Synthesis and Evaluation of Methacrylated Poly(2-ethyl-2-oxazoline) as a Mucoadhesive Polymer for Nasal Drug Delivery

Xiaoning Shan,Vitaliy V Khutoryanskiy,Daulet B Kaldybekov,Sam Aspinall,Fhataheya Buang,Adrian C Williams

doi:10.1021/acsapm.1c01097

Xiaoning Shan, Vitaliy V Khutoryanskiy + Show 4 more

Open Access

https://doi.org/10.1021/acsapm.1c01097

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Abstract

Methacrylated poly(2-ethyl-2-oxazoline) (PEOZ) was synthesized by partial hydrolysis of 500 kDa PEOZ, and the resulting poly[(2-ethyl-2-oxazoline)-co-ethylenimine] P(EOZ-co-EI) was subsequently reacted with methacrylic anhydride. The successful synthesis of methacrylated PEOZ (MAPEOZ) was confirmed by proton nuclear magnetic resonance (1H NMR), infrared spectroscopy, and differential scanning calorimetry. The degrees of hydrolysis and methacrylation were determined by 1H NMR spectra. MAPEOZ exhibited temperature-responsive properties, which were dependent on the degree of methacrylation. On that basis, three soluble MAPEOZ derivatives with different degrees of methacrylation were selected and investigated in cell toxicity studies, showing no significant cytotoxicity against the HEK293 cell line. A slug mucosal irritation assay showed that PEOZ and MAPEOZ do not cause mucosal irritation. The presence of methacryloyl groups and residual amines had a remarkable synergistic effect on the mucoadhesive properties of these polymers. These poly(2-ethyl-2-oxazoline) derivatives have excellent potential as mucoadhesive materials for developing formulations for drug delivery via mucosal routes of administration.

Highlights

Nasal administration is a readily accessible route for noninvasive treatment of rhinitis or nasal polyposis
It is likely that the strong mucoadhesive properties of the methacrylated PEOZ (MAPEOZ) result from the synergistic positive effects from both the MA groups and residual secondary amines being available to interact with the mucosal surface
This study demonstrated successful methacrylation of poly(2ethyl-2-oxazoline) through a reaction between hydrolyzed poly(2-ethyl-2-oxazoline) bearing secondary amino groups and methacrylic anhydride

Summary

INTRODUCTION

Nasal administration is a readily accessible route for noninvasive treatment of rhinitis or nasal polyposis. Bioadhesive or, more appropriately, mucoadhesive dosage forms such as microspheres,[9−11] liposomes,[12−14] and gels[15,16] have been studied to prolong their residence in the nasal cavity. Article chain 5 kDa poly(2-oxazolines)) nanoparticles became nonmucoadhesive in an ex vivo rat intestinal mucosal model[44] and enhanced mucus penetration through porcine stomach mucosa.[45] Larger molecular weight PEOZ (50, 200, and 500 kDa) exhibited weak mucoadhesive properties that were improved by complexation or mixing with Carbopol,[46] and films formed from chitosan and PEOZ blends demonstrated mucoadhesive properties with respect to bovine cornea[47] and sheep vaginal tissue.[48] These studies indicate that nonionic water-soluble poly(2-oxazolines) exhibit poor mucoadhesive properties unless mixed with more mucoadhesive materials such as chitosan or Carbopol. Aqueous solutions of PEOZ and its methacrylated derivatives containing sodium fluorescein were prepared and their retention on sheep nasal mucosa was evaluated using a fluorescence flow-through assay

EXPERIMENTAL SECTION

RESULTS AND DISCUSSION

CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES