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Lipid nanoparticles as vehicles for oral delivery of insulin and insulin analogs: preliminary ex vivo and in vivo studies

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Abstract

Aims

Subcutaneous administration of insulin in patients suffering from diabetes is associated with the distress of daily injections. Among alternative administration routes, the oral route seems to be the most advantageous for long-term administration, also because the peptide undergoes a hepatic first-pass effect, contributing to the inhibition of the hepatic glucose output. Unfortunately, insulin oral administration has so far been hampered by degradation by gastrointestinal enzymes and poor intestinal absorption. Loading in lipid nanoparticles should allow to overcome these limitations.

Methods

Entrapment of peptides into such nanoparticles is not easy, because of their high molecular weight, hydrophilicity and thermo-sensitivity. In this study, this objective was achieved by employing fatty acid coacervation method: solid lipid nanoparticles and newly engineered nanostructured lipid carriers were formulated. Insulin and insulin analog—glargine insulin—were entrapped in the lipid matrix through hydrophobic ion pairing.

Results

Bioactivity of lipid entrapped peptides was demonstrated through a suitable in vivo experiment. Ex vivo and in vivo studies were carried out by employing fluorescently labelled peptides. Gut tied up experiments showed the superiority of glargine insulin-loaded nanostructured lipid carriers, which demonstrated significantly higher permeation (till 30% dose/mL) compared to free peptide. Approximately 6% absolute bioavailability in the bloodstream was estimated for the same formulation through in vivo pharmacokinetic studies in rats. Consequently, a discrete blood glucose responsivity was noted in healthy animals.

Conclusions

Given the optimized ex vivo and in vivo intestinal uptake of glargine insulin from nanostructured lipid carriers, further studies will be carried out on healthy and diabetic rat models in order to establish a glargine insulin dose–glucose response relation.

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Acknowledgements

The authors thank Italian MIUR (Ricerca Locale 2016–2017 and FFABR 2018) for funding.

Author information

Author notes

  1. Elisabetta Muntoni and Elisabetta Marini have contributed equally to this work.

Authors and Affiliations

  1. Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, Turin, Italy

    Elisabetta Muntoni, Elisabetta Marini, Paola Milla, Corrado Ghè & Luigi Battaglia

  2. Department of Chemistry, University of Sistan and Baluchistan, University Boulevard, Zahedan, Iran

    Nahid Ahmadi

  3. Dipartimento di Scienze della Sanità Pubblica e Pediatriche, Università degli Studi di Torino, Piazza Polonia 94, Turin, Italy

    Alessandro Bargoni

  4. Dipartimento di Scienze Veterinarie, Università degli Studi di Torino, Largo Paolo Braccini 2, Grugliasco, Italy

    Maria Teresa Capucchio

  5. Histopathology Department CIBA, Istituto Zooprofilattico Sperimentale del Piemonte, Via Bologna 148, Turin, Italy

    Elena Biasibetti

Authors
  1. Elisabetta Muntoni
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  2. Elisabetta Marini
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  9. Luigi Battaglia
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Correspondence to Luigi Battaglia.

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Ethical approval

Animal experiments were performed owing to Italian and International Guidelines (DL 26/2014 implementation of directive 2010/63 UE). An experimental protocol approved by the Turin University Bioethical Committee and the Italian Ministry of Health (Aut. N. 32/2016-PR) was employed.

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Muntoni, E., Marini, E., Ahmadi, N. et al. Lipid nanoparticles as vehicles for oral delivery of insulin and insulin analogs: preliminary ex vivo and in vivo studies. Acta Diabetol 56, 1283–1292 (2019). https://doi.org/10.1007/s00592-019-01403-9

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  • DOI: https://doi.org/10.1007/s00592-019-01403-9

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