Hydrogel Formulations Incorporating Drug Nanocrystals Enhance the Therapeutic Effect of Rebamipide in a Hamster Model for Oral Mucositis

Noriaki Nagai,Noriko Hiramatsu,Ryotaro Seiriki,Saori Deguchi,Hiroko Otake,Naoki Yamamoto,Hiroshi Sasaki

doi:10.3390/pharmaceutics12060532

Noriaki Nagai, Noriko Hiramatsu + Show 5 more

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https://doi.org/10.3390/pharmaceutics12060532

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Abstract

A mouthwash formulation of rebamipide (REB) is commonly used to treat oral mucositis; however, this formulation does not provide sufficient treatment or prevention in cases of serious oral mucositis. To improve treatment, we attempted to design a hydrogel incorporating REB nanocrystals (R-NPs gel). The R-NPs gel was prepared by a bead mill method using carbopol hydrogel, methylcellulose and 2-hydroxypropyl-β-cyclodextrin, and another hydrogel incorporating REB microcrystals (R-MPs gel) was prepared following the same protocol but without the bead mill treatment. The REB particle size in the R-MPs gel was 0.15–25 μm, and while the REB particle size was 50–180 nm in the R-NPs gel. Next, we investigated the therapeutic effect of REB nanocrystals on oral mucositis using a hamster model. Almost all of the REB was released as drug nanocrystals from the R-NPs gel, and the REB content in the cheek pouch of hamsters treated with R-NPs gel was significantly higher than that of hamsters treated with R-MPs gel. Further, treatment with REB hydrogels enhanced the healing of oral wounds in the hamsters. REB accumulation in the cheek pouch of hamsters treated with the R-NPs gel was prevented by an inhibitor of clathrin-dependent endocytosis (CME) (40 μM dynasore). In conclusion, we designed an R-NPs gel and found that REB nanocrystals are taken up by tissues through CME, where they provide a persistent effect resulting in an enhancement of oral wound healing.

Highlights

Pain caused by serious oral mucositis affects food intake, nutrition, speaking, and swallowing, can cause life-threatening bacteremia, and leads to poor quality of life for patients [1,2]
We previously found that drug nanocrystals were taken up by cells, provided high efficiency, and showed that a hydrogel is suitable as a base for gel formulations, since the drug nanocrystals were released from the hydrogel base [33,34,35]
The aggregates of REB particles were observable in the R-MPs gel (Figure 1A,B) with the naked eye; bead mill treatment caused a decrease in REB particle size, after which aggregates were no longer visible in the R-NPs gel (Figure 1A,C)

Summary

Introduction

Pain caused by serious oral mucositis affects food intake, nutrition, speaking, and swallowing, can cause life-threatening bacteremia, and leads to poor quality of life for patients [1,2]. Chemoradiotherapy for patients with head and neck cancer often causes serious oral mucositis, and the severe pain interferes with subsequent treatment and quality of life [3,4,5]. Caphosol®, MuGard®, MucotrolTM, Gelclair®, Episil® and Palifermin have surfaced on the market. Caphosol® is a supersaturated calcium phosphate, electrolyte mouth rinse used as artificial saliva, and MuGard® (oral mucoadhesive) causes the formation of a protective coating over oral mucosa. Gelclair® is a viscous gel that is used as a mouthwash and forms a protective film by adhering to the mucosa of the oropharyngeal cavity, helping to provide pain relief in mouth lesions. The keratinocyte growth factor stimulates the growth of cells that line the surface of the mouth and intestinal tract. Serious oral mucositis remains a frequent and critical complication of head and neck cancers [8,9,10]

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