Transdermal delivery of a somatostatin receptor type 2 antagonist using microneedle patch technology for hypoglycemia prevention


Hypoglycemia is a serious and potentially fatal complication experienced by people with insulin-dependent diabetes. The complication is usually caused by insulin overdose, skipping meals, and/or excessive physical activities. In type 1 diabetes (T1D), on top of impaired pancreatic α-cells, excessive levels of somatostatin from δ-cells further inhibit glucagon secretion to counteract overdosed insulin. Herein, we aimed to develop a microneedle (MN) patch for transdermal delivery of a peptide (PRL-2903) that antagonizes somatostatin receptor type 2 (SSTR2) in α-cells. First, we investigated the efficacy of subcutaneously administered PRL-2903 and identified the optimal dose (i.e., the minimum effective dose) and treatment scheduling (i.e., the best administration time for hypoglycemia prevention) in a T1D rat model. We then designed an MN patch using a hyaluronic acid (HA)-based polymer. The possible effect of the polymer on stabilizing the native structure of PRL-2903 was studied by molecular dynamics (MD) simulations. The results showed that the HA-based polymer could stabilize the PRL-2903 structure by restricting water molecules, promoting intra-molecular H-bonding, and constraining torsional angles of important bonds. In vivo studies with an overdose insulin challenge revealed that the PRL-2903-loaded MN patch effectively increased the plasma glucagon level, restored the counter-regulation of blood glucose concentration, and prevented hypoglycemia. The proposed MN patch is the first demonstration of a transdermal microneedle patch designed to deliver an SSTR2 antagonist for the prevention of hypoglycemia. This counter-regulatory peptide delivery system may be applied alongside with insulin delivery systems to provide a more effective and safer treatment for people with insulin-dependent diabetes.

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The authors would also like to thank the Banting and Best Diabetes Centre (BBDC) Seller Fellowship to A.GN., Ontario Graduate Scholarship and BBDC Travel Award to B.L., Graduate Department of Pharmaceutical Sciences scholarship to B.L. and F.L., and the staff of the DCM facility at the University of Toronto for help with certain experiments.


The work was supported through funding from JDRF (2-SRA-2016-268-A-N) to X.Y.W. and A.G. and the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery (RGPIN 170460-13) and Equipment grants (EQPEQ 374799-09; EQPEQ 440689-13) to X.Y.W.

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A.GN., B.L., A.G., and X.Y.W. designed the in vitro and in vivo experiments. A.GN. synthesized the materials and fabricated the MN patches. A.GN., B.L., M.S., J.F.L., and L.Z. performed the experiments. A.GN., B.L., and S.M. wrote the manuscript. S.M. designed and performed the simulation studies. S.P. performed the statistical analysis. A.G. and X.Y.W. provided resources and supervised the project. The manuscript was edited through contributions of all authors.

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Correspondence to Xiao Yu Wu.

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GhavamiNejad, A., Lu, B., Samarikhalaj, M. et al. Transdermal delivery of a somatostatin receptor type 2 antagonist using microneedle patch technology for hypoglycemia prevention. Drug Deliv. and Transl. Res. (2021).

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  • Hypoglycemia prevention
  • Drug delivery systems
  • Microneedle patch
  • Somatostatin receptor type 2 antagonist
  • Molecular dynamics simulation