrin-based polymer systems, disks and microparticles, are demonstrated to provide the long-term release of all four tested non-conventional wound-healing drugs for up to 30 days. Higher drug affinity binding, as determined from PyRx binding simulations and surface plasmon resonance in vitro, corresponded with extended release amounts, while drug molecular weight and solubility correlated with the improved drug loading efficiency of cyclodextrin polymers. These results, combined, demonstrate that leveraging affinity interactions, in combination with drug choice, can extend the sustained release of drugs with an alternative, complimentary action to resolve wound-healing and reduce fibrotic processes. 126To first predict the relative binding affinities of the chosen drugs for the β-CD versus dextran 127 (chemically similar control without inclusion complex), a molecular docking program was utilized 128 (PyRx with Autodock Vina software [28,35]). The β-CD monomer, dextran, and drug molecule 129 structure files were downloaded from online databases as specified in the methods section (Figure 130 1A). DFOA, RIF, MTP, and PYR were individually simulated to determine minimal binding energy 131 configurations with either β-CD or dextran as the target host macromolecule. The results were 132 converted to dissociation constants for each simulated pair. 133 134 Figure 1. (A) Molecular structures of rifampicin (RIF), metyrapone (MTP), pyrvinium (PYR), and 135 deferoxamine (DFOA) represented in 3D with JMOL software showing relative size and potential 136 binding conformations for the β-CD inclusion complex formation. (B) PyRx simulations were 137 performed to predict the binding affinity of drugs with β-CD versus dextran as a chemically similar, 138 but non-inclusion-forming, control, as dextran lacks the binding cavity of β-CD. 139The lowest KD (highest binding affinity) was predicted for RIF and β-CD (0.04 mM), while the 140 KD for MTP and PYR β-CD complexes were more than twice as large at 0.098 and 0.104 mM, 141 respectively ( Figure 1B). DFOA resulted in the highest KD out of all the β-CD simulations at 1.463 142 mM. When the drugs were simulated with dextran, the KD values were higher. The combination of 143 RIF and dextran demonstrated a KD of 1.776 mM, followed by PYR-dextran (4.770 m...

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Drug-Encapsulated Cyclodextrin Nanosponges

Tannous

Caldera

Hoti

et al. 2020

Methods in Molecular Biology

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In Vitro Enhanced Skin Permeation and Retention of Imiquimod Loaded in β-Cyclodextrin Nanosponge Hydrogel

Cited by 64 publications

References 36 publications

Imiquimod/β-Cyclodextrin Inclusion Complex: Experimental and Theoretical Studies

Imiquimod/β-Cyclodextrin Inclusion Complex: Experimental and Theoretical Studies

Affinity Effects on the Release of Non-Conventional Antifibrotics from Polymer Depots

Drug-Encapsulated Cyclodextrin Nanosponges

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