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Peer-reviewedCC BY-NC 4.0International Journal of Nanomedicine

3D-Printed Rebamipide Nanocrystal Oral Thin Films for Gastroprotection Against Indomethacin-Induced Gastric Lesions in Arthritic Rats

  • Hiroko Otake1
  • Riku Azuma1
  • Fumihiko Ogata1
  • Yosuke Nakazawa2
  • Naoki Yamamoto3,4
  • Manju Misra5
  • Masanobu Tsubaki6
  • Naohito Kawasaki1
  • Noriaki Nagai1
6 affiliations
  1. 1Faculty of Pharmacy, Kindai University, Higashi-Osaka, Osaka, Japan
  2. 2Faculty of Pharmaceutical Sciences, Doshisha Woman’s College of Liberal Arts, Kyotanabe, Kyoto, Japan
  3. 3University Startup Promotion Center, Research Promotion Headquarters, Fujita Health University, Toyoake, Aichi, Japan
  4. 4Faculty of Engineering, Sanyo-Onoda City University, Sanyo-Onoda, Yamaguchi, Japan
  5. 5Department of Pharmaceutics and PhaM. Technology, L. M. College of Pharmacy, Ahmedabad, GJ, India
  6. 6Laboratory of Pharmacotherapy, Tokushima Bunri University, Sanuki, Kagawa, Japan
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Abstract

Purpose: Gastric mucosal injury caused by long-term nonsteroidal anti-inflammatory drug therapy remains a significant clinical concern, particularly in patients with rheumatoid arthritis. In this study, we developed a three-dimensional (3D)-printed oral thin film (OTF) formulation incorporating rebamipide (REB) nanocrystals (REB-NP@OTF) with enhanced gastroprotective potential.

Methods: REB nanocrystals were prepared by wet bead milling using methylcellulose and hydroxypropyl-β-cyclodextrin as stabilizers. The nanocrystals were incorporated into a polymeric OTF matrix using semi-solid extrusion-based 3D printing. Particle size was measured by nanoparticle tracking analysis using a NanoSight LM10 system, and in vitro drug release was compared with that from OTF containing micro-sized REB (REB@OTF). Gastric mucosal drug retention was evaluated using rats, and therapeutic efficacy was assessed in an indomethacin (IND)-induced gastric injury model using adjuvant-induced arthritis (AA) rats.

Results: REB nanocrystals had a mean particle size of approximately 114 nm. Compared with REB@OTF, REB-NP@OTF exhibited a smoother and more uniform internal structure with densely packed particles. Both formulations satisfied the pharmacopeial criteria for weight and content uniformity; however, nanocrystal incorporation significantly altered the pharmaceutical properties. Compared to REB@OTF, REB-NP@OTF showed a 4.2-fold increase in solubility, enhanced hydration behavior, and faster drug release under simulated intestinal conditions. Importantly, particle size analysis confirmed that REB was released from REB-NP@OTF while maintaining its nanoparticulate state. In vivo studies revealed prolonged gastric mucosal retention following oral administration of REB-NP@OTF. In an IND-induced gastric acute injury model using AA rats, REB-NP@OTF markedly reduced the gastric lesion area relative to the REB@OTF containing conventional REB powder.

Conclusion: These findings indicate that 3D-printed REB nanocrystal OTFs represent a promising and versatile strategy for improving gastroprotective therapy.

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Cite

BibTeXRIS
BibTeX
@article{otake20263dprinted,
  title = {{3D-Printed Rebamipide Nanocrystal Oral Thin Films for Gastroprotection Against Indomethacin-Induced Gastric Lesions in Arthritic Rats}},
  author = {Hiroko Otake and Riku Azuma and Fumihiko Ogata and Yosuke Nakazawa and Naoki Yamamoto and Manju Misra and Masanobu Tsubaki and Naohito Kawasaki and Noriaki Nagai},
  journal = {International Journal of Nanomedicine},
  year = {2026},
  month = oct,
  doi = {10.2147/ijn.s654551},
  url = {https://doi.org/10.2147/ijn.s654551},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - 3D-Printed Rebamipide Nanocrystal Oral Thin Films for Gastroprotection Against Indomethacin-Induced Gastric Lesions in Arthritic Rats
AU  - Hiroko Otake
AU  - Riku Azuma
AU  - Fumihiko Ogata
AU  - Yosuke Nakazawa
AU  - Naoki Yamamoto
AU  - Manju Misra
AU  - Masanobu Tsubaki
AU  - Naohito Kawasaki
AU  - Noriaki Nagai
PY  - 2026
DA  - 2026/10/30
JO  - International Journal of Nanomedicine
DO  - 10.2147/ijn.s654551
UR  - https://doi.org/10.2147/ijn.s654551
AB  - Purpose: Gastric mucosal injury caused by long-term nonsteroidal anti-inflammatory drug therapy remains a significant clinical concern, particularly in patients with rheumatoid arthritis. In this study, we developed a three-dimensional (3D)-printed oral thin film (OTF) formulation incorporating rebamipide (REB) nanocrystals (REB-NP@OTF) with enhanced gastroprotective potential.  Methods: REB nanocrystals were prepared by wet bead milling using methylcellulose and hydroxypropyl-β-cyclodextrin as stabilizers. The nanocrystals were incorporated into a polymeric OTF matrix using semi-solid extrusion-based 3D printing. Particle size was measured by nanoparticle tracking analysis using a NanoSight LM10 system, and in vitro drug release was compared with that from OTF containing micro-sized REB (REB@OTF). Gastric mucosal drug retention was evaluated using rats, and therapeutic efficacy was assessed in an indomethacin (IND)-induced gastric injury model using adjuvant-induced arthritis (AA) rats.  Results: REB nanocrystals had a mean particle size of approximately 114 nm. Compared with REB@OTF, REB-NP@OTF exhibited a smoother and more uniform internal structure with densely packed particles. Both formulations satisfied the pharmacopeial criteria for weight and content uniformity; however, nanocrystal incorporation significantly altered the pharmaceutical properties. Compared to REB@OTF, REB-NP@OTF showed a 4.2-fold increase in solubility, enhanced hydration behavior, and faster drug release under simulated intestinal conditions. Importantly, particle size analysis confirmed that REB was released from REB-NP@OTF while maintaining its nanoparticulate state. In vivo studies revealed prolonged gastric mucosal retention following oral administration of REB-NP@OTF. In an IND-induced gastric acute injury model using AA rats, REB-NP@OTF markedly reduced the gastric lesion area relative to the REB@OTF containing conventional REB powder.  Conclusion: These findings indicate that 3D-printed REB nanocrystal OTFs represent a promising and versatile strategy for improving gastroprotective therapy.
SN  - 1176-9114
SN  - 1178-2013
ER  -