Polypseudorotaxanes of Pluronic® F127 with Combinations of α- and β-Cyclodextrins for Topical Formulation of Acyclovir.

Cristina Di Donato,Gaetano Malgieri,Carla Isernia,Angela Varela-Garcia,Angel Concheiro,Carmen Alvarez-Lorenzo,Rosa Iacovino

doi:10.3390/nano10040613

Cristina Di Donato, Gaetano Malgieri + Show 5 more

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https://doi.org/10.3390/nano10040613

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Journal: Nanomaterials	Publication Date: Mar 27, 2020
Citations: 20	License type: CC BY 4.0

Affiliation: University of Campania "Luigi Vanvitelli"

Abstract

Acyclovir (ACV) is one of the most used antiviral drugs for the treatment of herpes simplex virus infections and other relevant mucosal infections caused by viruses. Nevertheless, the low water solubility of ACV limits both its bioavailability and antiviral performance. The combination of block copolymer micelles and cyclodextrins (CDs) may result in polypseudorotaxanes with tunable drug solubilizing and gelling properties. However, the simultaneous addition of various CDs has barely been investigated yet. The aim of this work was to design and characterize ternary combinations of Pluronic® F127 (PF127), αCD and βCD in terms of polypseudorotaxane formation, rheological behavior, and ACV solubilization ability and controlled release. The formation of polypseudorotaxanes between PF127 and the CDs was confirmed by FT-IR spectroscopy, X-ray diffraction, and NMR spectroscopy. The effects of αCD/βCD concentration range (0–7% w/w) on copolymer (6.5% w/w) gel features were evaluated at 20 and 37 °C by rheological studies, resulting in changes of the copolymer gelling properties. PF127 with αCD/βCD improved the solubilization of ACV, maintaining the biocompatibility (hen’s egg test on the chorio-allantoic membrane). In addition, the gels were able to sustain acyclovir delivery. The formulation prepared with similar proportions of αCD and βCD provided a slower and more constant release. The results obtained suggest that the combination of Pluronic with αCD/βCD mixtures can be a valuable approach to tune the rheological features and drug release profiles from these supramolecular gels.

Highlights

Acyclovir (ACV), 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one (Figure 1) is a purine nucleoside with an amphoteric behavior due to the presence of two ionizable groups that can be deprotonated or protonated as a function of the pH of the solution
The visualization of two phases in the PF127/αCD 7% system suggested that the polypseudorotaxanes were somehow collapsed and could not form a complete 3D supramolecular gel filling the whole volume of the dispersion
This phase separation was not observed in previous reports on PF127/αCD polypseudorotaxanes prepared in pure water [37,38,39,40] and may be caused by an enhanced aggregation of the αCDs in the buffer pH 4.9 used to prepare the formulations

Summary

Introduction

Acyclovir (ACV), 2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one (Figure 1) is a purine nucleoside with an amphoteric behavior due to the presence of two ionizable groups that can be deprotonated or protonated as a function of the pH of the solution. ACV neutral form predominates in the pH range of 3–8.5 [1]. ACV is a first line drug in the treatment of viral infections caused by herpes simplex viruses (HSV), Epstein–Barr virus (EBV), varicella zoster virus (VZV), Nanomaterials 2020, 10, 613; doi:10.3390/nano10040613 www.mdpi.com/journal/nanomaterials. Nanomaterials 2020, 10, x FOR PEER REVIEW neutral form predominates in the pH range of 3–8.5 [1]. ACV is a first line drug in the treatment of viral infections caused by herpes simplex viruses (HSV), Epstein–Barr virus (EBV), varicella zoster virus (VZV), and cytomegalovirus (CMV) [2,3]. ACV is phosphorylated, resulting in acyclovir triphosphate, which is able to interact with the viral DNA polymerase for and cytomegalovirus (CMV)

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