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Insulin-Loaded pH-Sensitive Hyaluronic Acid Nanoparticles Enhance Transcellular Delivery

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Abstract

In the present study, we developed novel insulin-loaded hyaluronic acid (HA) nanoparticles for insulin delivery. The insulin-loaded HA nanoparticles were prepared by reverse-emulsion-freeze-drying method. This method led to a homogenous population of small HA nanoparticles with average size of 182.2 nm and achieved high insulin entrapment efficiencies (approximately 95%). The pH-sensitive HA nanoparticles as an oral delivery carrier showed advantages in protecting insulin against the strongly acidic environment of the stomach, and not destroying the junction integrity of epithelial cells which promise long-term safety for chronic insulin treatment. The results of transport experiments suggested that insulin-loaded HA nanoparticles were transported across Caco-2 cell monolayers mainly via transcellular pathway and their apparent permeability coefficient from apical to basolateral had more than twofold increase compared with insulin solution. The efflux ratio of P app (B to A) to P app (A to B) less than 1 demonstrated that HA nanoparticle-mediated transport of insulin across Caco-2 cell monolayers underwent active transport. The results of permeability through the rat small intestine confirmed that HA nanoparticles significantly enhanced insulin transport through the duodenum and ileum. Diabetic rats treated with oral insulin-loaded HA nanoparticles also showed stronger hypoglycemic effects than insulin solution. Therefore, these HA nanoparticles could be a promising candidate for oral insulin delivery.

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ACKNOWLEDGMENT

The authors gratefully acknowledge the Fundamental Research Funds for the Central Universities (project no. 09ykpy67) for their financial support of this research.

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Authors and Affiliations

  1. Department of Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou, 510006, People’s Republic of China

    Lina Han, Yuefang Zhao, Lifang Yin, Yang Liang, Huan Huang, Chuanbin Wu & Min Feng

  2. Research and Development Center of Pharmaceutics of Guangdong Province, University Town, Guangzhou, 510006, People’s Republic of China

    Lina Han, Yuefang Zhao, Lifang Yin, Yang Liang, Huan Huang, Chuanbin Wu & Min Feng

  3. The First Affiliated Hospital, Sun Yat-sen University, 80 Zhongshan Road II, Guangzhou, 510080, People’s Republic of China

    Ruiming Li & Shirong Pan

Authors
  1. Lina Han
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  2. Yuefang Zhao
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  3. Lifang Yin
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  4. Ruiming Li
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  5. Yang Liang
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  6. Huan Huang
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  7. Shirong Pan
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  8. Chuanbin Wu
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  9. Min Feng
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Correspondence to Min Feng.

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Han, L., Zhao, Y., Yin, L. et al. Insulin-Loaded pH-Sensitive Hyaluronic Acid Nanoparticles Enhance Transcellular Delivery. AAPS PharmSciTech 13, 836–845 (2012). https://doi.org/10.1208/s12249-012-9807-2

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  • DOI: https://doi.org/10.1208/s12249-012-9807-2

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