Therapeutic Effects of Rebamipide Nanocrystals as Carbopol Gel Formulation Containing Gum Arabic in a Hamster Model of Oral Mucositis

Abstract

Severe oral mucositis is a major cause of a low quality of life in patients; however, the therapeutic effect of traditional treatments is insufficient. Therefore, we designed a carbopol gel based on rebamipide nanocrystals (REB NCs) and gum arabic (GA-REB@NP), and investigated its efficacy in accelerating wound healing in a hamster model of oral mucositis. REB NCs were prepared by bead milling, and GAREB@ NP were prepared by incorporating REB NCs into a carbopol gel.

The REB sizes were measured using a SALD-7100 and NanoSight LM10, and both powder X-ray diffraction and differential thermal analysis were used to analyze the crystalline form. Drug release from the gel formulations and therapeutic effects were evaluated using hamsters. The particles of milled-REB without GA were microsized, whereas the particle size of milled-REB with GA was in the range of 30–180 nm, and the crystalline form was similar to that of REB with or without bead milling. Next, we evaluated the characteristics of GA-REB@NP. The particle size of REB in GA-REB@NP was in the range of 45–200 nm, and drug release from GA-REB@NP was higher than that from the gel incorporating REB microcrystals (GA-REB@MP).

In addition, REB nanoparticles were released from GA-REB@NP. Moreover, inhibitors of both clathrin- (dynasore) and caveolae-dependent endocytosis (nystatin) attenuated the enhanced REB levels in the cheek pouches of hamsters treated with GA-REB@NP. GA-REB@NP also enhanced the healing of the wound area compared with GA-REB@MP in hamsters injected with acetic acid. We prepared GA-REB@NP, which provided high REB delivery into the cheek pouch tissue via endocytosis. Additionally, we demonstrated that wound healing in acetic acid-injected hamsters was promoted by the application of GA REB@NP.

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Chemicals

N,N-dimethylformamide, dynasore（clathrin-dependent endocytosis［CME］inhibitor, and rottlerin micropinocytosis [MP］inhibitor）were purchased from Nacalai Tesque（Kyoto, Japan). REB, GA, isoflurane, 10％ ammonia solution, cytochalasin D（phagocytosis［Pha］inhibitor, and methyl p-hydroxybenzoate were obtained from Wako Pure Chemical Industries, Ltd. Osaka, Japan. Additionally, we utilized Carbopol® 934（Serva, Heidelberg, Germany), pentobarbital（Tokyo Chemical Industry Co. Ltd., Tokyo, Japan), nystatin（caveolae-dependent endocytosis [CavME］inhibitor; Sigma-Aldrich, St. Louis, MO, USA), and Bio-Rad Protein Assay Kit（Bio-Rad, Hercules, CA, USA. All chemicals used were of the highest purity.

Hiroko Otake, Shuya Masuda, Reita Kadowaki, Fumihiko Ogata, Yosuke Nakazawa, Naoki Yamamoto, Naohito Kawasaki, and Noriaki Nagai, Therapeutic Effects of Rebamipide Nanocrystals as Carbopol Gel Formulation Containing Gum Arabic in a Hamster Model of Oral Mucositis, Journal of Oleo Science, Copyright ©2024 by Japan Oil Chemists’ Society, doi : 10.5650/jos.ess24160, J. Oleo Sci. 73, (12) 1479-1491 (2024)