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Microneedle-Array Patches: An Innovative Way to Treat Type 2 Diabetes

Mar 3, 2018
 

Patch delivery system shows promise as a new developing treatment option for diabetes.

Diabetes management remains difficult, despite the increasing advancements in treatment options. This is largely due to the consistently high blood glucose readings in this patient population. Adherence seems to be much of the issue caused by the required mealtime-related administration with antidiabetic agents and the unwanted side effects (weight-gain & hypoglycemic risk).  Recently, glucagon-like peptide-1 (GLP-1) receptor agonists have been prescribed to avoid/lessen these adherence issues and associated side-effects.  Exendine-4 (Ex4) acts as a GLP-1 receptor agonist.  It unfortunately has a short half-life, requiring twice daily subcutaneous administration.  The need for more administration leads to a decrease in adherence and potential overdosing.  Adverse reactions include dose-limiting nausea and vomiting.  These limitations have ignited the interest in developing a better dosage form for convenience and adherence.  Currently, artificial pancreases have been developed but are expensive, complicated, uncomfortable, and has a high risk of mishandlings.  Focusing on closed-loop systems will help with glucose-sensing, leading to regulated drug release.  Glucose oxidase (GOx) is typically applied to catalyze the oxidation reaction of glucose to induce an acidic, hypoxic, and hydrogen peroxide rich microenvironment.  In most devices/products, the glucose-sensing element is combined with the drug-releasing component.  This not only poses a glucose related challenge, it also affects protein activity.  To overcome this challenge, a closed-loop system is needed to selectively stabilize and immobilize the glucose-sensing element, and separately dissociate the drug-releasing component when needed.

This article reviews the new microneedle-array patches which delivers dual mineralized particles containing Ex4 and GOx.  This technology is painless and non-invasive, while allowing the different particles to be released independently in response to biological stimuli.  This patch is made up of a few different elements.  The glucose-sensing element is made up of copper phosphate mineralized particles which form a hybrid nanoflower around GOx to immobilize it and prevent premature release.  This complex works as a stabilizing enzyme to convert glucose stimuli to proton signals.  The drug-releasing component is made up of calcium phosphate, which surrounds the Ex4 component.  They work together to provide a pH-sensitive biomineral that can spontaneously disintegrate in low pH conditions.  This design hopes to serve as a reliable and effective treatment option for glucose management in type 2 diabetes.  In vivo studies were conducted on mice with this patch.

The patch formulation, when tested, responded remarkably well in response to glucose levels. In-vivo testing showed a mild inflammation reaction and minimal fluctuations of blood glucose levels (~401.8 ± 15.6 to 453.3 ± 31.2 mg dl−1).  When the glycemic index fluctuated, the glucose responsive systems (GRS) with dual mineralized particles rapidly responded for five rounds without hesitation in comparison to the GRS with free GOx, which failed to respond.  It is noted that lower GOx amount led to a slower Ex4 release.  This was due to a delayed glucose responsiveness of the unit.  The amount of Ex4 had less influence on release kinetics in comparison to GOx.  Both are important in total administered dose, but the GRS could be controlled simply by adjusting the GOx amount in the system.  It should also be noted that the microneedle array is needed to provide a response.  Lastly, it was also reported that continuous Ex4 administration did not increase the risk of hypoglycemia.

In conclusion, this technology exhibits promising glucose-regulation capabilities. Encapsulating the glucose-sensing element helps to avoid rapid loss of the drug in the release step.  Isolating the glucose-sensing element and drug-releasing component could guarantee long-term responsiveness and smooth drug release.  The copper phosphate and calcium phosphate elements help regulate the GRS.  It can also help with drug adherence and overcome diabetes management issues. This is a closed-loop and feedback-controlled Ex4 treatment for type 2 diabetes.  To optimize this technology for humans, changes will have to be made to accommodate human skin thickness. More trials need to be conducted with this new technology before determining its safety and efficacy in humans.

Practice Pearls:

  • Exendin-4 acts as a GLP-1 agonist in this microneedle-array patch.
  • Traditional antidiabetic treatment possesses certain obstacles that this patch can overcome.
  • New and innovative technology can provide pain free and non-invasive blood glucose control.

References:

Chen, Wei, et al.  “Microneedle-Array Patches Loaded with Dual Mineralized Protein/Peptide Particles for Type 2 Diabetes Therapy.” Nature Communications, vol. 8, no. 1, 24 Nov. 2017, pp. 1-11., doi:10.1038/s41467-017-01764-1.

Adrianna Jackson, Doctor of Pharmacy Candidate: Class of 2018; LECOM College of Pharmacy