Hydrophobically Grafted Pullulan Nanocarriers for Percutaneous Delivery: Preparation and Preliminary In Vitro Characterisation.

Mohammad F Bostanudin,Eugen Barbu,Kai Bin Liew

doi:10.3390/polym13172852

Abstract

Polymeric colloidal nanocarriers formulated from hydrophobically grafted carbohydrates have been the subject of intensive research due to their potential to increase the percutaneous penetration of hydrophilic actives. To this goal, a series of hydrophobically grafted pullulan (BMO-PUL) derivatives with varying degree of grafting (5–64%) was prepared through functionalisation with 2-(butoxymethyl)oxirane. The results demonstrated that monodispersed BMO-PUL nanocarriers (size range 125–185 nm) could be easily prepared via nanoprecipitation; they exhibit close-to-spherical morphology and adequate stability at physiologically relevant pH. The critical micellar concentration of BMO-PUL was found to be inversely proportional to their molecular weight (Mw) and degree of grafting (DG), with values of 60 mg/L and 40 mg/L for DG of 12.6% and 33.8%, respectively. The polymeric nanocarriers were loaded with the low Mw hydrophilic active α-arbutin (16% loading), and the release of this active was studied at varying pH values (5 and 7), with a slightly faster release observed in acidic conditions; the release profiles can be best described by a first-order kinetic model. In vitro investigations of BMO-PUL nanocarriers (concentration range 0.1–4 mg/mL) using immortalised skin human keratinocytes cells (HaCaT) evidenced their lack of toxicity, with more than 85% cell viability after 24 h. A four-fold enhance in arbutin permeation through HaCaT monolayers was recorded when the active was encapsulated within the BMO-PUL nanocarriers. Altogether, the results obtained from the in vitro studies highlighted the potential of BMO-PUL nanocarriers for percutaneous delivery applications, which would warrant further investigation in vivo.

Highlights

The development of percutaneous drug delivery has aroused enormous interest owing to its potential to avoid first-pass effect and gastrointestinal enzyme-catalysed degradation
Pullulan possesses functional groups that facilitate a range of chemical modifications that can make it more amenable for use in various applications [20]; for example, when modified into a material with a hydrophobic character, it can spontaneously self-assemble into nanocarriers with a high loading capacity and low critical micellar concentration (CMC) [21,22]
Investigating the hypothesis that nanoformulations prepared from hydrophobically grafted polymers can provide improved drug carrier characteristics that are suitable for percutaneous delivery, we present here the synthesis and characterisation of hydrophobically grafted pullulan (BMO-PUL) that was grafted with hydrophobic alkylglycerol, 2-(butoxymethyl)oxirane, through a SN2 nucleophilic substitution reaction under aqueous alkaline conditions

Summary

Introduction

The development of percutaneous drug delivery has aroused enormous interest owing to its potential to avoid first-pass effect and gastrointestinal enzyme-catalysed degradation. Actual progress in the delivery of numerous water-soluble actives has been restrained by their inadequate percutaneous penetration due to the nature of the skin lipid layer that has a high affinity for hydrophobic, ionised, and low molecular weight compounds [1,2]. In an alternative approach that shows promising results, ongoing research actively aims at the polymeric colloidal nanocarriers development for percutaneous drug delivery [6–8]. Well-known for its biodegradability and lack of toxicity, pullulan has been used mainly in the pharmaceutical and food industries [10]. It has been investigated for skin and percutaneous administration, with results suggesting its potential in treating skin wounds and in enhancing percutaneous drug delivery [11–13]. Additional benefits of amphiphilic nanocarriers such as decreased drug cytotoxicity, prolonged blood circulation time, and enhanced permeation make these systems very promising for percutaneous delivery [23–28]

Methods

Results

Conclusion